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The Impact Of A Developing Regulatory Framework Governing LDTS In Precision Oncology: Re-Envisioning The Clinical Risk Assessment Paradigm.


In 2013 and 2015 The New York Times published two articles written by Angelina Jolie, revealing to the public her BCRA1 status and decision to undergo a series of medical interventions intended to reduce her risk of developing breast and ovarian cancer. This publicity in conjunction with a burgeoning increase in the genetic testing market fueled by President Obama's Precision Medicine Initiative propels more genetic tests into clinical care. This article will examine the practice of using laboratory developed tests (LDTs) for the purpose of risk assessment and to aid clinical decision-making in context of breast and ovarian cancer. Until recently, the FDA has exercised enforcement discretion over the genetic testing industry; thus many of LDTs currently on the market and used in clinical practice are not FDA approved. A recent FDA report enumerated serious concerns revealing grave shortcomings in LDTs' accuracy, reliability, and ability to provide clinically meaningful information to physicians and patients. The surge in LDTs, particularly risk assessment testing and LDTs designed to diagnose and prognosticate the pathway of DCIS has the potential to pathologize a new class of patients and extend the widely discussed risks associated with overdiagnosis and overtreatment. This article critically examines three risk reducing measures designated by the National Cancer Institute: (1) endocrine therapy; (2) preventive mastectomy and reconstruction; (3) preventive salpingo-oophorectomy and HRT, evaluating current evidence pertaining to these interventions and proposing a novel method to re-envision the clinical risk assessment paradigm that comports with physicians' legal and ethical duties of informed consent.


In 2013 and 2015, The New York Times published two articles written by Angelina Jolie, revealing to the public her BCRA1 status and decision to undergo a series of medical intervendons intended to reduce her risk of developing breast and ovarian cancer. (1) These articles ignited a firestorm of controversy, commentary by physicians and the public, and sparked an increase in the uptake of women requesting pre-symptomatic risk assessment testing for breast and ovarian cancer through BRCA testing. (2) This publicity in conjunction with a burgeoning increase in the genetic testing market fueled by President Obama's Precision Medicine Initiative propels more genetic tests into clinical care, both at the points of risk assessment and for use in aiding clinical decisionmaking during the course of treatment. (3) This article will examine the practice of genetic testing specifically in the context of assessing risk of breast and ovarian cancer and the potential impact of genetic test results on corresponding clinical care interventions for this population of patients.

The FDA classifies laboratory developed tests (LDTs) for use in the diagnosis, treatment, or prevention of disease as medical devices subject to pre-market and approval. (4) Until recently, the FDA has exercised enforcement discretion over the genetic testing industry, meaning many of LDTs currently on the market and used in clinical practice are not FDA approved. (5) Despite increased availability and utilization of LDTs, a recent report by the FDA and independent research called into question the preliminary assumption that clinicians and patients can rely on corporate assurances of analytic validity, clinical validity, and clinical utility. (6) Each of these elements are crucial: Analytic validity ensures that the test's positive or negative result will correlate with the gene sequence that the test targets and consistently predict the presence or absence of the gene variant. (7) Clinical validity ensures that the test accurately calculates the correlations between the presence or absence of the gene variant and the increased risk of disease. (8) Finally, clinical utility means the test provides useful information, accurately describes the implications of the test results, and its limitations. (9) The FDA's report, The Public Health Evidence for FDA Oversight of Laboratory Developed Tests, enumerated serious concerns with the current framework it uses to oversee laboratory developed tests, revealing grave shortcomings in LDTs' accuracy, reliability, and ability to provide clinically meaningful information to physicians and patients. (10)

The FDA is in the process of revising its regulatory structure related to FDTs, but in the interim physicians face mounting uncertainty of how to integrate the information provided by LDTs into clinical practice. (11) The aim of LDTs for pre-symptomatic risk assessment and personalized treatment lays at the heart of precision medicine in oncology--we want more effective strategies that account for individual variability to allow physicians to predict more accurately which individuals are at increased risk of developing cancer and which treatment strategies for a particular type of cancer will work. (12) Increasing the effectiveness of care, however, assumes that the oncologist's testing tools are accurate. (13)

The surge in LDTs, particularly risk assessment testing and tests designed to diagnose and prognosticate the pathway of Ductal Carcinoma In Situ (DCIS) has the potential to pathologize a new class of patients and extend the widely discussed risks associated with overdiagnosis and overtreatment. (14) This article will focus on the narrow category of LDTs pertaining to breast and ovarian cancer and assess the subsequent interventions designated by the National Cancer Institute (NCI) as risk reducing measures. (15) Physicians may offer patients classified as "high risk" a variety of risk reducing, including (1) endocrine therapy, (2) preventive mastectomy with optional implant reconstruction, and or (3) preventive salpingo-oophorectomy with synthetic hormone replacement therapy (HRT). (16) Each of these interventions corresponds to serious and varied risks, many of which have been obscured by a pattern of systematic practices including data suppression, scientific article ghostwriting, extensive marketing campaigns downplaying risks and touting unproven benefits, and manufacturer influence in clinical practice guidelines. (17)

This article proposes it is necessary to re-envision the clinical risk assessment paradigm because it artificially truncates reduction in risk based on the sole calculation of how one intervention reduces risk of cancer without factoring in the increased risk from subsequent interventions. (18) Physicians are bound by both professional ethics as well as a legal duty to the principle of informed consent. (19) In order to satisfy such duty, physicians as must consider and communicate the concept of what 1 refer to as the Unified Composite Risk Benefit Analysis: the amount of risk reduction from the proposed intervention calculated against the cumulative potential risks from all subsequent interventions related to the initial intervention. (20)


A. Precision Oncology

In early 2015 President Obama announced the Precision Medicine Initiative (PMI), which included a $70 million increase in funding for the National Cancer Institute (NCI) to advance the field in Precision Oncology. (21) As part of the larger PMI, the Precision Oncology initiative will examine the genetics of disease to identify genetically related risk and examine patterns of patient response to therapies to develop more effectively tailored treatments with the aim of accelerating the pace of discovery and increasing patient benefit. (22) The PMI includes integrating FDA's expertise and regulatory oversight, and the FDA stated its goals for precision medicine are overseeing the development of targeted diagnostic devices and tailored therapeutics. (23)

The NCI defines cancer as a genetic disease because it is caused by either inherited or somatic mutations to the ways genes control cellular functioning relating to growth and division. (24) Inherited mutations that contribute to the cause of cancer account for only 5-10% of all cases of cancer, with a substantial percent of remaining risk attributed to environmental and lifestyle factors. (25) Researchers have currently identified more than 50 hereditary cancer syndromes that may predispose someone to developing a certain type of cancer. (26) Yet even these genetic variants are not 100% penetrant: a person may carry a BRCA1 variant that predisposes her to risk of breast and ovarian cancer, but never develop the disease. (27) Researchers have also cautioned against genetic determinism, noting that even in the 5-10% of cases of cancer attributed to genetic variation, this risk is mediated by other factors such as environment, diet, exercise, and stress. (28)

B. The Jolie Effect

In 2013 and 2015, Jolie's articles revealed her BCRA1 status and explained her decision to undergo a series of medical interventions as a means to reduce her risk of developing breast and ovarian cancer. (29) These articles incited a flurry of media attention not only to the actress's personal decisions, but also raised patient awareness of concept of inherited risk from the gene variants BRCA1 and BRCA2 relating to breast and ovarian cancer and the use of genetic testing to predict cancer risk. (30) In the first article, "My Medical Choice," Jolie wrote "the truth is I carry a faulty gene" and her physician estimated she had an 87% risk of developing breast cancer and a 50% risk of developing ovarian cancer based on genetics and family history. (31) In 2013, Jolie underwent a preventive mastectomy with implant reconstruction, and in 2015, she elected to undergo a bilateral salpingo-oopohorectomy with hormone replacement therapy. (32) Jolie did not have either breast or ovarian cancer. (33) Instead, she explained she made a personal decision and felt empowered to take measures to reduce her risk of cancer. (34)

Jolie's articles provoked a flood of media responses, and her decisions raised a number of issues related to perception of disease development, risk assessment, and the concept of preventive measures. (35) Some commentators lauded Jolie's decision as a brave choice to reduce the possibility of her children having to lose their mother to cancer and a positive measure to raise public awareness of the role of inherited genetic variants in breast and ovarian cancer risk. (36) Specialists approved of her decision as "wise," confirmed both surgeries constitute the recommended methods to lower the risk of developing breast and ovarian cancer, and endorsed her use of HRT. (37) Jolie's case illustrated the concept of the cascade of interventions connected to the initial risk reducing measure: after her preventive double mastectomy she obtained implant reconstruction, and following her preventive salpingo-oophorectomy she disclosed her plan for HRT. (38)

This case raises even more questions applicable to the general population: Can we be sure that a pre-symptomatic risk assessment test has analytic and clinical validity to accurately measure the risk of developing breast and ovarian cancer? What are the limitations of pre-symptomatic risk assessment testing? How much do these surgeries reduce the risk of cancer? What residual risks of cancer remain in addition to the risk of surgery and removing healthy breasts and organs from the body? What additional risks are introduced from subsequent related interventions such as the implant reconstruction and HRT? And finally, these questions raised the primary issue: How can physicians successfully articulate this complex analysis of risk and benefit for patients?

C. LDTs for Breast and Ovarian Cancer

1. BRCA Testing

A confluence of factors exponentially increased the availability and amount of LDTs on the market used for determining risk assessment and determining personalized treatment options. (39) The combination of these factors makes it imperative to ask such preliminary questions because it creates a distinct class of patients--including asymptomatic patients--who are thrust into a system of risk assessment and face recommendations for additional medical interventions. (40)

There are a number of genetic variants correlated with an increased risk in breast and ovarian cancer. (41) Perhaps the most well known genetic variants are BRCA1 and BRCA2, which rose to notoriety during litigation that challenged Myriad Genetics' gene patents for its BRCA test. (42) Following the Supreme Court's decision in Association for Molecular Pathology v. Myriad Genetics, the Court's partial invalidation of some of Myriad's patents spurred the competitive entry of other risk assessment tests into the marketplace, increasing availability and reducing cost. (43) A study in JAMA Oncology also quantified what genetic counselors had labeled the "the Angelina Effect," observing the rates of women seeking risk assessment testing skyrocketed after her articles ran in The New York Times. (44) This study recommended all women with breast cancer should be tested for BRCA1 and BRCA2 status, while Geneticist Dr. Mary Claire King (who co-discovered BRCA1) boldly asserted all women over age 30 should be tested for BRCA1 and BRCA2. (45) In December 2013, the United States Preventive Services Task Force recommended that women who have family history of certain types of cancer or who are diagnosed with breast cancer prior to fifty years old, BRCA variant testing is clinically appropriate. (46)

NCI defines BRCA1 and BRCA2 as genes that produce tumor suppressor proteins. (47) According to the NCI, "these proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of the cell's genetic material. (48) When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly. (49) As a result, cells are more likely to develop additional genetic alterations that can lead to cancer." (50) Women who have the BRCAlvariant have a 55-65% lifetime risk of developing breast cancer, women who have a BRCA2 variation have a 45% risk of developing breast cancer as compared to the risk in the general population of 12%. (51) Women who have the BRCA1 variant have an estimated 39% risk of developing ovarian cancer and women who have the BRCA2 variant have an estimated 11-17% risk of developing ovarian cancer as compared to the general population risk of 1.2% chance that women will develop ovarian cancer. (52)

2. LDTs for Risk Assessment

There are currently a number of LDTs on the market that offer risk assessment testing for breast and ovarian cancer, such as those offered by Myriad Genetics, Quest Diagnostics, Ambry Genetics, and a direct-to-consumer test from Color Genomics. (53) Myriad Genetics was the first corporation to begin offer risk assessment testing for BRCA variants in 2008. (54) In addition to BRCA variants, research also suggests variation in the PALB2 gene confers a 33% risk of breast cancer and increases risk of developing ovarian cancer, although studies on this particular variant are not as developed as research on the BRCA variants. (55) Several tests on the market include additional variant analysis for a panel of genes that some research studies have connected to an increased risk of breast and ovarian cancer. (56) Increasing the number of tested variants on an LDT panel has been a contentious topic in the literature, because it increases the amount of variant information reported back to the physician and patient, but studies have not sufficiently established clinical utility, which may lead the physician or patient to integrate this information into the risk calculus inappropriately. (57)

LDTs vary with respect to the amount of variants on the panel, how many variants of unknown significant the panel reports, and significantly, even differences in interpretation whether the variants found constitutes a deleterious mutation. (58) As Law Professor Christopher Holman noted, assessing genetic variation related to the BRCA gene is not a binary distinction of deleterious mutation versus no mutation. (59) Instead, some variants are associated with a high likelihood of developing cancer, some variants are associated with a slightly increased risk of developing cancer, some variants are believed to be neutral, and around forty percent constitute variants of unknown significance (VUS). (60) Not only may some BRCA variation be neutral or unknown, some research suggest that out of the 500 recently identified variants on the BRCA gene, some variants actually confer benefit and constitute a favorable prognostic factor. (61)

LDTs advertise on their respective websites varied marketing claims, such as asserting their corporation has performed "extensive validation," uses "the newest technology" such as next-generation sequencing and "proprietary software for data analysis to help ensure accuracy and confidence in the result," or lists collaboration with leading clinicians, scientists, and institutions. (62) Physicians and patients may make a decision to obtain a LDTs either for the purpose of pre-symptomatic risk assessment or risk assessment following a diagnosis of breast cancer. (63) Ambry Genetics and Quest Diagnostics specifically cite the benefit that their test will enable pre-symptomatic patients to consider increased screening and surveillance or consider treatment interventions such as the use of chemo-preventive drugs, preventive mastectomy, and or preventive salpingo-oophorectomy. (64) Despite these numerous claims, at the time of this writing the FDA has approved only Myriad Genetics' BRACAnalysis CDx in 2014 as a companion diagnostic following a cancer diagnosis, but the FDA has not assessed the analytic validity, clinical validity, or clinical utility of risk assessment LDTs offered by Ambry Genetics or Quest Diagnostics. (65)

3. LDTs for Determining Prognosis and Treatment

In addition to risk assessment tests, there are several LDTs on the market used in clinical practice to guide physician determinations of prognosis and treatment. (66) In 2007, the FDA cleared MammaPrint, manufactured by Agendia designed for use following a cancer diagnosis. (67) MammaPrint analyzes a biopsy of the tumor sample and uses a formula to score the potential for recurrence based on assessing a panel of seventy genes. (68) Agendia advertises it provides "an unambiguous result of high risk vs. low risk for recurrence of patient's breast cancer," which Agendia states is intended to assist physicians in determining the appropriate course of treatment. (69) Agendia advertises "FDA clearance provides reassurance that the tests have been sufficiently reviewed and validated and are clinically indicated and useful" and FDA's clearance of its newest iteration, MammaPrint FFPE "confirmed the robust accuracy" and its "prognostic value is highly statistically significant." (70)

These statements have the potential to mislead physicians and consumers into believing them as undisputable fact rather than marketing claims or presume FDA clearance constitutes the same standard as FDA approval. (71) Importantly, FDA clearance constitutes a lower and less rigorous standard that premarket approval, because clearance requires the manufacturer demonstrates the product is substantially equivalent to another marketed device. (72) This pathway does not require the manufacturer to demonstrate the product's safety or efficacy through the premarket review process. (73) The significance of this distinction means FDA did not ascertain the product's efficacy or likely review sufficient information to support the basis of Agendia's claims. (74)

Genomic Health also manufacturers a series of LDTs called Oncotype DX to predict the risk of local recurrence and for use in determining the benefit of traditional chemotherapy versus endocrine therapy. (75) Genomic Health uses a twenty-one gene biomarker assay in the Oncotype DX Breast Cancer Assay, advertising it is both "predictive and prognostic" because "it provides a clear picture of tumor biology, allowing you to make treatment decisions with increased confidence and insight" for patients with a certain type of estrogen receptor positive breast cancer. (76) Genomic Health asserts numerous claims, including Oncotype DX Breast Cancer Assay "offers critical information not available from any other genomic test or traditional measure," it is "validated," "proven," constitutes "the standard of care" and has been in use for over ten years. (77) Genomic Health also offers the Oncotype DX DCIS Breast Cancer Test, which is intended for patients diagnosed with DCIS to predict the risk of local recurrence and the risk of local invasive carcinoma. (78) Similar to Agendia, Genomic Health also touts its influence in treatment decisions, stating Oncotype DX has been ordered by over 10,000 doctors for more than 230,000 patients, and "studies show that use of the Oncotype DX Recurrence Score result changes treatment decisions approximately 30% of the time" and guides physicians' critical therapy decisions. (79)

4. Conflicting Evidence for Clinical Use

Scientific literature and the American Society of Clinical Oncology guidelines provide conflicting and potentially confusing conclusions about the clinical validity and clinical utility of both MammaPrint and Oncotype DX, which renders it difficult for physicians to evaluate the claims set forth by Agendia and Genomic Health. (80)

In 2015, Michael Marrone and colleagues from the Office of Public Health Genomics at the Centers for Disease Control and Prevention published a review of both OncotypeDX and MammaPrint, finding no direct evidence of clinical utility for either test demonstrating that the tests correlated to improved treatment outcomes. (81) Despite this finding, the review noted both tests did in fact influence physician treatment recommendations, ranging from 21-74% of cases. (82)

One year later in 2016, a team of researchers led by Dr. Joseph Sparano published a prospectively conducted study in the New England Journal of Medicine that assessed the clinical validity of OncotypeDX as a biomarker to determine risk recurrence and guide treatment decisions. (83) Dr. Clifford Hudis from the Memorial Sloan Kettering Cancer Center praised the study, calling it a "confirmation" that the LDT can identify "a cohort of patients who can be spared chemotherapy" and the validation "cannot come soon enough" because the test has already been in practice 10 years. (84) Despite the findings published in the prestigious journal, the authors' numerous and varied conflicts of interest listed in the disclosure should not be overlooked. (85) The authors' disclosed conflicts of interest include a lengthy itemization ranging from holding numerous patents and royalties pertaining to gene sequences relating to breast cancer risk and OncotypeDX, as well as research support, grant support, and consulting fees from Genomic Health and pharmaceutical companies such as AstraZeneca, Novartis, Pfizer, Roche, Amgen, and GlaxoSmithKline. (86) Several of the authors stand to gain significant financial reward through patent royalties arising from increased uptake of OncotypeDx and would also constitute a gain for drug manufacturers independent of the result because it would lend credence to the physician's tailored drug of choice. (87) That is, physicians would use the test to imbue confidence in their determination of whether treat patients with a certain type of breast cancer with endocrine therapy or traditional chemotherapy. (88)

Although Sparano's study assessed only the Oncotype DX Breast Cancer Assay, it foreseeably may also be used as evidence to promote Genomic Health's reputation and increase sales of the Oncotype DX DCIS Breast Cancer Test. (89) This is significant because the Oncotype DX DCIS Breast Cancer Test has the potential to justify the basis of drug based interventions for an entirely new class of patients, who otherwise may have elected to forgo endocrine therapy in favor of active surveillance. (90)

In 2016, the journal of Clinical Oncology published its Clinical Practice Guidelines to assess the clinical utility of LDTs including MammaPrint and OncotypeDX, concluding numerous tests on the market lack evidence to support clinical utility with exception to OncotypeDX. (91) The Clinical Practice Guidelines asserted physicians should not use MammaPrint and that the evidence supporting the use of OncotypeDX's clinical validity was the highest of all LDTs evaluated and issued a strong recommendation for physicians to use Oncotype DX for certain classes of breast cancer patients. (92)

D. Mounting Evidence of Problems with Accuracy and Validity

Notably, the FDA has not approved either MammaPrint or Oncotype DX for prognosis and treatment. (93) Months prior to ASCO publishing its Clinical Practice Guidelines, the FDA reported starling findings related to Genomic Health's Oncotype DX HER2 RT-PCR. (94) In The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies (FDA Report), the FDA specifically called into question Oncotype DX IIER2 RT-PCR Test. (95) Genomic Health designed the HER2 RT-PCR portion of the test to provide physicians and patients personalized treatment based on the patient's tumor profile. (96) Oncotype DX HER2 RT-PCR tests whether certain drugs such as Herceptin, a drug commonly used to treat HER2 positive tumors, is clinically indicated. (97) The FDA Report evaluated evidence set forth by a group of independent pathologists who found discrepancies in test specificity and found the test produced false negatives, missing the diagnosis of patients with HER2 positive tumors and misinforming subsequent treatment decisions. (98) Specificity of HER2 status is imperative to guiding appropriate treatment-patients whose tumor is HER2 positive may elect to add Herceptin to the treatment protocol based on its targeted indication for treating HER2 positive cases. (99) Alternatively, potential overtreatment of patients with Herceptin is not only ineffective, but raises significant risks including cardiomyopathy, pulmonary toxicity, and death. (100) Accordingly, physicians face conflicting and confusing information arising from manufacturer claims, the literature, clinical practice guidelines, and the findings set forth in the FDA Report. (101)

LDTs's shortcomings related to accuracy and validity have been circulating in the scientific literature and media for the past several years. (102) Back in 2011, Dr. Kenneth Offit described how his laboratory at Memorial Sloan Kettering Cancer Center found both analytic and post-analytic errors by external academic and clinical laboratories that conducted risk assessment testing for BRCA variants. (103) According to Offit, individuals were sent "widely divergent results" when different laboratories tested the same sample, which indicated suspected analytic or post-analytic error. (104) This finding led Offit to conclude that manufacturer's clams of analytic validity cannot be presumed based on manufacturer assertions alone. (105) The Chicago Tribune reported a story on the clinical implications, uncovering a case where a patient obtained BRCA testing through a CLIA certified laboratory showing a deleterious mutation, the patient consulted with her physician about the results, and underwent a preventive oophorectomy. (106) The patient subsequently discovered she did not in fact have the BRCA mutation. (107) The lack of test accuracy has serious implications not only or individual patient care, but also broader public health implication based on the scale of how LDTs are integrated into clinical practice. (108)

The goals of both risk assessment and diagnostic/prognostic LDTs align with the concept of President Obama's PMI and the Precision Oncology initiative. (109) They aim to use genetic analysis and innovative molecular diagnostic products to discern clinically relevant information used by a physician for predicting individualized patient risk and construct appropriately tailored interventions. Precision Medicine as a field requires that LDTs be accurate, reliable, and communicate clinically meaningful information to physicians. (110) LDTs have become increasingly available and more complex along with the advancement of science and technology, but inaccurate and unreliable LDTs undermines any progress in Precision Medicine as well as raises negative implications for clinical care. (111) Perhaps most problematically, the FDA Report asserted physicians may not be aware of the LDTs' limitations and status as unapproved medical devices despite their powerful impact of the course of physician decisionmaking, making current practice not only imprecise medicine, but potentially ineffective and harmful. (112)


A. FDA Report and Current Regulatory Shortcomings

The FDA systematically evaluated twenty LDTs on the market, revealing grave shortcomings in test accuracy, reliability, and the ability to provide clinically meaningful information to physicians and patients. (113) The report listed that testing inaccuracies resulted in false positives for some tests, where patients were informed they had a condition they did not have, producing psychological distress and overtreatment. (114) Other tests produced false negatives, where patient illnesses went undetected and the patient failed to receive appropriate and timely treatment. (115) The FDA listed substantial concerns, including that the current regulatory framework: (1) falls short of overseeing LDTs' clinical validity; (2) lacks adverse reporting; (3) does not assess pre-market review of performance data; (4) the environment gives rise to numerous unsupported claims by manufacturers; (5) LDTs lack adequate product labeling; (6) there is a lack of transparency whether the LDT is FDA approved or FDA cleared, or whether the manufacturer's scientific claims are accurate; and (7) manufacturers have no incentive to obtain FDA approval, placing manufacturers who invest the resources to do so at a financial disadvantage. (116) Media picked up the story, noting both the staggering cost to public health resulting from inappropriate diagnosis, overtreatment, lack of treatment, and inappropriate treatment as well as the associated financial burden of such inaccuracies. (117)

In October 2014, the FDA published its Draft Guidance: Framework for Regulatory Oversight of Laboratory Developed Tests (FDA Draft Guidance), stating its intention to enforce its authority and begin regulating LDTs as medical devices. (118) The findings of the FDA Report in 2015 bolstered the FDA's assertion of the necessity for more stringent regulation of LDTs. (119) Under the Medical Device Amendments of 1976 to the Food, Drug and Cosmetic Act, Congress authorized the FDA to regulate medical devices "intended for use in the diagnosis ... or in the cure, mitigation, treatment, or prevention of disease." (120) Despite this authority, FDA has traditionally exercised enforcement discretion, and previously declined to develop a regulator}' framework for the regulation of LDTs. (121) Thus, many LDTs have not obtained pre-market approval, submitted data to the FDA demonstrating analytic and clinical validity, nor has the FDA assessed and approved many LDTs. (122)

Accordingly, many LDTs on the market have only been subject to requirements set forth in Clinical Laboratory Improvement Amendments of 1988 (CLIA). (123) CL1A sets forth requirements relating to the accreditation, inspection, and certification process for laboratories, governing aspects such as quality control and calibrating laboratory instruments. (124) CLIA does not assess clinical validity of the test, leading the FDA to conclude that CLIA alone "does not ensure that LDTs are properly designed, consistently manufactured, and are safe and effective for patients." (125) FDA's Draft Guidance outlines numerous shortcomings by using CLIA as the sole framework for regulation, finding: (1) the evaluation of analytic validity occurs after the laboratory has already offered testing to the public; (2) CLIA does not evaluate clinical validity so there is no assurance that the devices are clinically relevant; (3) it does not require adverse reporting to track devices that are inaccurate, ineffective, and unsafe; (4) it does not require removal of unsafe devices from the market; and (5) CLIA does not assess the quality manufacturing of devices. (126) These shortcomings, according to the FDA, translate to physicians using and relying upon LDTs that may lack clinical validity but are nonetheless being used to make critical clinical decisions, putting patients at risk of missed or incorrect diagnosis, failure to administer the appropriate treatment, of administering potentially harmful treatment with no benefit. (127) Importantly, the FDA also noted that neither physicians nor patients may know that the LDT they are relying upon was not FDA approved, which means they may not be aware that the FDA has not evaluated the device's analytic and clinical validity and making crucial decisions without the knowledge that the LDT may not be accurate. (128)

This distinction is critical because it increases the potential for physicians to make decisions premised upon a piece of potentially faulty information under the belief that the LDT confers certainty to remedy the existing difficulty related to assessing biopsies. (129) In 2015, an article in JAMA examined diagnostic concordance among pathologists examining breast biopsies of atypia (benign masses in breast tissue), DCIS, and invasive breast cancer, finding that only 48% of physician participants agreed with the consensus diagnosis for atypia cases. (130) That is, pathologists who examined biopsies from women without breast cancer were not in agreement 52% of the time on that diagnosis and concluded the patient had either DCIS or invasive breast cancer. (131) Relying upon potentially faulty risk assessment and diagnostic tools increases the potential for incorrect and harmful risk assessment, diagnosis, and treatment particularly if physicians believe these tools indemnify them against unavoidable human error. (132)

B. Changes in FDA Regulation of LDTs

To remedy these issues, the FDA issued its intent to enforce the regulation of LDTs as medical devices. (133) This framework would ensure manufacturers register the LDT, submit data on analytic and clinical validity for pre-market review as part of the approval process, and it would require the manufacturer to conduct ongoing reporting to the FDA should a device malfunction or contribute to serious injury. (134) The FDA plans to use a risk-based approach to determine whether to regulate LDTs as Class I, II, or III devices as determined by the device's intended use, technological characteristics, and risk to the patients should the device fail. (135) The FDA determined it will consider devices as Class II Moderate Risk or Class III High Risk by examining a number of factors: "if the device is intended for use in a high risk disease; whether the device is used for screening and diagnosis; the nature of the clinical decision that will be based on the result; whether a physician/pathologist would have other information about the patient to assist in making a clinical decision; alternative diagnosis and treatment options available to the patient; the potential consequences/impact of erroneous results; and the number and type of adverse events associated with the device." (136) Finally, the FDA also stated that it intends to regulate LDTs as Class III devices if a physician uses the LDT to direct patient therapy. (137)

Examining these factors, the FDA will likely classify both risk assessment and diagnostic/prognostic tests as Class III High Risk devices. (138) This category of LDTs provides patients information about cancer, which constitutes a high risk disease because inappropriate treatment interventions can lead to patient mortality, whether through incorrect treatment, missed treatment, or overtreatment. (139) Physicians use this class of LDTs for screening to assess patient risk based on genetic variation or diagnosis to determine tumor biology and select appropriate treatment. (140) While a physician would have other information available, the LDT constitutes the driving factor of the physician's treatment decision. (141) Notably, LDTs specifically advertise their product as a mechanism to direct subsequent interventions, ranging from preventive surgeries to choosing personalized drug treatment. (142) Finally, the potential consequences of an inaccurate or incorrect result pose serious risks to patients, ranging from missed diagnosis, incorrect diagnosis, inappropriate treatment, under and overtreatment such as leading the physician to recommend preventive surgeries or prescribe a drug with serious side effects and no benefit. (143) Each of these considerations highlights both the current shortcomings of the regulatory framework as well as the likelihood that the FDA will begin to regulate LDTs used in precision oncology as Class III High Risk devices. (144) According to FDA's Draft Guidance, it will phase in regulatory guidelines over the next several years and LDTs will remain on the market in the interim. (145)

C. Limitations of LDTs to Assess Risk for Multi-factorial Disease

Even when the FDA begins to enforce its regulation of LDTs, there are a number of intrinsic limitations in developing LDTs that limit the goals of improving individual risk prediction. (146) Attorney Sharonmoyee Goswami noted there are numerous permutations that could give rise error in the design, analysis, and prediction of results. (147) According to Goswami, molecular markers may not correctly predict the presence of a disease allele and if the statistical correlation is false, this can lead to both false positives and false negatives. (148) The LDT's prediction is based on algorithms that approximate the disease pathway, but Goswami asserts the algorithm may be inaccurate. (149) First, the algorithm may not account for genetic variability within the population or epigenetic modulation by environmental factors. (150) Second, the algorithm may not assess unforeseen interaction between genes, noting that the interaction between genes is not fully understood, not tested directly by the LDT, and the unforeseen interaction between genes could render the risk assessment invalid. (151) Based on these factors, even if the FDA approved an LDT for risk assessment or diagnostic purposes, the physician should use it with an appreciation for a margin of inherent uncertainty greater than that disclosed by the manufacturer. (152)

Presuming each test has analytic validity, there are additional limitations to using LDTs for risk assessment and diagnosis. (153) First, BRCA variants are only found in a small percentage (0.2%) of the general population, which means only a fraction of the cases of breast and ovarian cancer that occur can be attributed to BRCA genetic variants. (154) Even for women who do have a BRCA variant, about 50% never develop breast cancer. (155) The nature of cancer as a disease invokes numerous ambiguities because it is defined as a multi-factorial disease: there are numerous factors contributing both to individual risk of developing the disease and its subsequent progression, including individually modifiable factors such as environmental toxin exposure, nutrition, exercise, sleep, and stress. (156) According to the Fred Hutchinson Cancer Research Center, up to one-third of cancer related deaths are due to obesity and sedentary lifestyle, stating that exercise is "one of the most important actions you can take to help guard against many types of cancer. (157) In addition to the benefits of exercise, a randomized trial published in JAAIA Internal Medicine confirmed the strength of dietary modification as a preventive measure. (158) A team of Spanish investigators led by Dr. Estefania Toledo found that women who followed a Mediterranean diet including the consumption of olive oil reduced their risk of invasive breast cancer by 68%, leading the investigators to conclude dietary modification should be recommended as method of primary prevention of breast cancer. (159)

Integrating individually modifiable factors and their epigenetic potential to reduce risk supports the concept that risk estimates are probabilistic rather than absolute. (160) The cumulative effect of each of these factors highlights both the inaccuracy and danger from adopting views of genetic determinism. (161) Integrating these findings into clinical decision-making calls into question recent literature asserting the only available methods of risk reduction constitute use of endocrine therapy, preventive mastectomy, and or preventive oophorectomy. (162) These limitations are especially pertinent because patients are both concerned about genetic risk and act according to that perception of risk. (163) Research demonstrates women are concerned about genetic risk: 95.3% of women who have a diagnosis of breast cancer underwent BRCA testing. (164) Genetic risk also influences serious decision-making, with one study showing 86% of patients diagnosed with breast cancer who found out they had a BRCA variant opted for a mastectomy. (165)


A. The Impact of Terminology on Perception

The combination of all the factors enumerated supra in Section III creates tiers of uncertainty and ambiguity. (166) If clinicians rely upon LDTs without an appreciation for these factors, this pattern of decision-making will likely exacerbate existing concerns related to overdiagnosis and overtreatment. (167) Overdiagnosis refers to detecting cancers through screening that would not have caused the patient any symptoms and would not have been detected in the patient's lifetime except through detection by screening. (168) Overtreatment refers to when physicians intervene with treatment that exposes the patient to myriad side effects, adverse effects, and risks but is not medically necessary and holds no scientific benefit. (169) Not every diagnosis requires treatment, and initiating treatment exposes patients to iatrogenic harm arising from the intervention, not the diagnosed disease. (170) Problematically, both physicians and patient would likely be unaware of the overdiagnosis and overtreatment precisely because they employ the paradigm that the LDT is precise, accurate, and that genetic risk is immutable: the patient becomes a cancer survivor rather than a patient exposed to harm. (171)

Linguistic choices to describe cancer heavily influence perception of disease and corresponding inventions. (172) According to Dr. Laura Esserman and colleagues, "the word 'cancer' often invokes the specter of an inexorably lethal process; however, cancers are heterogeneous and can follow multiple paths, not all of which progress to metastases and death, and include indolent disease that causes no harm during the patient's lifetime." (173) Though cancer may be perceived as an incurable or fatal disease, cancer constitutes different pathologic entities that vary in their course. (174) According to Drs. Jaimin Bhatt and Laurence Klotz, we all have mutant cells that could lead to cancer unless our immune system checks and destroys them. (175) Furthermore, tumors that do develop may stop growing, grow slowly; and according to recent research, even invasive tumors found in breast cancer can spontaneously regress. (176) Esserman and colleagues have called for a re-labeling of cancer terminology, eliminating the term "cancer" for precancerous lesions including those classified currently as DCIS and replacing DCIS with the term "indolent lesions of epithelial origin." (177)

B. Overdiagnosis

1. Relabeling DCIS

Recognizing that cancer should be classified as a heterogeneous disease by integrating the new classification system would dramatically impact the 50,000 patients who are currently annually diagnosed with "cancer" under the DCIS label in the United States, and potentially influence the estimated 20,000 women (without BRCA variants) who currently decide to undergo a mastectomy after hearing the words "breast cancer" with a DCIS diagnosis. (178) Esserman and colleagues asserted that the basis of labeling a lesion as "cancer" should arise from knowledge and assessment of the lesion's behavior and outcome. (179) Research demonstrates that 75-90% of DCIS never progresses to invasive cancer, undermining the proposition that intervening and "treating" DCIS constitutes an appropriate clinical choice rather than exposing patients to harmful interventions. (180) This statistic is also concerning in conjunction with the study showing 95.3% of women who are diagnosed with breast cancer undergo BRCA testing, and 86% of patients who discovered they have a BRCA variant opt for a mastectomy. (181) These studies examined together suggests that women who have DCIS or early state breast cancer may be choosing to intervene from presumptions about the meaning of their risk derived from LDT testing that are unsupported by current evidence and expose them to a cascade of additional interventions and corresponding risks. (182)

2. Mammography

In addition to disentangling DCIS from cancer, a review of the research also demonstrates the substantial impact of mammography screening on the overdiagnosis of breast cancer, harms associated with screening, and lack of benefit. (183) Drs. Karsten Juhl Jorgensen and Peter Goetzsche of Nordic Cochrane Center published a systematic review for The Cochrane Collaboration, finding that: over a period of ten years, if 2000 women undergo screening, one will avoid dying, ten healthy women who would not have otherwise been diagnosed will be treated unnecessarily, and two hundred women will receive a false positive from the mammography, informing them they have cancer when they do not, prompting additional testing, anxiety, and psychosocial distress. (184) Jorgensen notes that this systematic review presents a starkly different assessment of benefit compared to other studies that exaggerate the benefit of mammography screening, downplay the risks, or fail to discuss risks entirely. (185)

Mammography advertisements present it as a safe public health necessity instead of a personal intervention available for patients to choose after being informed accurately of risks and benefits. (186) Mammography screening constitutes a massively profitable industry grossing $5 billion dollars annually in the U.S., and screening campaigns are comprised of entangled conflicts of interest in the form of promotional advertising designed to promote uptake of screening, not informational campaigns that present accurate facts relating to risks and benefits. (187) In addition to advertising to the public, the industry strongly influences physician opinion with strategies designed to promote mammography, such as through "funding conferences and scientific meetings, provision of ghost writers to get positive findings published quickly, suppression of publication of negative findings, direct lobbying of the government ... funding patient pressures groups ... In the trade, the technique that involve pressure groups and patient advocates as known as 'astroturfing' and 'guerilla marketing' because they successfully create the impression that the lobbying is coming purely from grassroots opinion and not from the industry." (188) As a Consultant for the UK National Screening Program and former Programmes Director of the UK National Screening Committee point out, systematic manipulation through each of these channels obfuscates the truth by using targeted promotional marketing dressed as irrefutable science, the effect of which promotes integration and circulation of an advertising message rather than an accurate depiction of the science.

C. Overtreatment

The net impact of systematically controlling the flow of scientific research and available evidence while simultaneously disseminating "public health" advertisements disables both physicians and patients from obtaining an accurate understanding of the limitations of screening as well as the serious harms that may result when combined with other available tools to assess risk, diagnosis, and prognosis. (189) Overdiagnosis of cancer is closely tied to overtreatment, which "turns women into cancer patients unnecessarily, with life-long physical and psychological harms." (190) These tactics blur the distinction between advertising and evidence based practices, precluding an unbiased assessment of the implications even when mammogram accurately diagnoses a patient. Research demonstrates trying to predict the prognosis and impact for even invasive breast cancer proves difficult. (191) As noted supra, invasive breast cancer can spontaneously regress, and invasive breast cancer may exist yet cause no discernible symptoms, only to be discovered posthumously after patient death from unrelated causes. (192) Thus, even if mammography accurately detects cancer, not all cancer requires treatment. (193)

The impact of this misinformation is startling: after ten years, the cumulative incidence of true false positives is 61%, and a five country meta-analysis demonstrated a 52% rate of overdiagnosis. (194) Thus, mammography may uncover cancer that never would have caused the patient harm, but prompts additional intervention with LDTs through BRCA testing, diagnostic testing, and recommendations for a cascade of interventions designed to reduce risk but that exposes the patient to numerous harms. (195) Literature asserts many physicians favor an aggressive approach, offering and recommending interventions stemming from defensive medicine as a means of avoiding malpractice litigation arising from patient perception that a physician could have offered more rapid or aggressive treatment interventions. (196) Indeed, the concept of "doing nothing" has even been mislabeled by some media to connote the absence of mastectomy. (197) Time Magazine author Sioban O'Connor defined "doing nothing" to include not only active surveillance through frequent mammography, MRI, and tamoxifen, which is a particularly inaccurate mischaracterization because tamoxifen corresponds to severe and potentially permanently disabling adverse effects. (198) Aggressive treatment can also have "unforeseen and devastating consequences," which O'Connor refers to as "collateral damage" from the numerous follow-up surgeries, infection, and unnecessary chemotherapy. (199)

There are also powerful psychological messages underlying each intervention, which promote additional interventions over surveillance. (200) Dr. Steven Katz's research demonstrates patients rely heavily upon physician recommendation after being diagnosed with cancer, and physician recommendations usually constitute the most aggressive approach. (201) This practice includes integrating evolving LDTs advertised by the manufacturer to assist the physician with diagnosis and risk prognostication. (202) However, relying upon manufacturer assertions of test accuracy and validity without caution ignores emerging research and FDA's Report demonstrating the numerous shortcomings of LDTs currently on the market. (203) Thus, if physicians attempt to prognosticate risk or outcome based on LDTs to address the problems of overtreatment, this has the potential to have the appearance of providing tailored prognostic and diagnostic confidence but instead introduces additional variables of uncertainty. (204) Furthermore, it problematically reinforces the notion that overtreated patients constitute cancer survivors instead of patients who survive potentially unnecessary interventions. (205)

D. Lessons from Ovarian Cancer Screening

Unlike the context of breast cancer, the imprecision of screening and its harms has been more widely discussed and accepted relating to ovarian cancer. (206) In 2012, the U.S. Preventive Task Force affirmed its recommendations that found no benefit of screening asymptomatic women for ovarian cancer and found that screening resulted in subjecting patients to unnecessary interventions, including surgery. (207) Ovarian cancer screening through assessing cancer serum antigen (CA-125) lacks precision: it has both a high rate of false positives, where only 1.6 women who tested positive out of 100 actually had ovarian cancer and it produces a high rate of false negatives, where it missed 50% of early stage ovarian cancer entirely. (208) Importantly, the psychological anxiety of false positives heavily influences patient decision to undergo surgery. One study published in JAMA demonstrated 32.9% of women who received false positives and had no ovarian cancer nonetheless opted for oophorectomy. (209) The powerful impact of anxiety should not be overlooked as a substantial factor influencing patient decision to undergo interventions designed to reduce cancer risk even in circumstances where the patient may not be at risk, or where a predicted increase risk in developing the disease based on BRCA status in fact simultaneously confers a prognostic benefit. (210)


A. Re-examining the Conversation Between Physician and Patient

The convergence of each of these factors--the burgeoning LDT industry to assess complex genetic risk which may or may not be accurate, combined with known problems of overdiagnosis and anxiety driven overtreatment has the potential to create a new group of patients, either who are asymptomatic, diagnosed with DCIS, or potentially diagnosed with breast cancer that never would have produced symptoms. (211) This group of patients will be swept into a system where the clinically recommended treatments constitute serious interventions including endocrine therapy, preventive mastectomy with optional implant reconstruction, and or preventive salpingooophorectomy with HRT. (212) However, clinical guidelines for treatment to reduce risk artificially truncates reduction in risk based on the sole calculation of how one intervention reduces risk of cancer without factoring in the increased risk from subsequent interventions. (213) This section describes a physician's legal and ethical duties related to informed consent for medical interventions and describes required elements of the conversation between physician and patient during the discussion of risks and benefits. (214)

B. General Requirements for Informed Consent

Physicians are bound by professional ethics as well as a legal duty to the principle of informed consent arising out of state statutory law and medicolegal jurisprudence. (215) The American Medical Association journal of Ethics describes informed consent, whereby a physician must explain the risks, benefits, and alternatives of a medical intervention and obtain the patient's consent prior to initiating treatment. (216) The court in Canterbury v. Spence developed this standard by holding that a physician must disclose: (1) the condition being treated; (2) the nature and character of the proposed treatment or surgical procedures; (3) the anticipated results; (4) recognized alternative forms of treatment; and (5) recognized serious possible risks, complications, and anticipated benefits involved in treatment or surgical procedure, as well as recognized possible forms of treatment, including nontreatment. (217) Although courts vary across jurisdictions relating to specific requirements for informed consent, these principles provide general guidelines of important elements forming the substantive foundation for informed consent. (218)

Physicians are required to disclose information relating to risks and benefits where a reasonable person in the patient's position would find the information relevant, including disclosing risks that might affect the patient's treatment decisions. (219) Some courts, such as Arato v. Avendon, interpret this to mean a physician is required to disclose the available choices with respect to proposed therapy and of the dangers inherently and potentially involved in each. (220) In Canterbury, the court held even a small risk (1%) for a severe outcome (paralysis) would be relevant to the patient's decision and constitutes a risk of which the patient would want to be aware. (221) Physicians are not permitted to withhold information relating to risks under the belief that such risk information may lead the patient to refuse treatment, even if the physician believes a treatment is in the patient's best interest. (222) In addition to disclosing information that a reasonable patient would want to know, the physician also must disclose information that would be central to this specific patient's decision based on individual life circumstances and priorities. (223) Some court such as Arato limited this disclosure, holding that physicians may properly communicate the patient's prognosis generally but does not include requiring that physicians estimate a specific individualized numerical statistic of life expectancy following cancer diagnosis. (224)

Thus, the physician must disclose and discuss risks of serious adverse events or side effects for each proposed treatment even if the physician believes that such information would sway patient opinion to reject the treatment that the physician proposes. (225) The implication of this for cancer is significant because there is a class of patients based on pre-symptomatic risk assessment LDTs for whom "treatment" constitutes interventions on otherwise healthy individuals. (226) In addition to this class, Esserman and colleagues' new recommendations classify patients who are diagnosed with DCIS as patients without cancer. (227) I assert these categories comprise two classes of asymptomatic patients, which means interventions should not be weighed against a state of disease, but rather comparing a healthy individual with risk of disease to interventions that have serious and irreversible effects. (228) For many patients, a crucial piece of information they would want to know relates to residual cancer risk: how much each intervention would reduce their risk of cancer for that particular site, residual risks of cancer for that particular site, risks of cancer for other related sites despite the intervention, and serious adverse risks from the cumulative proposed interventions. (229) Finally, requiring physicians to discuss estimated numerical risk reduction and the addition of other risks from subsequent procedures comports with Arato's holding, because this communication constitutes information that patients will use to form the basis of their decision of whether to consent for treatment interventions without requiring physicians to estimate life expectancy. (230)

C. Brown v. Dibbell: Informed Consent Considerations Relating to Cancer

The facts and holding in Brown v. Dibbell provide further instruction for determining the standard and content of disclosure required for informed consent specifically relating to discussing cancer and subsequent interventions designed to reduce risk. (231) In Brown, Plaintiff Marlene Brown brought medical malpractice and informed consent actions against Defendant physicians arising out of Brown's bilateral mastectomy procedure. (232) Brown sought medical care upon finding a lump in her right breast and testified she communicated her anxiety related to developing cancer based on family history, disclosing to Defendants that her twin sister, mother, and multiple other female relatives had breast cancer. (233) Defendants told Brown she was in the "high risk" category based on family history and according to Brown, they offered two treatment options to address the suspicious lump: either repeating a mammogram in six months or they could perform a mastectomy. (234)

Brown claimed Defendants violated their statutory duties of informed consent set forth in Wisconsin state law because they failed to disclose the risks, alternatives, and disadvantages of mastectomy. (235) First, Brown asserted Defendants did not disclose the lump was not cancer, but rather informed her it was difficult to assess because she had pre-existing implants and her family history supported classifying her as high risk. (236) Defendants argued they disclosed the lump was inconclusive and Brown "felt she had to do something" besides undergoing inconclusive testing. (237) Brown also asserted that Defendants incorrectly represented to her that "mastectomy would prevent the development of breast cancer" but did not quantify the risk information relevant to the decision-making process. (238) Thus, conversations between Brown and Defendants reflected a substantial disconnect about crucial pieces of information: whether the lump was benign or cancerous, how much a mastectomy would decrease her risk of breast cancer, and whether Brown should have asked more questions during the interactions with her physicians. (239)

Both Defendant's arguments and the court's decision centered around whether Brown had a duty to seek and request additional information pertaining to her risk of developing cancer and the benefits and risks of mastectomy as a treatment intervention. (240) The court unequivocally held "a patient has no affirmative duty to ascertain the truth or completeness of the information presented by the doctor; nor does a patient have an affirmative duty to ask questions or independently seek information." (241) According to the court, the "patient is not in a position to know treatment options and risks, and if unaided, is unable to make an informed decision." (242) Importantly, the court noted "the very nature of the physician-patient relationship assumes trust and confidence on the part of the patient" and a patient has the right to rely on the professional skills and knowledge of the physician. (243)

Examining the facts set forth in Brown reveals several notable elements that are crucial to the informed consent process while applying the factors set for the in Canterbury, (244) Although Brown is jurisdictionally limited, the standards set forth in the case raise several important considerations. (245) The court in Brown held physicians to a high standard of discussion and disclosure based on the nature of the physician-patient relationship and the trust patients imbue in their physicians. (246) Importantly, physicians must clearly distinguish whether they are addressing: (1) treatment of cancer currently present; (2) an increased risk of cancer but no cancer present; or (3) an increased risk of cancer with possible physical indications of cancer but no definitive diagnosis confirming or denying the presence of cancer. (247) Disclosing sufficient information is crucial for the patient to understand her condition and appropriately assess the calculus of risks, benefits, and alternatives. (248) Further, Brown assumes the physician's communication of risks must be sufficient to form the basis of the patient's informed decision. (249) Thus, the burden is on the physician to take affirmative measures to not only adequately disclose risks, benefits, and alternatives, but to also assess patient comprehension of this calculus prior to initiating further intervention. (250)

D. Statistical Literacy and Distorted Perceptions of Risk

Emphasizing effective physician-patient communication constitutes an essential tool to address shortcomings in statistical literacy documented in the literature. (251) A study by Dr. Amy Finch and colleagues assessed patient understanding of statistical risk for ovarian cancer from BRCA variant and risk reduction from prophylactic salpingo-oophorectomy. (252) The study found 47% of women with a BRCA1 variant overestimated their risk of ovarian cancer, 61% of women with a BRCA2 variant overestimated their risk of ovarian cancer, and a significant minority (on average 20%) believed the surgery eliminated their risk of cancer completely to 0% rather than reducing their risk by 80%. (253) For example, if Patient A had an estimated 40% risk of ovarian cancer, the preventive oophotectomy would reduce the risk of ovarian cancer to 8% and she would also still have a 4.3% risk of peritoneal cancer. (254) If Patient A underwent HRT, her risk of other cancers and adverse health effects would increase. (255) In the discussion, Finch and colleagues noted numerous studies where genetic counseling did not remedy these issues in statistical literacy, and additionally noted physicians should convey the residual risk of peritoneal cancer. (256)

Other research affirms this disconnect in health literacy and risk comprehension: in one study, participants overestimated their risk of dying from breast cancer within 10 years by more than 20-fold. (257) In another study of patients participating in endocrine therapy trials, the participants perceived their pre-treatment risk of breast cancer at 50%, when their actual risk was only 15%. (258) Even following educational intervention, participants still believed they had a 25% chance of developing breast cancer. (259) These findings reiterate the massive chasm between patient understanding of risk and comprehension of benefit, each of which are essential for understanding the risk benefit calculus making an informed decision. (260) If patients believe they have a high risk of developing cancer, a high risk of dying from cancer, and do not fully understand the combined risks from subsequent treatment interventions, this disconnect substantially skews the patient's decision-making calculus. (261)


A. Examining Notions of Risk

As this group of patients without cancer increases presenting more potentially healthy women with interventions to decrease risk, it becomes imperative to address both shortcomings in statistical literacy as well as the substantive informational content relating to measures designed to decrease risk. (262) Although the NCI and clinical guidelines recommend risk reducing measures such as endocrine therapy, mastectomy, and salpingo-oophorectomy, numerous and serious risks are appreciably absent or minimized in the literature (263) The following section will describe the risks of the three recommended interventions and related therapies, and address how some risks have been obscured by a pattern of systematic practices including data suppression, scientific article ghostwriting, extensive marketing campaigns downplaying risks and touting unproven benefits, and conflicts of interest affecting clinical practice guidelines. Physicians have an ethical duty to advance their scientific knowledge, and I assert this includes discerning where inappropriate influence has co-opted the guiding consensus of the safety and risk profile of medical interventions and re-evaluating their recommendations accordingly based on their professional judgment.

B. Endocrine Therapy

1. Clinical Recommendations for Endocrine Therapy

For some patients who have an increased risk of breast or ovarian cancer, physicians may prescribe endocrine therapy such as aromatase inhibitors or anti-estrogen therapies. (264) This section of the article will discuss Nolvadex, an anti-estrogen drug and one of several chemopreventive agents on the market manufactured by AstraZeneca. (265) Physicians may prescribe Nolvadex to asymptomatic women with an increased risk of cancer, women with DCIS, or as a measure to prevent cancer recurrence. (266) Nolvadex is a pill that blocks the effects of estrogen, a hormone that influences the growth and development of many breast tumors. (267) Some research presents risk reduction information as relative risk reduction, asserting Nolvadex can reduce women's risk of breast cancer by 49%. (268) However, a review by the American Cancer Society found the risk reduction is closer to 38%, and information about the patient's personal absolute risk presents a vastly different numerical assessment. (269) For example, if Patient A has a BRCA2 variant and an estimated 45% risk of developing breast cancer, a 38% risk reduction from taking Nolvadex merely reduces her risk to a 29.7%, which is still much higher than the general population risk of 12%. (270) Thus, presenting risk information through relative risk reduction has the potential to mislead patients into believing an anticipated benefit greater than the actual benefit. (271) Furthermore, it should not be overlooked that some studies such as publication quoting the 49% risk reduction received substantial funding from the manufacturer AstraZeneca who has a financial stake at promoting a product's perceived benefits. (272)

In 2013, the American Society of Clinical Oncology published its Clinical Practice Guidelines in an article by Dr. Kala Visvanathan and colleagues specifying the clinical indication for chemopreventive agents prescribed for women at an increased risk of breast cancer. (273) Visvanathan and colleagues state there are more than two million women in the United States who could benefit from chemopreventive agents, and advises that not only should oncologists advocate the use of pharmacologic interventions for cancer risk reduction, but gynecologists, primary care physicians, and general practitioners should also use the recommendations set forth in the guidelines and discuss the option of chemoprevention for women at increased risk of breast cancer. (274) The ASCO Guidelines specifically identify a number of issues identified as current barriers preventing the uptake of chemopreventive drugs for risk reduction and discuss methods to increase prescribing. (275)

Oncologists such as Dr. Larry Wickerham promote the message set forth in the ASCO Clinical Guidelines in the media, and stated every woman at high risk of developing breast cancer should be offered chemopreventive drugs in an interview for The Chicago Tribune. (276) Wickerham classified chemopreventive agents as "enormously underutilized tools," and asserted the National Cancer Institute should run a sustained campaign to urge women at high risk of breast cancer to take chemopreventive agents "to prevent the disease." (277) In addition to his interview in The Chicago Tribune, Wickerham published research findings stating chemoprevention drugs including Evista (raloxifene) and Nolvadex (tamoxifen) have shown "substantial clinical benefit." (278) Wickerham laments chemopreventive drugs are a "hard sell" because "patients have been unbelievably oversold on the side effects." (279)

ASCO Guidelines promote an aggressive push for all relevant physicians to offer a class of more than two million women chemopreventive agents, and oncologists echo the message that push the benefits of chemoprevention while assuaging public fears of undesirable side effects. (280) Wickerham's statements also have the potential to reify the shortcomings in statistical literacy because without quantifying what it means to "prevent the disease," the public may assume this refers to complete or near complete prevention. (281) Sorting through the authors' conflict of interest disclosures, multiple authors of the ASCO Clinical Guidelines are consultants, own stock, received honoria, and or receive research funding from manufacturers of the class of drugs referenced such as AstraZeneca, Pfizer, Novartis. (282) In addition to those relationships, Wickerham is a consultant to Eli Lilly (manufacturer of Evista) and received honoraria from AstraZeneca (manufacturer of Nolvadex), both of which he specifically evaluated in an article touting the benefits of chemopreventive drugs. (283) It is exceedingly difficult to disentangle the blanket recommendation to increase the uptake of chemopreventive drugs to women when the authors of the Clinical Guidelines and oncologists' professional assessments have extensive financial ties to the industry about which they should be independently assessing. (284)

2. Risks from Endocrine Therapy

An accurate depiction and understanding of benefit constitutes a crucial element of the equation when balancing benefits against the risks. (285) Side effects from Nolvadex include hot flashes, night sweats, vaginal dryness, as well as musculoskeletal pain, depression, and hair loss. (286) Rather than a minor nuisance, a number of women allege these side effects were so severe and debilitating that they were unable to work and suffered disability that precluded them from working. (287) Plaintiffs describe their hot flashes were not merely inconvenient, but occurred around twenty times per day and lasted up to an hour along while also experiencing the other symptoms of depression, joint pain, and "bone-numbing fatigue." (288) Treatment with Nolvadex also has the potential to initiate a cascade of additional serious pharmacological interventions such as the use of Effexor to address depression, which ironically also lists hot flashes and night sweats as side effects, and carries a Black Box warning based on its risk related to suicidal ideation. (289) Notably, some courts refused to recognize disability that cannot be verified by clinical exam or measured by physician testing. (290) Thus, because Plaintiffs' alleged disabling conditions that arose out of treatment rather than a measurable disease, courts rejected the evidence these plaintiffs used to support their claims for disability. (291)

Nolvadex also increases the risk of serious adverse events such as osteonecrosis, confers a two-fold risk of endometrial cancer, aggressive uterine cancer, stroke, and pulmonary embolism. (292) Data indicates uterine cancer arising from Nolvadex use is more likely to be classified as State 3 or Stage 4, and the patient will have a poorer prognosis and shorter survival time. (293) Emerging research also lends support to explain the mental fatigue and memory loss often referred to as "chemo brain," side effects that may have been dismissed or attributed to depression or fatigue that occur not only with traditional chemotherapy but also for patient prescribed endocrine therapy. (294) Dr. Mark Noble discovered that exposure to Nolvadex is highly toxic to the brain and central nervous system. (295) After being exposed to Nolvadex for 48 hours, Nolvadex destroyed 75% of a type of brain cells that cells that are essential for making myelin, which is required for nerve cells to work properly. (296) According to Noble, as the length of treatment increases so does the damage to this type of brain cell, which leads to short-term memory loss, mental cloudiness, and trouble concentrating. (297) Although the effects may wear off over time for some patients, other patients may experience permanent adverse effects and experience symptoms that can lead to job loss, depression, and other debilitating events. (298) Although most other research in this area examines both patients undergoing Nolvadex and patients undergoing traditional chemotherapy, studies show 82% of breast cancer survivors report they continue to suffer from some type of cognitive impairment. (299) Noble's research supports the basis that Nolvadex can impart a drastic and potentially permanently disabling impact on the brain and central nervous system, which is not commonly discussed as a risk but nonetheless constitutes a crucial element of which patients should be aware. (300) 3. Revised Assessment of Endocrine Therapy Risks

Thus, ASCO Clinical Guidelines and some physicians aggressively promote the uptake of endocrine therapy, but their recommendations are entangled with financial conflicts of interest that would directly benefit from increased pharmaceutical sales. (301) Literature routinely inflates Nolvadex's benefits, but key risks related to an increased risk of endometrial cancer, aggressive uterine cancer, stroke, pulmonary embolism, and potentially permanent neurological damage are noticeably absent. (302) These risks are crucial for both physicians and patients to assess when assessing the professional guidelines and scientific evidence for determining the appropriateness of endocrine therapy. (303)

C. Preventive Mastectomy and Implant Reconstruction

1. Clinical Recommendations for Preventive Mastectomy

According to the National Cancer Institute, preventive mastectomy constitutes an appropriate option for women at high risk of breast cancer based on genetic or family history. (304) Literature demonstrates preventive mastectomy reduces the risk of breast cancer by approximately 90%. (305) Most women who undergo mastectomy also undergo reconstruction with implants. (306) Rates of reconstruction with implants vary, but some studies show reconstruction with implants range between 63-80% for all women who undergo mastectomy. (307) Most state and national cancer databases do not collect information on healthy women without breast cancer, so tracking the precise number of preventive mastectomies nationally is difficult but research suggests rates of preventive mastectomies are increasing based on increased awareness of genetic risk, increased genetic testing, and improvements in mastectomy and reconstruction techniques. (308)

As more women opt for preventive mastectomy based on risk assessment or as a means to reduce cancer anxiety, they face making a complex decision about a permanent procedure. (309) In 2010, The Cochrane Collaboration published a review of current research relating to preventive mastectomy for breast cancer prevention, cautioning that "given the drastic and irreversible nature of prophylactic mastectomy, it is essential that women considering this procedure be able to make informed decisions based on the best available evidence, consider both the benefits and limitations of the procedure, and weigh the risks and benefits of other alternatives." (310) The Cochrane Collaboration review considers preventive mastectomy a "radical surgical procedure" that should not routinely be considered by most women, and notes that even in women with a BRCA variant, this gene is not fully penetrant and these patients may never develop breast cancer. (311) Even if they do develop breast cancer, they will most likely not die from breast cancer, concluding that physicians will overtreat a population of patients through preventive mastectomy. (312) The authors additionally observe the convergence of several troubling factors: women considering prophylactic mastectomy overestimate their risk of developing cancer and may not understand that developing cancer does not equate to dying from cancer, women who chose preventive mastectomy believed it was "inevitable" they would develop breast cancer, and the surgery functioned to reduce anxiety in this population of women but exposed them to unexpected physical morbidities and postoperative surgical complications. (313) The authors suggest that clarifying risk to patients and enabling them to understand their true risk may reduce anxiety and perception of inevitability. (314)

2. Risks of Breast Implants

The two surgeries involved with the preventive mastectomy and implant reconstruction carry a number of risks, arising both from the surgery as well as the implant itself. (315) The NCI states preventive mastectomy has potential risks of surgery such as bleeding or infection. (316) According to the FDA, some of the main risks from breast implants include complications such as breast pain, capsular contracture, infection, undesirable changes in sensation or appearance. (317) The FDA also cautions that implants are not lifetime devices, may need to be removed, and will require periodic monitoring to ensure the implant has not ruptured silently. (318)

The Cochrane Collaboration noted that physical morbidities and postoperative surgical complications should be addressed as part of the decision-making process. (319) Physicians and patients should be aware of not only the general risks of the surgery and of implants, but should scrutinize credible evidence relating to implant safety that arose pursuant to litigation discovery against implant manufacturers and during Congressional investigation of the FDA approval process of breast implants. (320)

3. Re-Examining Risks of Implants

Women began receiving breast implants back in the 1960s prior to FDA regulation of medical devices under the Medical Device Amendment Act of 1976. (321) In 1988, the FDA requested manufacturer data relating to product safety, and in the early 1990s the FDA initiated hearings based on an increasing number of consumer complaints related to patient injuries including implant contracture, rupture, autoimmune dysfunction, and reports of connective tissue disease. (322) Although the FDA found none of the early application for pre-market approval contained sufficient data to demonstrate safety, silicone implants remained on the market and available to patients seeking reconstruction or revision. (323)

In Hopkins v. Dow Corning Corporation, the court upheld a judgment in favor of the Plaintiff Mariann Hopkins, who presented evidence that following mastectomy and implant reconstruction she developed mixed connective tissue disease, a rheumatological disorder with symptoms including "extreme fatigue, weakness, muscle aches and pains, arthralgia, myalgia, and arthritis." (324) Notably, the court in Hopkins upheld a S6.5 million punitive damages award to Hopkins arising out of evidence consisting of internal memoranda within Dow Corning that Plaintiffs' attorneys introduced during discovery. (325) The court concluded "Dow was aware of possible defects with the implants, that Dow knew long-term safety studies of the implants safety were needed, that Dow concealed this information as well as negative results of the few short term laboratory studies performed , and that Dow continued for several years to market its implants as safe despite this knowledge" which "expos[ed] thousands of women to a painful and debilitating disease." (326) Despite a significant shift in jurisprudence marked by excluding evidence demonstrating a causal connection of implants to connective tissue disease and autoimmune dysfunction, the crucial finding from Hopkins related to Plaintiffs discovery of Dow Coming's damaging internal memoranda. (327)

In 1993, the U.S. House of Representatives Subcommittee of Human Resources and the Intergovernmental Relations Committee on Government Operations published the findings from an investigation titled "The FDA's Regulation of Silicone Breast Implants" (Congressional Report) relating to the safety of silicone breast implants. (328) The Congressional Report uncovered horrifying evidence of grotesque reactions in Dow Coming's internal studies involving animal models. (329) In dogs, the implants caused hemorrhage and hyperplasia of lymphoid tissue in the intestines. (330) One FDA scientific reviewer expressed concern that approximately 25% of the rats who received implants developed malignant tumors, experienced large and extensive necrosis, tumors metastasized to distant organs, and silicone gel migrated throughout the animals' lymphatic tissue. (331) Additional internal Dow Corning memoranda discussed numerous inflammatory reactions in animal models, high rates of contracture resulting from antibody reaction, and silicone migration into distant organs including the kidney and liver. (332) Testimony by scientists, physicians who performed implant surgery, and physicians who examined patients following surgery stated the inflammatory reaction from the implant could incite a number of serious health effects such as autoimmune conditions including chronic fatigue syndrome, joint and muscle pain, lupus, scleroderma, arthritis, and could contribute to the development of cancer as indicated by animal models. (333)

However, none of this evidence raised in Congressional testimony or by internal FDA reviewers is reflected in subsequent official FDA documents. (334) According to the Congressional Report, the FDA Acting Chief documented in official FDA minutes results from these animal models were "inconclusive," argued the type of tumors seen in rats would not be likely to occur in humans, and concluded further agency action was not warranted. (335) An internal FDA reviewer found "numerous sources of errors, biases, methodological limitations" in manufacturer data submitted pursuant to the pre-market approval process, noted none of the studies examined the adverse health effects in question such as autoimmune disease or cancer risk, and maintained the FDA's decision to approve silicone implants ran contrary to evidence presented by FDA's own expert scientific review panel. (336) The Congressional Report concluded that the lack of written explanation as to why FDA officials overruled the opinion of its own experts suggested extensive improper exertion of influence by the manufacturing industry and pervasive conflicts of interest between high level FDA officials and the pro-implant manufacturing lobby. (337) Despite the damaging facts uncovered in Congress' scathing analysis, subsequent reports and official FDA consumer information buried mention of these issues. (338)

In 1999, the Institute of Medicine published a report asserting that although animal models showed tumor development after receiving implants "no studies demonstrated that such tumors ever develop in humans" and although "foreign body insertion can incite surrounding fibrous tissue reaction" "there is no evidence that silicone breast implants contribute to an increase in autoimmune (connective tissue) diseases." (339) Thus, the Institute of Medicine report purports to reflect scientific consensus but does not address the fundamental concerns related to the Congressional Report's allegations of conflict of interest and the lack of appropriate data ascertaining the product's safety. (340)

The FDA states it has not detected any association between implants and autoimmune disease or breast cancer, but studies would need to be longer to rule out such an association. (341) The long latency time between onset of disease, the lack of long term investigation, and failure to clinically connect any correlation between subsequent autoimmune disease makes it difficult to track associations. (342) Despite these barriers, recent literature provides compelling reviews of studies examining the connection between implants and autoimmune disease, hypothesizing the methodology by which implants induce autoimmune conditions in some women. (343) This literature in conjunction with the Congressional Report's findings make a convincing combination of evidence indicating the association between implants and autoimmune disease is certainly a possibility and should not be dismissed as a potential risk. (344)

The FDA does caution there is a "very low but increased risk" of developing analplastic large cell lymphoma (ALCL) from implants. (345) Early estimates suggest that women who receive breast implants are eighteen times more likely to develop ALCE. (346) However, there are difficulties with gathering data about the incidence of both latent autoimmune reactions and ALCL if neither patients are aware of the condition, physicians do connect the incidents and do not report them, or if physicians deny any connection. (347) In 2011, Dr. Sidney Wolfe and Dr. Michael Carome of the Public Citizen's Health Research Group wrote to the FDA regarding the content of an educational webinar session held by the American Society of Plastic Surgeons and the American Society of Aesthetic Plastic Surgery. (348) Wolfe and Carome expressed concern that the educational material referred to ALCL as a "condition" that has a "benign course," blatantly omitting the appropriate word cancer to intentionally disconnect the accurate portrayal of the implants increasing the risk of developing ALCL. (349) Wolfe and Carome characterized the educational campaign as "misleading, dangerous, and unethical." (350) Five years later, the American Society of Plastic Surgeons updated its web content, and now cautions against the small but increased risk of ALCL, but it is unclear how physicians perceive this conflicting information and whether in practice they disclose the small risk of ALCL. (351)

4. Revised Assessment of Preventive Mastectomy with Implant Reconstruction Risks

Preventive mastectomy decreases the risk of breast cancer, but evidence suggests numerous patients are currently overtreated. (352) These patients experience immense anxiety relating to cancer, overestimate their risk of developing and dying from cancer, and these perceptions fuel patient decisions to undergo a permanent and irreversible procedure. (353) The majority of women subsequently opt for implant reconstruction, which carries risks related to surgeries and implant complications. (354) In addition to widely recognized risks, evidence suggests implants also carry potential risks related to triggering the onset of autoimmune disease and a small but increased risk of ALCL. (355) Congressional investigation of this topic and materials discovered during litigation demonstrated how the lack of pertinent safety studies assessing long term safety blurs the ability for physicians to assess the weight of evidence pertaining to potential product risk on patients. (356)

D. Preventive Salpingo-Oophorectomy and HRT

1. Clinical Recommendations for Preventive Salpingo-Oophorectomy and HRT

The National Cancer Institute also recommends preventive salpingo-oophorectomy as an appropriate risk reducing measure against the development of breast and ovarian cancer in high risk patients. (357) Surgical removal of the ovaries reduces the amount of estrogen and progesterone circulating in the body, which is believed to contribute to the development of certain cancers. (358) Statistics suggest preventive salpingo-oophorectomy reduces the risk of breast cancer by up to 50% and ovarian cancer by 80-90%. (359) For example, if Physician X predicted Patient B to have a 50% risk of breast cancer and 40% risk of ovarian cancer, the preventive salpingooophorectomy would reduce Patient B's risk of breast cancer to 25% and risk of ovarian cancer to approximately 4-8%. (360) Based on difficulties associated with screening for ovarian cancer (discussed supra Section IV), literature and clinical practice guidelines characterize preventive salpingo-oophorectomy as an appropriate risk reducing surgical intervention for women at high risk of breast and or ovarian cancer. (361) According to a News Release posted on the American Society of Clinical Oncology's website, not only is preventive salpingo-oophorectomy an option, but physicians should perform the surgery "as soon as it is practical." (362) As Dr. Steven Narod stated in an ASCO News Release: "These data are so striking that we believe prophylactic oophorectomy by 35 should be the universal standard for women with BRCA1 mutations" because "waiting to have an oophorectomy until after 35 is too much of a chance to take." (363) This aggressive push to remove the ovaries and fallopian tubes from high risk women focuses narrowly on the decrease in risk in breast and ovarian cancer without acknowledging the increase in other risks following the procedure. (364)

As a means to address the loss of estrogen and progesterone from oophorectomy, some physicians advocate the use of HRT as a mechanism to manage menopausal symptoms. (365) HRT has been available on the market for decades since Wyeth first patented Premarin, a synthetic estrogen back in 1942 to "cure" the side effects of menopause. (366) Physicians touted its wonders as a mechanism to preserve women's youthful appearance and make women "adaptable, even tempered, and easy to live with." (367) Wyeth began massive marketing campaigns in the 1980s and 1990s and initiated "educational" campaigns claiming Premarin could prevent osteoporosis and prevent heart disease without increasing the risk of stroke and cancer. (368) Wyeth's marketing campaign proved successful at influencing prescribing behavior and patient uptake, and by the mid 1990s, Premarin was the most frequently prescribed drug in the United States. (369) In 1995, the FDA approved Wyeth's Prempro, the first combination synthetic estrogen and progestin on the market. (370)

Literature classifies HRT as "the gold standard" for treating menopausal symptoms, including in women with a BRCA variant. (371) Despite acknowledging HRT has not been well studied in this population of women, a recent review in the American journal of Clinical Oncology concurs HRT "appears to be reasonable" for women with a BRCA variant to address the adverse effects related to surgical menopause that negatively impact patients' quality of life following preventive salpingo-oophorectomy. (372) According to physician Dr. Susan Domchek, "It is unfortunate to have women choose not to have the surgery because they are worried about menopausal symptoms and told they can't take HRT. (373) Out data says that is not the case--these drugs do not increase the risk of breast cancer.," (374) Similarly, an article published in the journal of Oncology concluded preventive salpingo-oophorectomy and the use of HRT in women with a BRCA variant still reduces risk of breast cancer compared to controls. (375) These vehement assurances are not only unsupported by the extensive history of HRT, but patently against the weight of unbiased evidence and dangerously misleading. (376)

2. Risks of Preventive Salpingo-Oophorectomy

Although clinical guidelines enthusiastically advocate preventive salpingo-oophorectomy, it is associated with numerous risks from the initial procedure and risks from additional interventions. (377) Surgical risks of the procedure entail complications from infection, intestinal blockage and injury to other internal organs. (378) Removal of the ovaries exposes patients to increased risks stemming from losing the health benefits of ovaries by inducing menopause, which also corresponds to an increased risk for premature death, cardiovascular disease, cognitive impairment, lung cancer, Parkinson's disease, osteoporosis, and decline in psychological well-being. (379) Research demonstrates the intricate balance between ovary removal, health benefits from the naturally occurring hormonal balance associated with intact ovaries, and alternate morbidities. (380) In the past several years, women who opted for preventive salpingo-oophorectomy still developed aggressive uterine cancer, leading researchers to speculate preventive salpingo-oophorectomy does not decrease the risk of uterine cancer in women with BRCA variants. (381) Based on these findings, Dr. Noah Kauff stated choosing to also have a hysterectomy "is reasonable, but not required." (382) Physicians may also suggest hysterectomy as strategy to "simplify" post-surgery HRT to use an estrogen only drug such as Premarin. (383) Hysterectomy carries additional risks including bleeding, infection, and potential long term complications with bladder, bowel, and sexual function. (384) Based on current literature and recommendations, physicians may offer asymptomatic women classified as high risk the option to remove three healthy body organs--fallopian tubes, ovaries, and uterus--each of which carries additional risks from the surgery and risks arising from the removal of the respective internal organ. (385)

3. Re-Examining Risks of HRT

a. Troubling Data from the Women's Health Initiative

Both physician reassurances and statements asserting lack of data for the specific population of women at high risk for breast or ovarian cancer ignores the history of HRT as it has been utilized, promoted, and studied within the general population. (386) According to the FDA, HRT provides valuable therapy for many women but carries serious risks and it should be used at the lowest dose for the shortest duration possible. (387) Common side effects include headache, breast pain, nausea, depression, and changes in libido. (388) In addition to the common side effects, research conducted pursuant to the Women's Health Initiative demonstrated additional troubling adverse effects for both Premarin and Prempro. (389)

In the late 1980s, Wyeth sought FDA approval for Prempro and the FDA informed Wyeth it needed to evaluate the drug's long term safety. (390) In the 1990s, the National Heart, Lung, and Blood Institute (NHLBI) began the Women's Health Initiative, a massive research program that included protocol to examine the effects of estrogen (Premarin) and estrogen plus progestin (Prempro) on the prevention of coronary heart disease, osteoporotic fractures, and risk of breast cancer. (391) In 2002, the NHLBI announced it was halting the study of the combined Prempro trial prematurely because its harms outweighed it benefits. (392) The Women's Health Initiative data showed that although Prempro decreased the incidence of bone fractures, it was associated with a: 41% increase in stroke, 29% increase in heart attack, 22% increase in total cardiovascular disease, 26% increase in breast cancer, and it doubled the rates of venous thromboembolism. (393) According to the National Cancer Institute, Prempro also caused more breast tissue abnormalities, making mammograms less effective and increasing repeat mammograms as a means to determine whether the abnormalities consisted of benign or cancerous changes. (394) Furthermore, in addition to the increased risk of breast cancer from taking Prempro, the Women's Health Initiative found these breast cancers were invasive: they were larger and more likely to have spread to the women's lymph nodes. (395) Importantly, the Women's Health Initiative found the increased risk of invasive breast cancer did not stop when participants stopped taking Prempro, but participants' increased risk persisted for an average follow up period of eleven years. (396)

Data for Premarin showed similarly troubling effects: it increased the risk of stroke, venous thombembolism, dementia, and negatively impacted cognitive functioning. (397) Data for Premarin also indicated a 15-24 fold increased risk of endometrial cancer when used for five to ten years. (398) Notably, as with the results for Prempro that demonstrated lingering elevated risk following discontinuation of the drug, Wyeth's data indicated the increased risk for endometrial cancer persists for eight to fifteen years following the discontinuation of Premarin. (399) NHLBI also prematurely stopped the Premarin trial, similarly citing the risks outweighed the benefits. (400) As Law Professor Barbara Atwell characterized, HRT appears to be worse than ineffective, but "downright dangerous" and HRT "may be remembered as one of the terrible medical mistakes of the 20th century." (401)

This data showing an increased risk of serious adverse outcomes and invasive cancers directly undermines statements made by physicians who assert HRT does not increase the risk cancer. (402) Furthermore, this extensive body of research demonstrating the risks of HRT underscores the irony of surgically removing organs to alter a patient's hormone production and reduce cancer risk while subsequently prescribing synthetic hormone replacement that drastically increases cancer risk. (403) b. Lessons from HRT litigation

Cases litigating the adverse effects of HRT began to flood the court system and Wyeth rushed to defend itself and combat the decrease in prescription sales by investing S28 million in varied forms of promotional advertising. (404) In Wyeth v. Rowatt, consumers brought a lawsuit against Wyeth for personal injury and strict product liability related to risk labeling. (405) Three women who took HRT manufactured by Wyeth subsequently developed invasive breast cancer and alleged: Wyeth knew there was a potential increased risk of breast cancer but failed to study the association, Wyeth failed to warn physicians of an increased risk of breast cancer, and both Premarin and Prempro were unreasonably dangerous. (406) The jury found Wyeth was negligent, its products were defective, and Wyeth concealed material facts about the products' safety. (407)

The Nevada Supreme Court's key findings in Rowatt centered around the court's discussion of whether the evidence supported a finding of punitive damages to support Wyeth acted with "malice" through conduct intended to injure a person or with a conscious disregard for the rights or safety of others. (408) The court summarized based on available research, Wyeth knew HRT posed an increased risk of breast cancer but deliberately failed to conduct its own studies to examine the relationship and further acted to conceal material facts. (409) In the late 1980s and early 1990s, independent studies began publishing results showing estrogen and progestin corresponded to a four-fold increase in breast cancer. (410) Wyeth's internal documents showed it created an internal task force specifically to counteract these negative findings through public relations campaigns and increased its sales communications with physicians. (411) Wyeth ordered its Breast Cancer Working Group to keep negative results from a European study confidential despite quietly changing its European labeling to reflect an increased risk of breast cancer. (412) Around this time, the FDA approved Prempro conditioned upon Wyeth conducting long term studies on its safety. (413) In response, Wyeth provided Premarin and Prempro to the Women's Health Initiative studies as a means of fulfilling its commitment to examining the long term safety profile. (414)

Despite the FDA's approval for Prempro, numerous scientific articles continued linking HRT to an increased risk of breast cancer. (415) Wyeth forcefully responded through multiple channels of advertising and marketing in addition to systematically manipulating and directing scientific data designed to influence physician prescribing and professional assessment of risk. (416) Wyeth added $40.4 million to its existing annual marketing budget to counter the negative evidence and began promoting and advertising Prempro for additional unapproved uses, asserting it conferred cardioprotective and cognitive benefits. (417) The Nevada Supreme Court found Wyeth financed, manipulated, and sponsored articles touting the benefits of HRT and minimizing the risks by ghostwriting content, selecting physicians as authors, and hiding Wyeth's involvement by failing to disclose any involvement in the process in the final product. (418)

This data manipulation designed to influence the evidence underlying evidence based practices was particularly egregious: not only did Wyeth know of an increased risk of breast cancer, but it quietly buried this evidence, financed and pushed the scientific evidence to tip the scales, advertised unproven benefits, and concealed its involvement in the ghostwriting process. (419) The evidence as a whole led the court in Rowatt to uphold a massive punitive damages award and conclude Wyeth's misrepresentation and concealment showed reckless disregard for the health and safety of HRT patients. (420)

The court also held any warning label required by the FDA constitutes a minimum standard; accordingly, even if the FDA approves the product the manufacturer has a duty to ensure the product label is accurate and reflects current knowledge relating to risk. (421) Thus, when Wyeth knew of the link between HRT and an increased risk of breast cancer, it should have updated its warning label. (422) Although another court opined ghostwritten articles would not dilute any warning label, such a position is not only unconvincing but constitutes the very reason why Wyeth sought to manipulate existing scientific literature: to shift the balance of available evidence and distort clear indication of risk during physician prescribing. (423)

4. Revised Assessment of Preventive Salpingo-Oophorectomy and HRT Risks

Preventive salpingo-oophorectomy carries numerous risks from the procedure as well as the implication of inducing surgical menopause and removing healthy internal organs. (424) Although literature shows preventive salpingo-oophorectomy dramatic decreases risk of breast and ovarian cancer, the corresponding promotion and safety assurance for HRT is wholly unsupported by the weight of scientific evidence. (425) Current evidence demonstrates HRT increases the risk for stroke, heart attack, invasive breast cancer (Prempro), decline in cognitive functioning (Premarin), and endometrial cancer (Premarin). (426) Furthermore, jurisprudence in this area demonstrated how Wyeth systematically manipulated available data pertaining to the increased risk of breast cancer, blurring the ability for physicians to assess the weight of evidence pertaining to HRT's risks. (427)


A. Adopting a Novel Clinical Risk Assessment Paradigm

A comprehensive analysis of recommended interventions designed to increase risk of breast and ovarian cancer reveals extensive financial conflicts of interest, suppression of troubling safety data, ghostwritten scientific articles, and failure to mention key risk information. (428) By skewing available information, it makes it difficult for both physicians and patients to appreciate the nature and extent of increased risks arising from these interventions, incorrectly minimizing the perception of risks from intervening. (429) The convergence of high patient anxiety relating to cancer, documented overdiagnosis and overtreatment, and the perception that LDTs afford precision and accuracy create an impression of heightened benefit from intervention. (430) Both of these incorrect assessments tip the scale when assessing the risks and benefits of intervening with measures designed to reduce patient risk of breast or ovarian cancer. (431) However, precisely because physicians recommend these interventions as means to reduce risk of cancer, they have a legal and ethical duty to assess and communicate the additional risks from the interventions described supra to their patients. (432) During the process of assessing clinical guidelines and determining risks, physicians should be particularly aware of factors that may inappropriately influence the consensus of available information and exercise their professional discretion when assessing the evidence. (433)

In order to fulfill this duty, physicians should utilize a Unified Composite Risk Benefit Analysis to describe risks not only from the first proposed treatment intervention but all reasonably related treatment interventions. (434) The content of the Unified Composite Risk Benefit Analysis discusses risks related to any intervention included within patient's comprehensive treatment plan, such as endocrine therapy, preventive mastectomy and implant reconstruction, or preventive salpingo-oophorectomy and HRT. (435) Each subsequent intervention is directly related to the singular treatment objective of reducing risk, thus an appropriate calculation of risks and benefits of the treatment should include articulating the concept I refer to as Trading Risks.

Consider the following: Patient A approaches Physician X with anxiety related to developing ovarian cancer based on her family history and a test she ordered from Color Genomics that told her she has a deleterious BRCA mutation giving her a 30% risk of developing ovarian cancer. (436) Physician X suggests Patient A undergo BRCA testing through another laboratory, and orders BRCA testing through Quest Diagnostics. The result from Quest Diagnostics also shows Patient A has a deleterious BRCA mutation, but estimates her risk at 40%. (437)

Based on Patient A's test results and family history, Physician X recommends preventive salpingo-oophorectomy to Patient A to reduce her risk of ovarian cancer by 80-90%. (438) Physician X should not only discuss risks of surgery, but how removing healthy organs exposes her to risks from surgically induced menopause. (439) It also increases Patient A's risk of cardiovascular disease, cognitive impairment, lung cancer, Parkinson's disease, osteoporosis, and decline in psychological well-being. (440) Physician X should also note the procedure does not eliminate risk for ovarian cancer--Patient A would still have a 3-8% chance of developing ovarian cancer and would still have a small risk of endometrial and peritoneal cancer. (441) Physician X also recommends a preventive hysterectomy and discusses how it may decrease risk of uterine cancer, but entails surgical risks and potential long term complications with bladder, bowel, and sexual function. (442) If Physician X offers Patient A Premarin to address surgical menopause following a preventive salpingo-oophorectomy and preventive hysterectomy, this would increase Patient A's risk of stroke, heart attack, cognitive decline, and aggressive endometrial cancer, elevating her endometrial cancer risk even following the discontinuation of HRT. (443) If Physician X offers Patient A Prempro to address surgical menopause following salpingo-oophorectomy, this would increase Patient A's risk of stroke, heart attack, and invasive breast cancer, elevating her breast cancer risk even following the discontinuation of HRT. (444)

B. Clinical and Public Health Implications of Trading Risks

This scenario describes the complex content required to adequately communicate risk assessment based on an assessment of current evidence. (445) Physician X should extend the conversation beyond how the preventive salpingo-oophorectomy reduces Patient's A ovarian cancer risk to include an integrated assessment of risks and benefits from the composite interventions so the patient may appropriately consider all the risks and benefits involved prior to consenting to surgery. (446) Each of these serious risks of illness or adverse outcome are particularly important to address specifically because Patient A's reason for pursuing the preventive interventions are driven by a desire to reduce her risk of serious health outcomes. (447) Failure to re-envision the risk model into a Unified Comprehensive Risk Benefit Analysis not only negatively impacts the individual patient, but as the FDA Report noted, Trading Risks will reverberate on a macro level and pose massive public health implications for an entire class of patients. (448) Thus, without accounting for a large scale assessment, current practice guidelines may be reducing patient risk of breast and ovarian cancer while simultaneously creating a new class of patients exposed to iatrogenic harm through overtreatment or inappropriate treatment based on LDT results. (449) Without a thoughtful pause to consider how Trading Risks impacts end outcomes, this population of patients will suffer devastating morbidities directly related to each intervention including cardiovascular disease, cognitive impairment, depression, autoimmune disorders, and numerous types of invasive and aggressive cancer. (450)

The exponential increase in LDT availability and use for risk assessment and diagnostic testing has the potential to pathologize asymptomatic women and compound recognized issues associated with overdiagnosis and overtreatment. Based on the FDA's recent findings, despite manufacturer claims promoting T. DTs, these tests may lack analytic validity, clinical validity, and or clinical utility and expose patients to an incorrect clinical risk assessment, lead to overdiagnosis and overtreatment, or direct inappropriate treatment. Physicians should be aware of LDTs' limitations arising from both the current regulatory structure as well as the inherent complexities involved in risk assessment, diagnosis, and prognostication for a complex multi-factorial disease such as cancer. Physicians should address the dangerous combination of genetic determinism, high patient anxiety, and misperceptions of risk.

Bound by both a legal and ethical duty of informed consent, physicians should discuss the context and meaning of the patient's diagnosis and whether they suggest intervention based on asymptomatic risk, precancerous lesions, or cancer, and how the diagnosis impacts subsequent recommendations for interventions designed to reduce risk. As part of the duty of informed consent, physicians should critically examine how the pattern of systematic data suppression, scientific manipulation, and financial conflicts of interest has influenced available evidence and recommendations for clinical practice guidelines and interventions.

Finally, interventions designed to decrease the risk of breast and ovarian cancer correspond with increasing another set of risks for which physicians and patients should assess through a new framework, the Unified Composite Risk Benefit Analysis. This complex calculus entails Trading Risks, each of which are particularly relevant for patients seeking medical care as a means to reduce their risk of serious or fatal illness.

By Katherine Drabiak, JD, Assistant Professor, Department of Health Policy & Management, Department of Global Health, College of Public Health, University of South Florida, 13201, Bruce B. Downs Boulevard, Tampa, Florida 33612

(1) Angelina Jolie, My Medical Choice, N. Y. TIMES (May 14, 2013), available at; Angelina Jolie Pitt, Diary of a Surgery, N. Y. TIMES (March 24, 2015), available at

(2) See Pam Belluck, Experts Back Angelina Jolie Pitt in Choices for Cancer Prevention, N.Y. TIMES (Mar. 24, 2015), available at -prevention.html?_r=0 (discussing treatment recommendations for women under forty with BRCA1 and BRCA2 mutations); Lisa Esposito, Health Bwcc: More Young Women With Breast Cancer Genes Seeking Testing, Study finds, U.S. NEWS & WORLD REPORT (Feb. 11, 2016), -genetic-testing-study-finds (finding women were likely to undergo preventative removal after positive testing); Erika Check Hayden, Gene Counsellors Expect Resurgence of 'Jolie' Effect, NATURE NEWS (Mar. 26, 2015), available at (describing unknown variants and complications in BRAC1 testing).

(3) See NCI and Precision Medicine Initiative, national cancer institute, (last updated Mar. 10, 2016). The Precision Medicine Initiative allocated $215 million to biomedical research in 2016 to allow clinicians to develop therapies that work best in individual patients. U. Initially focusing on oncology, the program's four major goals were expanding precision medicine clinical trials, overcoming drug resistance, developing new laboratory models for research, and developing a cancer knowledge system. Id.

(4) See Draft Guidance: Framework for Regulatory Oversight of 1 laboratory Developed Tests, CENTER FOR BIOLOGICS EVALUATION AND RESEARCH, FOOD AND DRUG ADMINISTRATION (Oct. 3, 2014), ents/ucm416685.pdf [hereinafter Draft Guidance].

(5) See id. at 5 (emphasizing FDA's plan on enforcing new regulatory requirements for LDTs over time).

(6) See Office of the Commissioner, The Public Health Evidence for FDA Oversight of laboratory Developed Tests: 20 Case Studies, Office of Public Health Strategy and Analysis, FOOD AND DRUG ADMINISTRATION 4 (Nov. 16, 2015) (faulting lack of premarket review to assure quality of data referenced by manufacturers) [hereinafter "FDA Report"]; Kenneth Offit, Personalised Medicine: New Genomics, Old lessons 130 Human Genetics 3, 7 (2011) (questioning scope of personalized genomics in medicine).

(7) See Katherine Drabiak-Syed, Baby Gender Mentor: Class Action Litigation Calls Attention to a Deficient Federal Regulatory Framework for DTC Genetic Tests, Politicised State Statutory Construction, and a Lack of Informed Consent, 14 MICH. St. J. MED. & LAW 71, 74-75 (2010) (finding FTC has not yet issued enforcement actions against genetic testing companies for false advertisements).

(8) See FDA Report, supra note 6 (calling attention to need for FDA oversight due to various factors that will harm patient care).

(9) See id (discussing need to review available data referenced by manufacturer to

(10) See Jessica Cussins, F.DA. Attention to Inaccurate I Mb Tests Defers Hopes of "Predsion Medicine, " BIOPOLITICAL TIMES (Dec. 8, 2015), available at (elaborating on concerns over the future of precision medicine).

(11) See Allison Kurian & James Ford, Multigene Panel Testing in Oncology Practice: How Should We Respond? 1(3) JAMA ONCOLOGY 277 (2015) (pointing to events that marked breach in long-term barriers to cancer genetic testing).

(12) See FDA Report, supra note 6, at 3 (addressing increased complexity regarding LDTs).

(13) See FDA Report, supra note 6, at 3 (expressing concern for more accurate testing).

(14) See generally H. GILBERT WELCH, SHOULD I BE TESTED FOR CANCER? MAYBE NOT AND HERE'S WHY 82-86 (University of California Press, 2004) (describing DCIS treatment); H. GILBERT WELCH ET AL., OVERDIAGNOSED: MAKING PEOPLE SICK IN THE PURSUIT OF HEALTH 73-89 , 90-101 (Beacon Press, 2011) (discussing breast cancer and incidentalomas). These "incidentalomas," are tumors or growths that are statistically most likely benign, but set off a course of screening, biopsies, and potentially overtreatment. H. GILBERT WELCH ET AL., supra note 14, at 90-101.

(15) BRCA1 and BRCA2: Cancer Risk and Genetic Testing, NATIONAL CANCER INSTITUTE, http://www.cancer.gOv/about-cancer/causes-prevention/genetics/brca-fact-sheet#ql2 (last updated Apr. 1, 2015).

(16) See Hormone Therapy for Breast Cancer Tact Sheet, NATIONAL CANCER INSTITUTE, (last visited Mar. 27, 2017) (describing how hormone therapy slows or stops growth of hormone-sensitive tumors); Surgery to Reduce the Risk of Breast Cancer, NATIONAL CANCER INSTITUTE, (last updated Aug. 12, 2013) (explaining surgeries that can reduce the risk of breast cancer).

(17) See Karsten Juhl Jorgensen, Mammography Screening: Benefits, Harms, and Informed Choice, 60(4) DANISH MEDICAL JOURNAL 1, 4 (2013) (discussing mammography screening advertisements as marketing for business rather than evidenced based practice); STAFF OF THE HUMAN RESOURCES AND INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE OF THE COMMITTEE ON GOVERNMENT OPERATIONS, 102d CONG., THE FDA'S REGULATION OF SILICONE BREAST IMPLANTS 15 (U.S. Government Printing Office, 1992) [hereinafter Congressional Report] (critiquing FDA's involvement with Dow Corning manufacturer data and premarket approval application); Wyeth v. Rowatt, 244 P.3d 765, 771-73 (Nev. 2010) (discussing how Wyeth attempted to conceal unfavorable safety data relating to hormone replacement theory); Kala Visvanathan et al., Use of Pharmacologic Interventions for Breast Cancer Risk Reduction: American Society of Clinical Oncology Clinical Practice Guidelines, 31(23) journal of clinical Oncology 2942, 2959 (2013) (highlighting the need for women to make well-informed and individualized decisions regarding treatment). This article discusses how medical practitioners including oncologists, gynecologists, and general practitioners should all offer chemopreventive agents to women classified as being at high risk for breast cancer and outlines six specific strategies which to do so. See discussion infra Section VI.B.l (discussing clinical recommendations for endocrine therapy). Numerous authors issuing the guidelines also hold stock, obtain research funding, receive honoraria, and or consult for a variety of pharmaceutical corporations including AstraZeneca, Novartis, and Pfizer See E. Vrdoljak et. al., Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent I metastatic breast cancer; 27(11) ANNALS OF ONCOLOGY 2046, 2052 (Nov. 2016) (disclosing funding sources for clinical trials). AstraZeneca manufacturers Nolvadex, and such clinical practice recommendations would benefit the manufacturer. Martha Rosenberg, Why Women Are Not Flocking to Tamoxifen (Dec. 5, 2012), CENTER FOR HEALTH JOURNALISM, why-women-are-not-flockingtamoxifen.

(18) See Carmen E. Guerra, Melani Sherman, & Katrina Armstrong, Diffusion of Breast Cancer Risk Assessment in Primary Care, 22 J. AM. BOARD FAM. MED. 272, 277-78 (June 2010) (noting how physicians are likely to discuss risks with patients).

(19) See Bryan Murray, Informed Consent: What Must a Physician Disclose to a Patient?, 14 AM. MED. ASS'N OF J. ETHICS 563 (July 2012) (explaining how informed consent is critical for patient's decision making).

(20) See discussion infra Part VII. (explaining content of Unified Composite Risk Benefit Analysis and how physicians should interact with patients).

(21) NCI and the Precision Medicine Initiative, supra note 3.

(22) Id.

(23) See Paving the Way for Personalised Medicine: FDA's Role in the New Era of Medical Product Development, FDA (Oct. 2013), 72421.pdf (discussing personalized medicine and how it impacts advances in medical care) [hereinafter Paving the Way for Personalised Medicine].

(24) See The Genetics of Cancer, NATIONAL CANCER INSTITUTE, available at (discussing the genetic component to cancer risk, testing, and DNA sequencing)..

(25) Id.

(26) Id.

(27) See NATIONAL CANCER INSTITUTE, supra note 15 (discussing impact of BCRA1 and BCRA2 genes on increased cancer risk).

(28) See Michael Joyner, Moonshot Mediane Will Let Us Down, N. Y. Times, Jan. 29, 2015, at A27 (discussing precision medicine's focus on genetic diseases rather than commonly preventable diseases); Liana Lianov & Mark Johnson, Physician Competencies for Prescribing! Lifestyle Medicine, 304 JAMA 202, 202-03 (2010) (discussing lifestyle changes that doctors can prescribe to mitigate disease risks); T. Colin Campbell, the china study 158-68 (BenBella Books, 2004) (discussing rarity of BRCA genes and risk modulation resulting from environmental exposures, diet, and HRT); Cheryl Lin et al., The Case Against BRCA1 and BRCA2 Testing, 149 surgery 731, 732-734 (2011) (discussing how environmental factor mediate genetic expression and limitations of BRCA testing). Despite the BRCA genes raising the risk of cancer in an individual, the presence of these genes does not mean an individual will inevitably develop cancer, especially when mitigating factors are taken into account. NATIONAL CANCER INSTITUTE, supra note 15. However, these mitigating factors in disease risk reduction need to be properly implemented to see that decreased risk. Lianov & Johnson, supra, at 202. "Inadequate confidence and lack of knowledge and skill" are "major barriers to counseling patients about lifestyle interventions." Id.

(29) Jolie, supra note 1; Jolie Pitt, supra note 1.

(30) See supra note 2.

(31) Jolie, supra note 1; Jolie Pitt, supra note 1.

(32) Jolie Pitt, supra note 1.

(33) Id.

(34) See Christine Mai-Due, Angelina Jolie's message was 'choose what's right for you,' and experts agree, LOS ANGELES TIMES (March 24, 2015), -20150324-story.html (discussing Jolie's decision to use surgery as a cancer prevention method); Elaine Schattner, Understanding Angelina Jolie Pitt's Cancer Risk And Her Decision To Tell About It, FORBES (March 24, 2015), http://www.forbes.eom/sites/elaineschattner/2015/03/24/angelina-jolie-pitts-cancer-risk-brcaand-decision-for -prophylactic-surgery-to-remove-ovaries/#51 Icld726e89 (discussing Jolie's bravery for sharing her medical decision in public forums). Part of Jolie's decision was based on her family's medical history. Mai-Due, supra. Jolie's "grandmother, mother, and aunt all died from related cancers" meaning Jolie was at a heightened risk for cancer when viewed in conjunction with her BRCA-1 mutation. Id. Ovarian cancer poses a particularly grave risk due to the difficulty of treatment. Id. Once ovarian cancer metastasizes, "it is considered incurable." Id.

(35) Id.

(36) Id.

(37) Belluck, supra note 2 (discussing the medical community's response to Jolie's public discussion of her salpingo-oophorectomy).

(38) Id. In her discussion of her surgical interventions Jolie is careful to note that her decision was personal to her and that "these decisions are 'far harder' for women who still want to get pregnant." Id.

(39) See generally Christopher Holman, The Critical Role of Patents in the Development, Commercialization, and Utilisation of Innovative Genetic Diagnostic Tests and Personalised Medicine, 21 B U.J. of sci. & tech. L. 297 (2015) (discussing patents for molecular diagnostic tests and genetic diagnostic tests). One of the most significant factors that led to the increase in availability and amount of LDTs was the incentive of investment created by issuing patents. Id. at 307. By issuing patents, which "do not inhibit basic research," the labs developing these tests are incentivized to make the "substantial investment required to translate the results of basic research into high-quality, commercially available diagnostic tests that meaningfully impact people's lives." Id.

(40) Judy Peres, Breast Cancer Screening Offers Vital Information, Uncertainty, THE CHICAGO TRIBUNE (Sept. 25, 2014), -20140925-story.html (discussing increased availability of genetic testing for cancer risk).

(41) BRCA 1 and BRCA2: Cancer Risk and Genetic Testing, supra note 15 (discussing the link between BRCA1 and BCRA2 and breast or ovarian cancer).

(42) Myriad Gene Patent Litigation, GENOMICS LAW REPORT, (last visited Apr. 3, 2017) (cataloging various blog entries that discuss Myriad Gene patent litigation). There are other genetic risk factors linked to breast cancer, such as CHEK2, BRIP1, and PATB2, but they are not commonly tested for due to their rarity and "technological barriers" to their discovery. Walter Bodmer & Ian Tomlinson, Rare genetic variants and the risk of cancer, 20 CURRENT OPINION IN GENETICS & DEVELOPMENT 262,262 (2010) (discussing rare genetic variants that are linked to increased cancer risk). Due to the infrequency with which these genes occur in the general population, developing tests and identifying them requires "thousands of cases and controls" which means they are rarely tested for in preventative settings. Id. at 263.

(43) Id.

(44) Esposito, supra note 2 (discussing increased rates of testing for those at risk of breast or ovarian cancer).

(45) Id.; Peres, supra note 40 (discussing availability of genetic screening for cancer risk).

(46) BRCA 1 and BRCA2: Cancer Risk and Genetic Testing, supra note 15 (providing multiple resources and hyperlinks to BRCA information).

(47) Id.

(48) Id.

(49) Id.

(50) Id.

(51) Id.

(52) See BRCA 1 and BRCA2: Cancer Risk and Genetic Testing, supra note 15. See also Sandhya Pruthi, et al., Identification and Management of Women with BRCA Mutations or Hereditary Disposition for Breast and Ovarian Cancer, 85 MAYO CLINICAL PROC. 1111 (2010), available at (discussing how genetic consultation and BRCA testing can reduce cancer risk); Angela M. Trepanier, et al., Public Health Approaches and Barriers to Educating Providers about Hereditary Breast and Ovarian Cancer Syndrome, 4 HEALTHCARE 19, 28 (2016), available at (explaining genetic test results for breast and ovarian cancer risk).

(53) See BRAC Analysis, MYRIAD GENETICS, services/hereditary-cancers/bracanalysis/ (last visited March 28, 2017) (discussing BRACAnalysis genetic test for BRCA1 or BRCA2 mutations); BRCAdvantage, quest diagnostics, name/BRCAvantage.html (last visited March 28, 2017) (providing example of company offering BRCA test); BreastNext, AMBRY GENETICS, (last visited March 28, 2017) (discussing BreastNext genetic test for BRCA1 or BRCA2 mutations); Color Test, COLOR GENOMICS, (last visited March 28, 2017) (discussing color test analyzation of 30 genes). Less knowledge about the risk and benefit analysis of available genetic testing increases public misconceptions, which may result in less enrollees. See J. Scott Roberts & Jenny Ostergren, Direct-to-Consumer Genetic Testing and Personal Genomics Services: A Review of Recent Empirical Studies, 1 CURR. GENETIC MED. REP. 182,190 (2013), available at (critiquing controversial industry approaches in light of current consumer risk perception of genetic tests). Roberts and Ostergren suggest that there needs to be more nuanced understanding of current direct-to-consumer genetic testing to ensure that the industry interacts appropriately with consumers. Id. at 200.

(54) Company Milestones, MYRIAD GENETICS, (last visited March 28, 2017) (providing timeline of Myriad Genetics).

(55) See Abnormal PAIJ32 Gene Increases Breast Cancer Risk More than Previously Thought, BRBASTCANCER.ORG, (Aug. 8, 2014), available at -risk (explaining increased risk in Breast Cancer amongst women with PALB2 gene).

(56) See BreastNext, supra note 53 (breaking down gene associations and respective data on increased risk for breast and ovarian cancer).

(57) Kurian & Ford, supra note 11; Gina Kolata, When Gene Tests for Breast Cancer Reveal Grim Data But No Guidance, N.Y. TIMES (Mar. 11, 2016), available at See Samuel P. Strom, Current practices and guidelines for clinical next-generation sequencing oncology testing 13 CANCER BIOL. & MED. 3 (2016), available at (detailing LTD panel testing).

(58) Holman, supra note 39, at 302.

(59) Id. at 302-03.

(60) Id. at 302. See also Peres, supra note 40 (stating that forty percent of individuals who underwent panel testing had variants of unknown significance).

(61) Lin et al., supra note 28 at 732. See Chaoyang Sun et al, The Role of BRCA Status on the Prognosis of Patients with Epithelial Ovarian Cancer: A Systematic Review of the literature with a Meta Analysts, PLOS ONE, (Alexander James Roy Bishop ed., May 1, 2014). "Sun et al. demonstrated in the majority of studies they reviewed, BRCA variants status conferred prognostic advantage and improved ovarian cancer survival." Using Begg's linear regression test, aggregate hazard ratios showed that patients with a BRCA2 mutation may have a more favorable prognosis than patients with a BRCA1 mutation. Id. Another study was consistent with these results, finding that "BRCA1 /2 mutation germline mutation was associated with improved survival and BRCA2 carriers had the best prognosis ..." Id.

(62) See Color's Technology and Coverage, color, (last visited Apr. 3, 2017) (discussing accuracy of LDTs and quality of resources used). See also News Releases, Quest Diagnostics IMunches Three Genetic Test Panels for Predicting Hereditary Cancer Risk, QUEST DIAGNOSTICS (May 26, 2016), Quest-Diagnostics-Launches-Three-Genetic-Test-Panels-for-Predicting-Hereditary-Cancer-Risk (describing Quest Diagnostics' new genetic test panels); BreastNext, supra note 53 (explaining BreastNext test and genes that are analyzed in the sequencing panel).

(63) See Why Get Tested, COLOR, (last visited Apr. 3, 2017) (examining various types of genetic testing plans attending to individualized needs). Through some LDTs, such as the color test, healthcare providers can create personalized screening plans for their patients, increasing the chance of early detection. Id. The LDT market is expected to grow in part due to the growing awareness of various types of laboratory tests. Laboratory-Developed Testing Market to Register a Strong Growth by 2020-Persistence Market Research, PERSISTENCE MARKET RESEARCH (Oct. 20, 2016), -register-a-strong-growth-by-2020-persistence-market-research-733717.htm.

(64) See BRCA 1 & BRCA2 Genetic Testing for Hereditary Breast and Ovarian Cancer: Patient Guide, Ambry Genetics, available at 1:2.pdf (last visited Apr. 3, 2017) (Listing recommendations for patients with a BRCA1/2 mutation and explaining the testing); see also Breast Cancer: iMboratory Support of Diagnosis and Management, quest diagnostics, (last updated Dec. 2012) (discussing the function of laboratory testing in diagnosing and managing breast cancer); News Releases, Quest Diagnostics Introduces BRCAvantage Plus, Providing New Choices in Genetic Breast Cancer Risk Testing, quest diagnostics (Nov. 4, 2014), -Genetic-Breast-Cancer-Risk-Testing (stating that discovery of mutations through testing may lead to intensive monitoring or medical intervention).

(65) See FDA Approves Myriad's BRACAnalysis CDx for Use with Ovarian Cancer Drug, genomeweb (Dec. 19, 2014), (announcing FDA approval of BRACAnalysis CDx). FDA approved BRACAnalysis CDx as a companion diagnostic under the requirements of a Class III device, the most stringent category of medical device regulation but it was not approved as a pre-symptomatic risk assessment test. See also Gowri Raman et al., Update on Genetic Tests Currently Available for Clinical Use in Common Cancers, agency for healthcare research and quality (July 19, 2013), available at (reporting on available genetic tests and their FDA-approval status).

(66) See Paving the Way for Personalised Medicine, supra note 23 (defining personalized medicine and use of LDTs to guide therapeutic decisions).

(67) Test Determines Risk of Breast Cancer Returning, FDA, (May 14, 2007),; Agendia Receives New FDA Clearance of MammaPrint FFPE Breast CancerTest, AGENDIA (Feb. 10, 2015), cancer-test/. The fact that the MammaPrint FFPE has a larger panel of genes than any other commercially available test means it surpasses all other tests because its capability covers all age groups and is not restricted by estrogen or HER 2 receptor status. Agendia Receives New t'DA Clearance of MammaPrint FFPE Breast Cancer Test, supra. The FDA's approval signified its commitment to personalized medicine because the additional insight that the test produces allows physicians to choose the best and most appropriate treatment for a given patient. Id.

(68) Id.

(69) Id.

(70) Id. Laboratory developed tests (LDTs) are generally not required to go through any premarket approval process with the FDA. See generally U.S. FOOD & DRUG ADMIN., laboratory Developed Tests (last updated Jan. 13, 2017) (providing background on integration of FDA clearance with LDTs). Recently developed LDTs are much more advanced than LDTs developed in the 1970s, and the FDA has identified several problems that may potentially be related to lack of oversight. Id. FDA concerns revolve around the impact on patient treatment and care resulting from potentially faulty LDTs. Id. The FDA published a discussion paper on LDTs to provide a more detailed explanation on what they perceive their direction will be in regards to the regulatory framework enforcing oversight of LDTs. Id.; U.S. FOOD & DRUG ADMIN., Discussion Paper on laboratory Developed Tests (LDTs) (Jan. 13, 2017), available at nostics/LaboratoryDevelopedTests/UCM536965.pdf. See also Deborah Mazer and Gregory Curfman, 21" Century Cures Act Lowers Confidence in FDAApproved Drugs and Devices, health affairs Blog (Feb. 14, 2017), -approved-drugs-and-devices/ (explaining that the modified approval procedures can weaken FDA's regulatory oversight).

(71) See Gregorio Garcia, Symposium, The FDA and the Regulation of Genetic Tests: Building Confidence and Promoting Safety, 48 JURIMETRICS J. 217, 226 (2008) (detailing that MammaPrint test was approved by the FDA as an IVDMIA). Indeed, even an attorney writing an article in jurimetrics journal repeated a mistaken classification from an article in FDA week, announcing that FDA "approved" the MammaPrint LDT. Id.

(72) See U.S. FOOD & DRUG ADMIN., supra note 70 (describing that cleared medical devices must be equivalent to another marketed device). See also Mazer & Curfman, supra note 70, and accompanying text (suggesting that regulatory changes may lower patient confidence in FDA's role in oversight). "[T]he 21st Century Cure Act ... require[es] that the FDA consider lower standard of evidence, including 'real-world evidence' ... broadly defined as 'data regarding the usage, or potential benefits or risk, of a drug derived from sources other than randomized clinical trials'." Id.

(73) See id. (explaining that the FDA will use the lease burdensome review standard of approving products).

(74) Id. See also AGENDIA, supra note 67 (noting MammaPrints' FDA clearance for Agendia).

(75) The OncotypeDX[R] Breast Recurrence Score[TM], ONCOTYPE DX[R] BREAST RECURRENCE SCORE[TM], (last visited Apr. 2, 2017) (describing the Breast Recurrence Score as a comprehensive assay); What is the Oncotype DX[R] Breast Recurrence Score[TM]?, ONCOTYPE DX[R] BREAST RECURRENCE SCORE[TM], -DCIS/WhatlsTheOncotypeDXCancerTest (last visited Apr. 2, 2017) (explaining in more detail the OncotypeDX[R] Breast DCIS Score[TM]).

(76) See The OncotypeDX[R] Breast Recurrence Score[TM], supra note 75 (noting intended use of OncotypeDX is predominantly for early stage cancer patients). Specifically, the OncotypeDX Breast Cancer Assay is intended for use in early state FR Positive, HER2 Negative, Node Negative or Node Positive patients. Id.

(77) Id.

(78) What is the Oncotype DX[R] Breast Recurrence Score[TM]?, supra note 75.

(79) The OncotypeDX[R] Breast Recurrence Score[TM], supra note 75.

(80) Emma Shitvelman, To Type or to Print? Oncotype DX and Mammal BluePrint Test for Breast Cancer, CANCER COMMONS (Oct. 30, 2015), or-to-print-oncotype-dx-and-mammablueprint-tests-for-breast-cancer/ (discussing that only Oncotype DX is recommended while MammaPrint has larger insurance support); Nick Mulcahy, NCCN Recommends Only One Genomic Test for Breast Cancer, MEDSCAPE (March 12, 2015), (Mar. 12, 2015) (emphasizing that Oncotype DX is the sole test endorsed by the National Comprehensive Cancer Network (NCCN)). The Oncotype DX test is the only test that NCCN endorses for patients with early-stage breast cancer, and that MammaPrint has yet to show evidence of this capability. Id.

(81) See generally Michael Marrone, et. al., Clinical Utility of Gene Expression Profiling in Women With Early Breast Cancer: an Overview of Systematic Reviews, 17 GENETICS IN MED. 519 (2015), available at (last visited Mar. 30, 2017).

(82) Id. But see Harris L, Fritsche H, Mennel R, et al., American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer, 25 J Clin Oncol 5287, 5289 (2007) (providing evidence of Oncotypc DX used for predicting risk of recurrence). The Harris et. al study emphasized that while these assessments and tests are available to help provide physicians with effective tools to help treat and diagnose patients, these tools are not expected to replace physician judgment. Id. Nor are these tools applicable in beneficial ways for all patients. Id. The study was intended to provide further guidance for physicians allowing them to supplement their experience with innovative approaches being considered by other physicians. Id.

(83) Joseph Sparano et al, Prospective Validation of a 21-Gene Expression Assay in Breast Cancer, 373 NEW ENGLAND JOURNAL OF MEDICINE 2005 (2015). See also Nick Mulcahy, Oncotype DX Trial: Some Breast Cancers Don't Need Chemo, MEDSCAPE MEDICAL NEWS (Sept. 28, 2015), available at [(detailing TAILORx study from the European Cancer Congress and New England Journal of Medicine).

(84) Mulcahy, supra note 83.

(85) Sparano et al., supra note 83, at 2005.; Mulcahy, supra note 83
   This study was sponsored by the National Cancer Institute, and was
   coordinated by the ECOG and subsequently the ECOG-ACR1N Cancer
   Research Group. Some of the study authors report financial ties to
   industry, including Genomic Health, the makers of the Oncotype DX
   test. Dr Hudis reprots receiving grant support from Genomic Health.

Id. See also Cited by for Prospective Validation of a 21-gene Expression Assay in Breast Cancer; Google Scholar, (enter "Prospective Validation of a 21-gene Expression Assay in Breast Cancer" into search bar) (noting 186 citations of article as of 3/29/2016).

(86) Sparano et al., supra note 83, at 2005.

(87) See id. (disclosing authors ownership of patent related to tests) See also supra note 85 and accompanying text (disclosing association of research to corporations that have financial interests in the results).

(88) See Marrone, supra note 81 (noting significantly increased treatment recommendations by physicians).

(89) See Sparano et al., supra note 83, at 2013 (demonstrating studies support to use of sponsored genetic tests in patient care).

(90) See infra Section IV and accompanying text. Not only do some tests result in treatment a patient might not otherwise have sought, it can also detect cells that never would have caused the patient harm and prompt treatment that would have otherwise been unnesessary. Id. See also Patient Stories, (collecting testimonials of such patients) (last visited Apr. 1, 2017).

(91) Tara Sanft and Lajos Pusztai, Clinical Utility of Biomarker Tests in Decisions on Extended Endocrine Therapy, 34 JOURNAL OF CLINICAL ONCOLOGY 32 (2016). See also Sparano et al., supra note 83, 2006 (identifying that study was designed to support and validate clinical usefulness of genetic testing).

(92) Supra note 91 and accompanying text (confirming research designs and focus to support commercially advertised use of genetic tests).

(93) Surabhi Dangi-Garimella, PhD, Payers Evaluate the Clinical Utility of Diagnostic Tests, AM. J. MANAGED CARE, (Feb. 16, 2015), -the-clinical-utility-of-diagnostic-tests. As the FDA heightens their scrutiny over genetic testings, the competitive playing field for development of genetic assays will increase, making innovation and accountability better for the consumer patient. Id. The increase in regulation is expected to create a better method for developing genetic assays, which will ultimately realize maximal benefit for the patients. Id.

(94) FDA Report, supra note 6, at 14 (describing Oncotype DX HER2 Breast Cancer RT-PCR Test).

(95) Id. at 14 (assessing the Oncotype DX HER2 Breast Cancer RT-PCR Test).

(96) See Press Release, Genomic Health, Inc., Genomic Health Announces Data Supporting Use of Oncotype DX to Accurately Assess HER2 Gene Expression in Breast Cancer Patients (Sept. 6, 2008), available <<? (last visited Mar. 30, 2017) (explaining that the test can give insight to individual tumor biology).

(97) FDA Report, supra note 6, at 15.

(98) See id. (describing how pathologists found errors in the FDA-approved tests).

(99) Id. (explaining the life expectancy can be increased with treatment). The projected life expectancy is "3 years longer for HER2 positive patients who receive trastuzumab" with chemotherapy, compared to those who just received chemotherapy. Id. See also Who Is Herceptin For? Genentech Inc., available at (last visited Mar. 30, 2017) (explaining various patient care uses of herceptin).

(100) See U.S. Food & Drug Admin, Herceptin Final labeling--Genentech, Inc., available at (describing warnings and precautions of Herceptin).

(101) FDA Report, supra note 6, at 3-4 (addressing several concerns for FDA oversight for LDTs). LDT tests often yield positive results when the disease is not present, or show negative results when the disease is actually present. Id. at 8, 14. Some LDTs, such as the CARE Clinics tests for Austism Spectrum Disorder, are linked to treatments that have been discredited by the medical community, leading to misdiagnoses. Id. at 23. However, supporters of LDTs have argued that they have helped cancer research progress, as they allow the physicians to practice "at the speed of science rather than the speed of the FDA." Jeff Lyon, Senator Confronts FDA Over laboratory Tests, 316 JAMA 18 (2016), available at (last visited Mar. 30, 2017).

(102) Offit, supra note 6, at 7.

(103) Id.

(104) See id. (describing errors and inconsistencies with laboratory tests).

(105) See id. (explaining that analytic validity of genotyping cannot be taken for granted).

(106) See Peres, supra note 40 (discussing the affects inaccuracy has on patients' lives).

(107) Id.

(108) Id.

(109) See Srivani Ravoori, PhD, What is Precision Medicine?, American Association for Cancer Research (AACR), available at (last accessed April 1, 2017) (discussing the importance of precision medicine to solve complex human health issues). President Barack Obama created Precision Medical Initiative (PMI) in the hopes of using scientific evidence to show the benefits of precision medicine in daily clinical practice. Id. Precision medicine offers tailored disease prevention and treatment opportunities that are individualized for each patient through use of their genomic information. Id. The obvious advantages this form of medicine should provide on cancer treatments are discussed in short and long term forecasts by the Obama Administration. Id. Overall, successful implementation of the PMI will certainly have a significant impact on genetic diseases such as cancer and the medical community is encouraged to keep an eye on the progress of this initiative in the coming years. Id.

(110) FDA Report, supra note 6, at 3.

(111) Id.

(112) Id. at 22.

(113) Id. at 2-5. Not all LDTs are proven to be relevant to medical conditions, and some have been associated with scientific concepts which have been proven to be refutable. Id. As the role of LDTs in medicine evolves, inaccuracies and false test results have a more significant impact on patient care. See laboratory Developed Tests, supra note 70, and accompanying discussion (contrasting historical and current oversight role of FDA on LDTs). While the government must carefully balance between over-exercising its authority to implement regulations and potentially stifling innovation, the government is responsible for ensuring the patient-consumers remain protected from the use of unreliable and underdeveloped tests. Id. The cost of inaccuracies may lead to unnecessary treatment and improper diagnoses. Id.

(114) See FDA Report, supra note 6, at 2-5 (detailing that inaccuracies in LDTs can result in unneeded treatment).

(115) Id.

(116) Id. Although LDTs have resulted in many benefits to patients, the complexity in oversight of patient volume has resulted in the possibility of harming patients. Id. See also discussion supra notes 70, 113 (examining complex role of FDA in LDT oversight).

(117) See Cussins, supra note 10 (reporting social, individual, and financial harms "caused by LDTs that don't perform as promised"); Robert Pear, T.D.A. Targets Inaccurate Medical Tests, Citing Dangers and Costs, the NEW YORK TIMES (Nov. 23, 2015), available at http://www.nytimes.eom/2015/ll/24/us/politics/fda-targets-inaccurate-medical-tests-citingdangers-and-costs.html (explaining FDA findings about harms and effects of prevalent LDT use by physicians); Peter Lurie, Why FDA Should Oversee Laboratory Developed Tests, FDA VOICE (Nov. 15, 2015), /why-fda-should-overseelaboratory-developed-tests/ (last visited Mar. 29, 2017) (highlighting FDA conclusions about real and potential harms of LDTs to patients and public health).

(118) See Draft Guidance, supra note 4, at 4 (describing "risk-based framework for addressing the regulatory oversight" of LDTs).

(119) FDA Report, supra note 6, at 2 (concluding lack of regulatory compliance by laboratories harms patients).

(120) Medical Device Amendments of 1976, Pub. L. No. 94-295, sec. 3, [section]201, 90 Stat. 539 (codified at 21 U.S.C [section] 321 (h)(2)). See Juliana Han, The Optimal Scope of FDA Regulation of Genetic Tests: Meeting Challenges and Keeping Promises, 20 HARV. J.L. & TECH. 423, 431 (2007) (describing FDA authority to regulate medical devices).

(121) Han, supra note 120, at 427-28; Draft Guidance, supra note 4, at 6-7.

(122) See Han, supra note 120, at 427-430 (explaining lax regulatory framework for LDTs); Sharonmoyee Goswami, Caught in the Middle: Reducing the Uncertainty Created By the FDA and the Patent System for Genetic Diagnostic Test Makers, 1 N.Y.U.J. INTELL. PROP. & ENT. 33, 40-44 (2011) (relating approval requirements for medical devices). Pre-Market Approval "is the FDA process of scientific and regulatory review to evaluate safety and effectiveness." Id. at 43. Prior to approval of a medical device (Pre-Market Approval), the FDA may require that a manufacturer submit clinical data supporting the safety and effectiveness of the product. Id. at 42-44.

(123) Draft Guidance, supra note 4, at 6-7; Goswami, supra note 122, at 40; Trevor Woodage, Gatekeepers and Goalposts: The Need for a New Regulatory Paradigm for Whole Genome Sequence Results, 11 NW. J. TECH. & INTELL. PROP. 1, 3-5 (2012).

(124) Draft Guidance, supra note 4, at 6-7; Goswami, supra note 122, at 40; Woodage, supra note 123, at 15.

(125) Draft Guidance, supra note 4, at 7.

(126) See id. at 9 (listing FDA's limitations in regulating LDTs under CLIA).

(127) See id. (describing FDA concern for lack of safety and effectiveness of LDTs).

(128) Id. at 10.1T

(129) See id. at 11 (discussing how a framework for oversight would provide greater patient protection).

(130) Joann Elmore et al., Diagnostic Concordance Among Pathologists Interpreting breast Biopsy Specimen, 313 JAMA 1122, 1127 (2015), available at

(131) Id. Variations of pathology interpretations that lead to disagreements vary because when "a biopsy is overinterpreted .... a woman may undergo unnecessary surgery, radiation, or hormonal therapy." Id. at 1130. The authors of the study focused on identifying specific patient and physician characteristics that increased the amount of discordance, in efforts to reduce this variation in interpretation as much as possible. Id. While the authors recognize that there is no gold standard for measuring the accuracy of a pathology diagnosis, the authors crafted an expert consensus-derived reference which was used to measure pathologist variance. Id at 1130-31. The authors suggest that while the pathologist variance was ultimately defined as approximately 75% agreement, further research would be required to determine the relationship between patient choice and pathologist variance. Id. at 1131.

(132) See Draft Guidance, supra note 4, at 9-11. FDA has noted concerns about the lack of independent review of the evidence of clinical validity of LDTs. Id. at 9. LDTs that have not been clinically validated for their intended use but are nonetheless used to make critical clinical decisions put patients at risk of incorrect diagnosis and potentially harmful treatment. Id. Considering reports of patient harm due to inaccurate, unsafe, ineffective, and poor quality LDTs, FDA proposes increased oversight to provide independent review and evaluation of LDT clinical and analytical performance. Id. at 10-11.

(133) See id. at 4-5 (discussing intent to regulate LDTs as medical devices and scope of guidance). According to the FDA, LDTs should only be designed, manufactured, and used by laboratories that meet the requirements for high-complexity testing under CLIA as described in 42 C.F.R 493.17(c)(4) and 42 C.F.R 493.25. Id. at 5 n.5. See also Federal Food, Drug, and Cosmetic Act, 21 U.S.C. [section] 321(h) (2016) (defining FDA authority to regulate genetic testing under definition of "device").

(134) See Draft Guidance, supra note 4, at 12-18, 19-20 (discussing medical device registration, reporting, and premarket review).

(135) See id. at 11 (reviewing risk-based approaches). Medical devices are classified as Class 1, II, or III based on the controls necessary to provide a reasonable assurance of the device's safety and effectiveness. Id. In determining how to classify a device, the FDA considers the device's intended use, technological characteristics, and the risk to patients if the device were to fail. Id. Class 1 devices, which are subject to only general controls, are the lowest-risk category of devices, whereas Class III devices, which are subject to general controls and premarket clearance, are the highest-risk. Id. See also Federal Food, Drug, and Cosmetic Act, 21 U.S.C. [section] 360c(a)(l) (2016) (discussing classes of devices intended for human use).

(136) See Draft Guidance, supra note 4, at 12 (providing FDA recommendation for evaluating riskiness of LDTs). The FDA examines factors such as:
   [W]hether the device is intended for use in high risk
   disease/conditions or patient populations, whether the device is
   used for screening or diagnosis, the nature of the clinical
   decision that will be made based on the test result, whether a
   physician/pathologist would have other information about the
   patient to assist in making a clinical decision (in addition to the
   LDT result), alternative diagnostic and treatment options available
   to the patient, the potential consequences/impact of erroneous
   results, number and type of adverse events associated with the


(137) Id. at 24.

(138) See Id. at 23-24.

(139) See Id. at 27.

(140) See Robert Lowes, FDA Warns Against Using Ovarian Cancer Screening Tests, MEDSCAPE (Sept. 7, 2016), (discussing the rise of complex and widely used LDTs for serious conditions such as cancer).

(141) See AMANDA K. SARATA & JUDITH A. JOHNSON, CONG. RESEARCH SERV., R43438, REGULATION OF CLINICAL TESTS: IN VITRO DIAGNOSTIC (IVD) DEVICES, LABORATORY DEVELOPED TESTS (LDTS), AND GENETIC TESTS 9 (2014) (explaining LDTs used in testing for conditions or diseases subject to quickly advancing scientific research).

(142) See supra notes 62-63 and accompanying text (describing physicians and patients response to LDTs advertising claims).

(143) See Draft Guidance, supra note 4, at 9 (discussing FDA's concern with clinical validity of LDTs).

(144) See Draft Guidance, supra note 4, at 7-11 (considering risks associated with LDTs).

(145) Id. at 12, 13, 25. Draft guidances refer to documents that have been proposed but FDA has not finalized whether the proposed regulations would be adopted in whole, partially, or not at all. See Proposed Regulations and Draft Guidance, U.S. FOOD & DRUG ADMINISTRATION, nsandDraftGuidances/ (last visited Apr. 2, 2017) (defining draft guidances and providing examples of draft guidances with accompanying commentary). The draft guidance merely demonstrates the FDA's thoughts on a particular subject. See Draft Guidance supra note 4, at 4 (indicating the guidance does not bind the FDA or public). Through coordination with the Centers for Medicare Services (CMS), the draft guidance allowed the FDA to propose framework for the oversight of LDTs. JEFFREY SHUREN & PATRICK H. CONWAY, FDA and CMS Form Task Force on LDT Quality Requirements, U.S. FOOD AND DRUG ADMINISTRATION, (last visited Apr. 2, 2017). Thereafter, the FDA reviewed public comments it received through an open public docket and two-day public meeting in order to modify the proposed final framework. Id

(146) See Goswami, supra note 122 at 49-56 (examining common errors in diagnostic testing).

(147) Id. at 54.

(148) Id. at 51-53.

(149) Id. at 53-55.

(150) Id.

(151) Id. at 55-57.

(152) See supra note 122, at 69-70 (proffering necessity of genetic counselor's analysis). Dr. Goswami suggests that "certain tests should require consultation with a genetic counselor" to augment a physician's understanding of the available genomic data. Id. A genetic counselor aids a physician's assessment by "taking into account family histories and environmental factors--elements that can affect the expression of the gene in question and help reduce errors from penetrance and expressivity-when interpreting [genomic] test results." Id. at 70.

(153) See id. at 49-56 (describing several limitations of genetic diagnostic tests). Dr. Goswami points to three principal concerns regarding genetic diagnostic testing: (1) molecular markers that do not correctly predict the presence of disease allele; (2) mistakes in genetic test interpretation due to genetic and environmental variation; and (3) mistakes in genetic test interpretation due to unforeseen interactions between genes. Id.

(154) Campbell, supra note 28, at 162 (noting that only 1 in 500 people carry BRCA genetic mutations).

(155) See id. (acknowledging that half of women carrying BRCA-1 and BRCA-2 genes develop breast cancer).

(156) See Woodage, supra note 123, at 2 (identifying genomic sequencing as method for cancer risk assessment); Holman, supra note 39, at 302 (explaining link between BRCA mutations and risk of developing breast cancer). See generally Campbell, supra note 28, at 161 (observing that dietary changes can prevent and treat cancer); Rubin Naiman, Healing Night: The Science and Spirit of Sleeping Dreaming, and Awakening 12, 14, 105 (NewMoon Media, 2d. ed. 2006) (discussing link between lack of sleep, immune suppression, and cancer); How Physical Activity Prevents Cancer, CANCER RESEARCH UK, how-physical-activity-prevents-cancer (last updated Mar. 24, 2015) (explaining role of exercise in modulation of hormones involved in cancer growth and development); J.K. Kiecolt-Glaser & R. Glaser, Psychoneuroimmunology And Cancer: Fact Or Fiction?, 35 EUR. J. CANCER 1603, 1603-06 (1999), available at (discussing stress and psychosocial influences on incidence or progression of cancer).

(157) Trim Your Cancer Risk With Exercise, FRED HUTCHINSON CANCER RESEARCH CENTER, (last visited Mar. 30, 2017).

(158) Estefania Toledo et al., Mediterranean Diet and Invasive Breast Cancer Risk Among Women at High Cardiovascular Risk in the PREDIMED Trial, 175 JAMA INTERNAL MED. 1752, 1758 (2015), available at

(159) Id. at 1752.

(160) See Woodage, supra note 123, at 2-3 (highlighting that genetic testing is predictive and not determinative).

(161) Id.

(162) See Colleen McLaughlin et al., Surveillance of Prophylactic Mastectomy: Trends in Use from 1995 Through 2005, 115 CANCER 5404 (2009), available at c&s=8f70cf77e9a700al424ce9027a2382eddac85142.

(163) See Woodage, supra note 123, at 8 (reporting academic and professional communities' concern regarding genetic testing's influence on patients).

(164) Shoshana Rosenberg et al., BRCA1 and BRCA2 Mutation Testing in Young Women With Breast Cancer, 2 JAMA ONCOLOGY 730 (2016), available at

(165) Id.; Esposito, supra note 2.

(166) See FDA Report and Current Regulatory Shortcomings, supra Section 111(A) (examining current regulatory barriers to improving approval of genetic tests); Changes in FDA Regulation of LDTs, supra Section 111(B) (analyzing current FDA initiatives to improve approval process); and Limitations of LDTs to Assess Risk for Multi-factorial Disease, supra Section III(C) (discussing risks inherent to genetic testing that will not be mitigated through regulatory changes).

(167) Jaiman Bhatt & Laurence Klotz, Overtreatment in Cancer--Is It A Problem? 17 expert opinion on Pharmacotherapy no.1, at 1,2-3 (2016), available at

(168) Jorgensen, supra note 17, at 8.

(169) See Bhatt & Klotz, supra note 167 (providing examples of over diagnosis).

(170) Isaac Kohane at al., The Incidentalome: A Threat to Genomic Mediane, 296 JAMA 212, 214 (2006).

(171) See generally Bhatt & Klotz, supra note 167 (discussing how benefit seemingly outweighs risk).

(172) Eva Mazzotti et al., Patient perception of disease control and psychological distress, 4 CANCER MANAG. res. 335 (2012), available at (discussing how patient knowledge of disease can affect success of treatment).

(173) Laura Esserman et al., Overdiagnosis and Overtreatment in Cancer: An Opportunity for Improvement, 310 JAMA 797 (2013); available at

(174) Bhatt & Klotz, supra note 167.

(175) Id. at 3. The research in the study notes that while cells mutate to become cancer cells, the mutations may equally be the reason why cancer spontaneously recedes. Id. at 2.

(176) See id. at 2-3 (discussing cancer as varied pathologic entities); Esserman et al., supra note 173, at 4 (discussing the range of indolent, slow growing, or invasive masses and the potential for regression); Per-Henrik Zahl et al., Natural History of Breast Cancers Detected in the Swedish Mammography Screening Programme: A Cohort Study, 12 LANCET ONCOLOGY 1118 (2011) (finding spontaneous regression of invasive breast cancer). Spontaneous regression refers to the "partial or complete disappearance of a malignant tumor in the absence of treatment or in the presence of therapy considered inadequate to exert a significant influence on the disease." Tilden C. Emerson, M.D. & Warren H. Cole, M.D., Spontaneous Regression of Cancer: Preliminary Report, 144 ANNALS OF SURGERY 366,366 (1956), available at The authors do not suggest that spontaneous regression requires a complete disappearance of tumor cells or ultimate cure of cancer, and noted that the most difficult aspect of spontaneous regression is being able to document its existence. See id. at 378-379 (discussing several factors influencing spontaneous regression that lend to its complexity for documentation).

(177) Esserman et al, supra note 131, at 9; see also Dana-Farber to Study Ways to Reduce Overtreatment of DCIS, Dana-Farber Cancer Institute (Feb. 5, 2016), available at:

(178) Esserman et al., supra note 173, at 7.

(179) Id.

(180) Id. at 3; Welch, supra note 12, at 58-59.

(181) Rosenberg, supra note 164.

(182) Esserman et al., supra note 173; Welch, supra note 14; Rosenberg, supra note 164.

(183) Jorgensen, supra note 17; Peter Gotzsche & Karsten J uhl Jorgensen, Screening for Breast Cancer with Mammography, COCHRANE DATABASE SYS. REV., no. 6, 2013, at 2, available at Mammography is the use of x-ray imaging to look for cancer before a lump can be felt so that cancer can be detected and treated earlier, when the chance of a cure is higher. Gotzsche & Jorgensen, supra, at 2. Although bias seems to identify and favor mammography screenings for women to identify breast cancer, the authors suggest that overtreatment and overdiagnosis as a result of mammography are masked pitfalls that are inherent to the use of mammography for breast cancer screening. Id. at 13.

(184) Jorgensen, supra note 17, at 14; Gotzsche & Jorgensen, supra note 183.

(185) Jorgensen, supra note 17, at 4-5, 15-16.

(186) Id. at 13-14.

(187) Id. at 14. Jorgensen discussed campaigns of advertisements both in the UK ("Screening Saves Uves") and in the U.S., where a poster from the American Cancer Society stated, "If you haven't had a mammogram, you need more than your breasts examined." Jorgensen, supra note 17, at 13.

(188) See Jorgensen, supra note 17, at 24 (describing industry influences on physicians). See also Angela Raffle & JA Muir Gray, SCREENING: EVIDENCE AND PRACTICE, Oxford University Press, Oxford, 2007.

(189) See generally Lowell E. Schnipper and Gregory A. Abel, Direct-to-Consumer Drug Advertising in Oncology Is Not Beneficial to Patients or Public Health, 2 JAMA ONCOL. 1397 (2016) (increasing risk of patient misunderstanding and misinformation will lead to reduced quality patient care).

(190) See Jorgensen, supra note 17, at 1 (testing sensitivity has increased the number of women diagnosed with breast cancer). New diagnosis of patients that would not have been detected previously within the patient's lifetime results in unnecessary treatment and increased life-long physical and psychological harm that would not traditionally occur without genetic testing. Id.

(191) See id. at 9; Zahl et al, supra note 176; Mette Kalager, Regression of Screening Detected Breast Cancer, 12 LANCET ONCOLOGY 1083 (2011) (discussing causes of overdiagnosis in breast cancer screening).

(192) See Jorgensen, supra note 17, at 9.

(193) See generally Kohane et al., supra note 170 (discussing implications of genomic testing).

(194) See Mei-Sing One & Kenneth Mandl, National Expenditure for False-Positive Mammograms And Breast Cancer Overdiagnosis Estimated $4 Billion A Year, 34 HEALTH AFFAIRS 576 (2015) (discussing the cumulative false positive rate over ten years as 61%); Jorgensen, supra note 17, at 8-9 (discussing the five country meta-analysis finding 52% rate of overdiagnosis).

(195) See generally Sandhya Pruthi et al., Identification and Management of Women With BRCA Mutations or Hereditary Predisposition for Breast and Ovarian Cancer, 85 MAYO CLIN. PROC. 1111 (Dec. 2010) (discussing the role of genetic consultation and BRCA testing).

(196) See Bhatt & Klotz, supra note 169, at 3 (discussing defensive medicine); Hannah Hoag, Marked Progress, 527 NATURE S115 (Nov. 19, 2015) (discussing surgeon's recommendation for mastectomy following patient's diagnosis of DCIS as example of aggressive medicine); Sioban O'Connor, Why Doctors Are Rethinking Breast Cancer Treatment, TIME MAGAZINE (Oct. 12, 2015) (discussing aggressive interventions and defensive medicine); Esserman et al., supra note 173, at 797-98 (recommending amending guidelines to recognize that active surveillance of DCIS constitutes appropriate standard of care). But see generally Kennedy v. United States, 750 F.Supp. 206 (W.D. La. 2006). (considering whether physician breached duty of care in referring patient for mammogram rather than biopsy).

(197) See O'Connor, supra note 196 (calling medical community to redefine "doing nothing"). Aggressive treatment may not be the proper treatment plan for all patients, and sometimes passive treatment serves the patient more appropriately. Id.

(198) Id.

(199) Id. (less aggressive treatments allow patients to wait for a definitive cancer diagnosis before initiating treatment). a recent study has shown that a less toxic form of chemotherapy is available. Brenda Goodman, Less Toxic Treatment for Aggressive Breast Cancers?' WEBMD HEALTH NEWS (Oct. 5, 2011), -aggressive-breast-cancers#l. The chemotherapy regimen involves the use of one medication as treatment rather than the standard multi-chemical components in typical chemotherapy treatments. Id. The new treatment, intended to have a lighter affect on the heart, can be offered as an alternative to a mastectomy in women who tested positive for proteins that stimulate the growth of cancer cells. Id.

(200) Id. The article notes that most women feel healthy when they are initially diagnosed. Id. Women diagnosed from the ages 55 to 64 may not be aware of their own mortality but their diagnosis will ultimately bring thoughts of mortality. Id. Some women describe a sense of shock, dizziness, and found themselves unable to concentrate after their diagnosis. O'Connor, supra note 196. Katz stated many patients find it difficult to rationalize how healthy they feel with their cancer diagnosis. Id.

(201) Id. (describing patient's deference to physician treatment plans as a natural instinct).

(202) Id. (noting new technology helping doctors determine whether a patient will respond to chemotherapy).

(203) O'Connor, supra note 196 (discussing many professional concerns for the minimal evidence that supports active surveillance).

(204) Id. (personalizing screening or annual screens changes treatment options).

(205) Bhatt & Kotz, supra note 169, at 3.

(206) See Ovarian Cancer Screening Method F ails to Reduce Deaths from the Disease, NAT'L CANCER INST. (July 27, 2011) See also Jose A Rauh-Hain et al., Ovarian Cancer Screening and Early Detection in the General Population, NCBI.COM (2011) (explaining approaches to screening methods for ovarian cancer). Common screening methods for ovarian cancer include ultrasounds and cancer antigen 125, as well as combining these methods to create greater specificity. Id.

(207) Mary Barton & Kenneth Linn, Screening for Ovarian Cancer. Evidence Update for the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement, U.S. PREVENTIVE SERVICES TASK FORCE (Apr. 2012), ovarian-cancer-screening.

(208) See Understanding CA-125 levels: A Guide for Ovarian Cancer Patients, FOUND. FOR WOMEN'S CANCER 5 (2011), content/uploads/CA1251evels.pdf (stating that the CA-125 test is unreliable for detecting ovarian cancer); see also supra note 194 and accompanying text (providing more statistics surrounding cancer screening).

(209) Saundra S. Buys et al., Effect of Screening on Ovarian Cancer Mortality: The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomised Controlled Trial, 305 JAMA 2295, 2300 (2011).

(210) Sun et al., supra note 61, at 9 (concluding that BRCA dysfunction status may indicate better patient outcomes). The American Cancer Society recognizes the impact of cancer on a patient's emotional health on patients. Anxiety, Tear, and Depression: Having cancer affects your emotional health, AMERICAN CANCER SOCIETY (last update May 24, 2016), These psychosocial factors often influence a patient's physical health, leading to potentially harmful effects in the future. See INST. OF MED., CANCER CARE FOR THE WHOLE PATIENT: MEETING PSYCHOSOCIAL HEALTH NEEDS 5 (Nancy E. Adler and Ann E. K. Page eds., 2008), available at

(211) See Allison Kurian & James Ford, Multigene Panel Testing in Oncology Practice: How Should We Respond?, 1 JAMA ONCOLOGY 277 (2015) (discussing the impact of over-testing on a patients' nerves). Studies have shown the significance of incorporating psychosocial health care into cancer treatment in order to address patients' concerns and anxieties. See INST. OF MED., supra note 210, at 9. Improvement in patient-provider communication plays a significant role in the patient's understanding of his/her illness and the ease and comfort with which he/she makes decisions regarding treatment strategy. Id. at 159.

(212) See generally Michael G. Muto, M.D., Risk-Reducing Bilateral Salpingo-Oophorectomy in Women at High Risk of Epithelial Ovarian and Fallopian Tubal Cancer, UPTODATE (2015), at-high-risk-of-epithelial-ovarian-and-fallopian-tubal-cancer; BRCA1 and BRCA2: Cancer Risk and Genetic Testing, NATIONAL CANCER INSTITUTE (Apr. 1, 2015) causes-prevendon/genetics/brca-fact-sheet#ql2 (discussing options for managing cancer risk in patients with positive BRAC1 and BRCA2 test results).

(213) Muto, supra note 212 (analyzing potential increased cancer risk of hormonal treatments for bilateral salpingo-oophorectomy induced premature menopause).

(214) Id.

(215) Murray, supra note 19, at 563-65 (discussing the development of jurisprudence relating to a physician's duties of informed consent); see also Brown v. Dibbell, 595 N.W.2d 358, 366 (Wis. 1999) (discussing Wisconsin's informed consent statute and the physicians' duties of disclosure); Bradley v. Sugarbaker, 809 F.3d 8, 16 (1st Cir. 2015) (discussing Massachusetts statutory requirements for informed consent related to a medical intervention); Figueroa v. Bieniewicz, 23 N.Y.S.3d 369, 372 (N.Y. 2016) (discussing standard for disclosing risks, benefits, and alternatives required under New York's informed consent statute).

(216) See generally Murray, supra note, at 564 (summarizing cases that have helped to establish the definition and standards governing informed consent).

(217) Canterbury v. Spence, 464 F2d 772 (D.C. Cir. 1972).

(218) Murray, supra note 19, at 564-65 (discussing informed consent requirements in different jurisdictions).

(219) Id. at 563.

(220) See Arato v. Avendon, 23 Cal.Rptr.2d 131, 142-44 (1993) (reckoning disclosure to include any information material to patient's decision).

(221) Canterbury, 464 F.2d at 778.

(222) Arato, 23 Cal.Rptr.2d at 137.

(223) Id. See also Brown, 595 N.W.2d at 364 (discussing Plaintiffs desire to understand the risk reduction from mastectomy and risks from implant reconstruction).

(224) Arato, 23 Cal.Rptr.2d at 143.

(225) See Esserman, supra note 173 (recognizing the importance of open conversations between doctors and patients).

(226) See Esserman, supra note 173. See also Peter Angelos, M.D., Ph.D., Prophylactic Mastectomy: Challenging Considerations for the Surgeon (April 19, 2016) (unpublished manuscript) (on file with the Department of Health and Human Sendees).

(227) Id.

(228) Id.; Murray, supra note 19, at 564; Brown, 595 N.W.2d at 363.

(229) Murray, supra note 19, at 564; Brown, 595 N.W.2d at 363.

(230) Murray, supra note 19, at 564.

(231) See Brown, 595 N.W.2d at 362-64; 370-72 (listing facts and stating holding of case). Although Brown's holding may be jurisdictionally limited, the facts are instructive for cases assessing issues that arise during the course of physician patient interaction related to investigating a possibility of cancer and subsequent medical interventions. Id.

(232) See id. at 364 (stating reason for filing of malpractice suit by Brown).

(233) See id. at 363-364 (describing why Brown sought medical attention based on family history of breast cancer).

(234) See Brown, 595 N.W.2d at 363 (explaining patient's risk of breast cancer and discussing treatment options). Plaintiff and Defendant's factual accounts differ. Id. Plaintiff testified that Defendants informed her they could not tell whether the lump was breast cancer because she had implants, but that she was in the high-risk category for developing cancer. Id. at 363. Defendants testified they told Plaintiff there was no evidence of cancer, but her two treatment options were to repeat a mammogram in six months or undergo mastectomy. Id.

(235) See id. at 364, 366 (discussing plaintiff allegations that doctors violated duties under Wisconsin state law). See also WIS. STAT. [section] 448.30 (2017) (creating guidelines for obtaining informed consent from patients).

(236) See Brown, 595 N.W.2d at 363 (discussing doctor's consultation with plaintiff). Dr. Dibbell explained to Brown that the lump she felt was simply part of her implant. Id.

(237) See id. at 363 (finding that examination was inconclusive and suggesting mastectomy as option for Brown).

(238) See id. at 364 (discussing plaintiffs allegation that doctor provided insufficient risk information relevant to her decision making).

(239) See generally Brown v. Dibbell, 595 N.W.2d 358 (1999) (examining whether defendants violated informed consent statute and discussing whether plaintiff was negligent).

(240) See id. at 363-364, 366-370 (discussing whether plaintiff was contributorily negligent).

(241) Id. at 369.

(242) Id. at 370.

(243) See id. at 368 (stating it would be unusual to find patient contributorily negligent when plaintiff relies on doctor).

(244) See id. at 366 (discussing how doctrine of informed consent focuses on reasonableness of a doctor's disclosure). See also Canterbury, 464 F.2d at 786 (discussing the scope of a doctor's duty to disclose).

(245) See generally Brown v. Dibbell, 595 N.W.2d 358 (1999) (discussing extent of a doctor's duty to disclose).

(246) See Brown, 595 N.W.2d at 362 (concluding patient's right to rely on doctor's skills and knowledge does not preclude contributory negligence).

(247) See id. at 371 (clarifying information a doctor must disclose to a patient).

(248) See id. at 366 (clarifying standard regarding what doctors must disclose as the "prudent patient standard"). According to this standard, a doctor must provide information "that a reasonable person in the patient's position would want to know" in making an informed medical decision. Id.

(249) See id. (discussing what constitutes a sufficient level of communication regarding medical risk).

(250) See id. (discussing physician responsibilities of informing patients of risk and ensuring their understanding of that risk).

(251) See generally Gerd Gigerenzer et al, Helping Doctors and Patients Make Sense of Health Statistics, 8 PSYCHOL. SCLIN the PUB. INT. 53 (2008) (discussing statistical illiteracy in the context of health statistics); Sunil Kripalani et al., Health literacy and the Quality of Physician-Patient Communication during Hospitalization, 5 J. HOSP. MED. 269 (May 2010) (discussing consequences of poor physician-patient communication during hospitalization).

(252) See Amy Finch et al, Breast and Ovarian Cancer Risk Perception After Prophylactic Salpingo-Oophorectomy Due to An Inherited Mutation In the BRCA1 or BRCA2 Gene, 75 CLINICAL GENETICS 220 (2009) (discussing shifts in perceived risk of cancer before and after preventative salpingo-oophorectomies).

(253) See id. (discussing skewed perceptions of cancer risk and risk reduction in the patient population).

(254) Id. at 222.

(255) See infra, Section VI (examining different risk reduction methods and their derived benefits).

(256) Id. Finch and colleagues found the residual risk of peritoneal cancer is approximately 4.3% over twenty years. Finch et al., supra note 252, at 223 (discussing perceived cancer risks as it related to prophylactic salpingo-oophorectomies).

(257) Erin Burke, Pamela R. Portschy & Todd M. Tuttle, Prophylactic Mastectomy: Who Needs It, When and Why, 111 J. OF SURGICAL ONCOLOGY 91, 91 (2015) (discussing the different circumstance in which a person may need a prophylactic mastectomy).

(258) Id.

(259) Id.

(260) Id. Additionally, Burke's study suggests that having initial discussions at the outset of treatment about prophylactic mastectomies provides patients with more accurate information and betters the patients' risk assessment skills. Id.

(261) Id. at 94-95. The conclusions of this study discuss patient satisfaction in conjunction with patient overestimation of their personal cancer risk. Burke, supra note 257, at 94-95. While the two phenomenons were not explicidy linked there is an implicit connection between misunderstanding risk and patient dissatisfaction. Id.

(262) See supra note 251 and accompanying text (discussing the lack of statistical literacy in general patient populations).

(263) See supra note 183 and accompanying text (discussing the unnecessary treatment of certain patients).

(264) See Hormone Therapy for Breast Cancer, NAT'L CANCER INST., (last visited Jun. 20, 2017) (providing resources related to breast cancer and hormone therapy).

(265) See AstraZeneca, Nolvadex Drug Label, FDA (Aug. 27, 2004), (last visited Jun. 20, 2017) (discussing Nolvadex's risks and benefits through scientific study).

(266) Id. See Bhatt supra note 167 (discussing defensive cancer treatment options).

(267) Breast Cancer Chemoprevention: Medicines That Reduce Breast Cancer Risk, MAYO CLINIC (Oct. 26, 2016), http://www. (discussing medications that decrease breast cancer risks); Medianes to Reduce Breast Cancer Risk, AMERICAN CANCER SOCIETY (Oct. 21, 2014), (discussing factors that patients should consider in preventative cancer treatment). See generally D. Lawrence Wickerham, Breast Cancer Chemoprevention: Progress and Controversy, 19(3) surgical oncology clinics of N. America 463 (July 2010) (discussing current industry controversy surrounding chemoprevention in the medical field).

(268) See Mitchell Gail et al., Weighing the Risks and Benefits of Tamoxifen Treatment for Preventing Breast Cancer, 91 (21) J. OF THE NAT'L CANCER INST. 1829 (Nov. 3, 1999) (quoting a 49% risk reduction). But see Medicines to Reduce Breast Cancer Risk, supra note 267 (quoting a 13-48% risk reduction and concluding the evidence supports an average 38% risk reduction).

(269) Id.; Medicines to Reduce Breast Cancer Risk, AMERICAN CANCER SOCIETY (2014), available at / groups/cid/documents/webcontent/002585-pdf.

(270) See Mitchell Gail et al., Weighing the Risks and Benefits of Tamoxifen Treatment for Preventing Breast Cancer, 91 J. of THE NAT'L CANCER INST. 1829,1831 (Nov. 3, 1999) (discussing risk reductions amongst patients with a BRAC2 variant).

(271) See supra Part V section D (discussing statistical literacy and distorted perceptions of risk).

(272) Visvanathan et al., supra note 17.

(273) Id.

(274) Id. at 2942, 2959.

(275) FDA Report, supra note 6, at 14.

(276) Judy Peres, Chemoprevention a hard sell but breast cancer experts believe it doesn't have to be, THE CHICAGO TRIBUNE, Sept. 24, 2014,

(277) Id.

(278) Id.

(279) Wickerham, supra note 267, at 8.

(280) Visvanathan et al., supra note 17, at 18.

(281) Wickerham, supra note 267, at 1.

(282) pereS; supra note 40.

(283) See Wickerham, supra note 267, at 1.

(284) See INST, OF MED., ET AL., CONFLICT OF INTEREST IN MEDICAL RESEARCH, EDUCATION, AND PRACTICE 189-215 (Bernard Lo & Marilyn J. Field eds., 2009) (ebook), available at (discussing how many societies receive significant funding from the industry).

(285) See generally Mitchell Gail et al., Weighing up risks and benefits, BMJ, available at http://clinicalevidence.bmj.eom/x/set/static/ebm/practice/807268.html (last updated July 10, 2015) (explaining risks and benefits of tamoxifen treatment for breast cancer).

(286) Nolvadex, supra note 265, at 26-29.

(287) See Corby v. Unum Life Ins. Co. of Am., No. 09-5890 WHA, 2010 WL 3768040 (N.D. Cal. 2010) (discussing termination of disability benefits where plaintiff alleged debilitating fatigue and depression from using tamoxifen); Oliver v. Colvin, No. 12-cv-00400-wmc, 2014 WL 941820 (W.D. Wise. 2014) (ruling upon appeal where plaintiff alleged tamoxifen use caused hot flashes, fatigue, and depression); BeUer v. Astrue, No. 12-cv-5112(VB), 2013 WL 2452168 (S.D.N.Y. 2013) (reviewing disability ruling where plaintiff alleged hot flashes, hair loss, numbness and myalgia from tamoxifen). See also Consumer Updates, Depression: FDA-Approved Medications May Help, FDA (Jan. 9, 2009), available at (explaining major side effects attached to FDA approved depression medications).

(288) Corby, 2010 WL 3768040, at *2.

(289) Effexor XR, RXLIST, (last updated Dec. 22, 2015). An estimated 30% of patients taking tamoxifen who experience depression are also prescribed antidepressant drugs. Id. Antidepressants and Tamoxifen, HARVARD HEALTH PUBLICATIONS, (June 2010), These patients would also likely not find support for a disability claim for the duration of their treatment. Id. Treatment on tamoxifen generally lasts five years, but some policies cap disability insurance for mental illness at twenty-four months. Id.

(290) See cases cited supra note 287 and accompanying text (discussing debilitating impact of depression as a prominent side effect).

(291) Id.

(292) Nolvadex, supra note 265, at 8, 11-13.

(293) Letter from Joseph Purvis, MD, Senior Medical Director of AstraZeneca to All Prescribing Physicians regarding Boxed Warning for Safety Alert of Human Medical Products (May 15, 2002), available at ... /UCM171067.pdf.

(294) Common Cancer Treatments Toxic to Healthy Brain Cells, UNIVERSITY OF ROCHESTER MEDICAL CENTER NEWS (Nov. 30, 2006), commoncancer-treatments-toxic-to-healthy-brain-cells.aspx; Researchers Detail Chemotherapy's Damage to the Brain, UNIVERSITY OI; ROCHESTER MEDICAL CENTER NEWS (Apr. 22, 2008), to-the-brain.aspx; Mental Fog with Tamoxifen is Real; Scientists Find Possible Antidote, UNIVERSITY OF ROCHESTER MEDICAL CENTER NEWS (Sept. 17, 2013),

(295) Mental Fog with Tamoxifen is Real, supra note 294.

(296) Id.

(297) Researchers Detail Chemotherapy's Damage to the Brain, supra note 294; Mental Fog with Tamoxifen is Real; Sdentists Find Possible Antidote, supra note 294.

(298) Id.

(299) Common Cancer Treatments Toxic to Healthy Brain Cells, supra note 294.

(300) Side Effects of Tamoxifen, SUSAN G. KOMEN, (May 12, 2016),; Tamoxifen (Oral Route): Side Effects, MAYO CLINIC (March 1, 2017), / tamoxifen-oral-route/side-effects/drg-20066208.

(301) Hope S. Rugo et. al., Endocrine Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Soaety of Clinical Oncology Guideline, 34(25) J. CLINICAL ONCOLOGY (Sept. 1, 2016), available at

(302) See Allen Hackshaw et. al., Ijing-Term Benefits of 5 Years of Tamoxifen: 10-Year Follow-Up of a Large Randomised Trial in Women atEeast 50 Years of Age with Early Breast Cancer, 29(13) J. CLINICAL ONCOLOGY (April 4, 2017), available at (discussing effects of tamoxifin on women with breast cancer during two and five year intervals).

(303) Rugo, supra note 301.

(304) See Surgery to Reduce the Risk of Breast Cancer, NAT'L. CANCER INST. (April 4, 2017), available at (detailing two kinds of surgery available to women at risk of developing breast cancer).

(305) See Burke et al., supra note 257 (citing breast cancer risk reduction arising from preventive mastectomy around 90%).

(306) See generally SUSAN KOLB, THE NAKED TRUTH ABOUT BREAST IMPLANTS: FROM HARM TO HEALING, CONDENSED VERSION (April 4, 2017), available at susan-kolb-on-silicone.pdf (discussing toxic effects of rupture or leakage of silicone from implants on patients). Health risks from implants discussed in the Kolb article pertain to implants as a class of medical devices because saline implants are encased in shell containing silicone. Id. See also Michelle Castillo, More Women Choosing Breast Reconstruction After Mastectomy, CBS news (April 4, 2017), available at -after-mastectomy/ (discussing percentage of patients likely to opt for breast reconstruction). Patients who choose to treat their breast cancer through undergoing a mastectomy have multiple post-treatment options available for them, however, Castillo suggests that perhaps not all patients are receiving the same information as there is lack of uniformity across post-treatment choices among patients. Castillo, supra.

(307) Id. Health risks apply to both silicone and saline implants because they constitute the internal insertion of a foreign body that has the potential to incite an inflammatory immune response. See infra note 333 and accompanying text (discussing why women are opting to use implants rather than existing tissue from their bodies).

(308) Burke et al., supra note 257, at 92.

(309) See Natasha Rueth et al., Preoperative Risk Assessment Among Women Undergoing Bilateral Prophylactic Mastectomy For Cancer Risk Reduction, 18(9) ANNALS OF SURGICAL ONCOLOGY 2515 (Sept. 2011) (detailing importance of cancer risk assessments for women who consider surgery). The majority of women opting to undergo preventive mastectomy choose this option based on genetic risk or family history the majority of the time, but one study showed a sizable minority (19.6%) opted for the surgery based on cancer risk anxiety or personal preference. Id.

(310) See Liz Lostumbo et al., Prophylactic Mastectomy for the Prevention of Breast Cancer, COCHRANE DATABASE OF SYSTEMATIC REV., Nov. 2011, at page 3 (discussing the limitations of current evidence available on the success of prophylactic mastectomies).

(311) Id.

(312) Id. at 16.

(313) See id. at 16-17 (finding women are likely to choose treatment without understanding their diagnosis).

(314) See id. at 17 (placing the responsibility to inform patients primarily with physicians).

(315) Surgery to Reduce the Risk of Breast Cancer, supra note 304.

(316) See id. (describing potential harms of risk-reducing surgeries).

(317) See Risks of Breast Implants, U.S. FOOD & DRUG ADMIN., Breastlmplants/ucm064106.htm (last updated Mar. 21, 2017) (discussing side effects and complications with breast implants).

(318) See id. (describing additional surgical possibilities the longer breast implants are kept in the body).

(319) See id. (noting the possibility of hardened breast tissue and hematoma infections).

(320) See Regulatory History of Breast Implants in the U.S., u.s. food & drug admin., Breastlmplants/ucm064461.htm (last updated Sept. 25, 2013) (describing FDA responses to safety concerns).

(321) Kathy King-Cameron, Carving Another Exception to the I earned Intermediary Doctrine: Application of the learned Intermediary Doctrine in Silicone Breast Implant IJtigation, 68 TUL. L. REV. 937, 960-961 (1994).

(322) See Hopkins v. Dow Corning, 33 F.3d at 1119 (discussing the high rupture rate for Dow implants). Where implants ruptured, Plaintiffs developed connective tissue disease, and the court found manufacturer Dow Corning had known long term safety studies were required but failed to conduct such studies, concealed negative test results, and continued to market and manufacturer the implant product despite these negative study results. See also In re Breast Implant Litigation, 11 F. Supp. 2d at 1227 (noting the scientific publications showing a link between implants and connective-tissue disease). Here, the Plaintiffs claimed immune dysfunction and connective tissue disease, however, the court excluded plaintiff testimony of their symptoms under Daubert standard. Norris v. Baxter Healthcare Corporation, 397 F.3d 878, 886 (10th Cir. 2005). The Plaintiffs alleged local injury from implants and systemic autoimmune disease and the court held physician testimony to show systemic injury was inadmissible. Id. at 883-884.

(323) See Regulatory History of Breast Implants in the U.S., supra note 320 (stating the history of FDA regulation for breast implants).

(324) Hopkins v. Dow Corning, supra note 322, at 1118.

(325) See id. (finding the record contains ample evidence to support damage awards).

(326) Id. at 1127. Breast implant litigation was eventually consolidated into class action lawsuits and courts began precluding broad categories of evidence under Daubert, which excluded Plaintiff testimony, physician's case reports and clinical evidence, as well as other scientific experts. See In Re Breast Implant Litigation, supra note 322 (citing epidemiological support for risk of connective tissue disease with breast implants).

(327) See Hopkins v. Dow Corning, supra note 322, at 1121 (finding Dow Coming intended to deceive patients about the possibility of breast implant ruptures).

(328) Congressional Report, supra note 14.

(329) Id. at 6-7, 29.

(330) Id. at 35.

(331) Id. at 8.

(332) Id. 15, 20.

(333) See Congressional Report, supra note 17, at 6 (noting concerns about microleakage and migration of silicone to lymphatic system, lungs, spleen, and cancer); id. at 9 (relating increased plastic surgeon reporting of lung and vulvar cancers among breast implant patients); id. at 15 (citing concern about inflammatory reactions and silicone migration); id. (stating FDA's concern about silicone causing autoimmune disorders and potentially fatal diseases).

(334) See U.S. Food & Drug Admin., Silicone Gel-filled Breast Implants, Breastlmplants/ucm063871.htm (last visited Jun. 20, 2017) (omitting references to prior FDA concerns and industry studies about effects of breast implants).

(335) Congressional Report, supra note 17, at 9.

(336) Id. at 9. See id. at 22-24 (observing that FDA request for manufacturer amendments ran contrary to FDA scientists' recommendation to reject). The FDA faced pressure from medical professionals within the industry to minimize disclosure of warnings and potential adverse effects due to breast implants. See id. at 38 (highlighting American Society of Plastic Reconstructive Surgeons' pressure on FDA to mitigate risks). 333 See Congressional Report, supra note 17, at 6 (noting concerns about microleakage and migration of silicone to lymphatic system, lungs, spleen, and cancer); id. at 9 (relating increased plastic surgeon reporting of lung and vulvar cancers among breast implant patients); id. at 15 (citing concern about inflammatory reactions and silicone migration); id. (stating FDA's concern about silicone causing autoimmune disorders and potentially fatal diseases).

(337) See id. at 21-31 (identifying lack of safety data, impact of manufacturing lobby, and disregard for FDA scientists' concern).

(338) See e.g., supra note 317 (burying connective tissue disease reference as seventh informational heading). The FDA states that there is currently no association between silicone breast implants and connective tissue disease, breast cancer, or reproductive problems, but notes that "[i]n order to rule out these and other rare complications, studies would need to be larger and longer than these conducted so far." Id.

(339) NAT'L INST. MED., Information for Women About the Safety of Silicone Breast Implants 6 (National Academies Press, 2000), available at See NAT'L. INST. MED., Safety of Silicone Breast Implants x (National Academies Press, 1999), (stating the committee is unconvinced implants are causally related to severe systemic illnesses); id. at 3 (conceding silicone can induce solid state carcinogenesis in rodents); id. at 4 (noting implants incite surrounding fibrous tissue reaction).

(340) See Congressional Report, supra note 17, at 8-9 (discussing Dow Coming's animal studies); id. at 9 (identifying errors, biases, and methodological limitations in manufacturer studies); id. at 15-17 (explaining Dow internal memoranda related to adverse health reactions in animal models); id. at 24-28 (discussing inadequate, misleading, and inaccurate data and conflicts of interest between industry and FDA).

(341) Risks of Breast Implants, supra note 317.

(342) Arthur Brawer, Bones, Groans, and Silicone, 21 lupus 1155 (2012) (explaining inadequacy of methodology and safety study length for autoimmune disease association); Franco Bassetto et al., Breast Prosthesis and Connective Tissue Disease (CTD): Myth or Reality?, 34 AESTHETIC PLASTIC SURGERY 257, 261 (2010), available at https://link.springer.eom/article/10.1007%2Fs00266-0099422-0 (concluding implants may increase risk of contracture thereby stimulating antibody response and autoimmune disease development); Franco Bassetto et al., The Periprosthetic Capsule and Connective Tissue Disease: A Piece in the Puzzle of Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants, 237 EXPERIMENTAL BIOLOGY AND MED. 1117 (2012) (discussing biological reaction to breast implants as potential trigger for autoimmune disease).

(343) See supra note 342 (providing articles discussing autoimmune response to implants). See also Could breast implants trigger disease?, THE TELEGRAPH (Jan. 8, 2007), (finding protein layers surrounding silicone implants may cause immune reactions).

(344) See Elise Bevan, Number of cancers linked to breast implants increases, PENNINGTONS MANCHES LLP (May 27, 2014), -to-breast-implants-increases/ (pointing out complaints of autoimmune disease after implants).

(345) U.S. FOOD & DRUG ADMIN. ANAPLASTIC LARGE CELL LYMPHOMA (ALCL) IN WOMEN WITH BREAST IMPLANTS: PRELIMINARY FDA FINDINGS AND ANALYSES (Jan. 2011), / Breastlmplants/ucm239996.htm. The FDA emphasizes that their cautionary language is not based information that has been confirmed as statistically certain. Id.

(346) See id. (reporting odds ratio estimate of 18.2 for ALCL in women with breast implants); Patients Considering Breast Implants Need Information on Risk of Very Rare Cancer, AM. SOC'Y' OF PLASTIC SURGEONS, implants-need-information-on-risk-of-very-rare-cancer (identifying a risk 18 times greater in women with implants than women without) (last visited Jun. 20, 2017).

(347) See U.S. FOOD & DRUG ADMIN, supra note 345 (observing that insufficient information exists to confirm causal connection with breast implants); AM. SOC'Y OF PLASTIC SURGEONS, supra note 346 (suggesting most surgeons don't discuss ALCL with patients or report incidents). See also Mark Clemens et al., Breast Implant Informed Consent Should Include the Risk of Anaplastic \Mrge Cell Lymphoma, 137 PLASTIC & RECONSTRUCTIVE SURGERY 1117, 1120 (2016) (asserting informed consent process should disclose risk of ALCL).

(348) Letter from Sidney Wolfe & Michael Carome, Pub. Citizen's Health Research Group, to Margaret Hamburg, Commissioner of Food & Drug Admin., & Jeffrey Shuren, Director of the Center for Devices and Radiological Health, Inaccurate Communications Regarding Risk of Breast Implant-Related Cancer, PUB. CITIZEN (Feb. 17, 2011),,

(349) Id.

(350) Id.

(351) See Breast Implant Associated ALCL, AM. SOC'Y OF PLASTIC SURGEONS, associated-alcl (last visited Jun. 20, 2017) (stating that "risk of association between breast implants and ALCL is extremely low").

(352) See NAT'L CANCER INST., supra note 304 (identifying most common risk-reducing surgery as bilateral prophylactic mastectomy); Steven J. Katz et al., Patient Involvement in Surgery Treatment Decisions for Breast Cancer, 23J. CLINICAL ONCOLOGY 5526, 5527 (2005), available at (noting "Ungering concern about overtreatment and failure to involve women in treatment decisions"); Erin e. Burke et al., Contralateral rophylactic mastectomy: are we overtreating patients, 14 EXPERT REV. OF ANTICANCER THERAPY 491 (2014), available at (questioning basis for 150% increase in preventive mastectomies between 1998 and 2003). Although prior studies "linked objective factors to treatment choice" by women with breast cancer, subjective preferences have also been shown to underlie treatment decisions. E. Dale Collins et al., Can Women with Early-Stage Breast Cancer Make an Informed Decision for Mastectomy, 27 J. CLINICAL ONCOLOGY 519 (2009), available at Multiple studies demonstrate "no significant difference in overall survival among women undergoing mastectomy versus BCS [breast-conserving surgery] plus radiation." Id. According to Lantz et al., medical professionals are concerned as to whether mastectomy is overused when equally effective alternative treatments exist. Paula M. Lantz et al., Is Mastectomy Overused? A Call for An Expanded Research Agenda, 37 HEALTH SERVS. RESEARCH 417, 419 (2002), available at http://onlinelibrary.wiley.eom/doi/10.1111/1475-6773.030/epdf.

(353) See Anxiety, Tear, and Depression, Having cancer affects your emotional health, AM. CANCER SOC'Y (May 24, 2016), anxiety-fear-depression.html (identifying anxiety, fear, panic attacks, and depression as common emotional impact of cancer diagnosis).

(354) See Katz, supra note 352 (noting "persistent trend" in mastectomy treatment for early-stage breast cancer); Breast Reconstruction with Implants, MAYO CLINIC (Nov. 24, 2016), (citing multiple risks associated with breast implant reconstruction). The Mayo Clime identifies numerous risks incident to breast implant reconstruction which may require additional surgery to correct complications such as: (1) breasts that don't match each other in size or appearance (asymmetry); (2) breast pain; (3) implant rupture or deflation; (4) poor healing of incisions; (5) increased risk of future breast surgery to replace or remove the breast implant; (6) changes in breast sensation; (7) infection; (8) bleeding; (9) scar tissue that forms and compresses the implant and breast tissue into a hard, unnatural shape (capsular contracture); (10) risks associated with anesthesia; and (10) very low, but increased risk of a rare immune system cancer called anaplastic large cell lymphoma (ALCL), though more research is needed to understand the relationship between ALCL and breast implants. MAYO CLINIC,, supra note 354 (outlining risks associated with breast reconstruction with implants).

(355) See supra notes 345-346 and accompanying text (discussing FDA's cautionary language for HRT). See Diana Zuckerman et al., What you need to know about breast implants, what-you-need-to-know-about-breast-implants/ (last visited Jun. 20, 2017) (citing research showing some symptoms of women with breast implants can be from autoimmune diseases).

(356) See Breast Implant Research and Information Act, H.R. 1961, 107th Congress (2001-2002), available at /text (explaining purpose of legislation to identify and evaluate health effects of breast implants) (last visited Jun. 20, 2017).

(357) See NAT'L CANCER INST., supra note 304 (identifying bilateral prophylactic salpingo-oophorectomy as alternative risk-reducing surgery); Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment (PDQ[R])--Health Professional Version, NAT'L CANCER INST., (recommending prophylactic oophorectomy for increased risk of ovarian cancer after age 35 and childbearing) (last updated Jan. 5, 2017); Amy Finch et al, Salpingo-Oophorectomy and the Risk of Ovarian, Fallopian Tube, and Peritoneal Cancers In Women With a BRCA 1 or BRCA2 Mutation, 292 JAMA 185, 185 (2006), (observing that "[wjomen with BRCA1 or BRCA2 mutation[s] are often advised to undergo preventive oophorectomy").

(358) See NAT'L CANCER INST., supra note 304 (reasoning a reduction in estrogen will slow the growth for some breast cancers).

(359) Prophylactic Oophorectomy: Preventing Cancer by Surgically Removing Your Ovaries, MAYO CUNIC (Apr. 14, 2014), (cautioning the risks associated with surgery may not be worth the reduction in cancer risk).

(360) See id. (computing oophorectomy's effectiveness in reducing cancer risks).

(361) See id. (characterizing oophorectomy as a safe procedure). See also Timothy Rebbeck et al., Meta-Analysis Of Risk Reduction Estimates Assoaated With Risk-Reducing Salpingo-Oophorectomy In BRCA1 Or BRCA2 Mutation Carriers, 101(2) J. NAT'L CANCER INST. 80 (2009) (concluding risk-reducing salpingo-oophorectomy "strongly associated" with reduction in breast, ovarian, and fallopian cancer); Jonathan Berek et al., Prophylactic and Risk-Reducing Bilateral Salpingo-oophorectomy: Recommendations Based on Risk of Ovarian Cancer, 116 (3) OBSTETRICS & GYNECOLOGY 733, 741 (2010) (discussing preventative methods for ovarian cancer). See also SGO Clinical Practice Statement: Salpingectomy for Ovarian Cancer Prevention, SOCIETY OF GYNECOLOGIC ONCOLOGY (Nov. 2013), sgo-clinical-practice-statementsalpingectomy-for-ovarian-cancer-prevention/(appropriating salpingectomy for ovarian cancer risk reduction).

(362) See Kate Blackburn, Large Study Shows Preventive Ovarian Surgery in BRCA 1 Mutation Carriers Should Be Performed Early for Greatest Benefit, AMERICAN SOCIETY OF CLINICAL ONCOLOGY (Feb. 24, 2014), -surgery-brcal-mutation (advocating for ovarian surgery sooner rather than later).

(363) See id. (reasoning the "striking data" evidences necessity for early prophylactic oophorectomy surgery).

(364) See id. (highlighting the overall benefits for prophylactic oophorectomy surgery).

(365) See Women with BRCA mutations can take hormone-replacement therapy safely after ovary removal, U. OF PA. PERELMAN SCHOOL OF MED. (June 1, 2011), (quoting study author Dr. Susan Domcheck). See also Linda Carroll, Ovary Removal by Age 35 to Reduce Cancer Risk?, FRED HUTCHINSON CANCER RESEARCH CTR. (Feb. 26, 2014), https: // (inquiring whether ovary removal reduces cancer risks).

(366) See Kate Miller, Hormone Replacement Therapy in the Wake of the Women's Health Initiative Study: An Opportunity to Re-Examine the Learned Intermediary Doctrine, 12 WILLIAM AND MARYJ. WOMEN AND L. 239, 242-44 (2005) (requiring manufacturer of hormone replacements to warn consumers of known dangers).

(367) See id. at 243 (describing Premarin to fix women's physical side effects from menopause).

(368) Id. (providing an effective marketing campaign for hormone replacement therapy). See also Jay Shulkin, Hormone Therapy, Medical Dilemmas, Medical Decisions, 36 J. L. MED. & ETHICS 73, 81 (2008) (discussing Wyeth's advertising of HRT).

(369) See Miller, supra note 366, at 243 (stating Wyeth's marketing campaign lasted for five years).

(370) See id. (implying that Premarin marketing campaign paved a path for FDA's approval of Prempro for Wyeth).

(371) Claudia Marchetti et al., Hormone therapy in oophorectomi%ed BRCA 1 /2 mutation carriers, 21 (7) Menopause: THE J. OF THE NORTH AM. MENOPAUSE SOC'Y, 763, 765 (2014) (stating HRT constitutes the gold standard to treat menopausal symptoms, including women with BRCA mutations).

(372) Nicole Birrer et al., Is Hormone Replacement Therapy Safe Tor Women With a BRCA Mutation?, AM. J. OF CLINICAL ONCOLOGY 1, 2 (2016) (deducing HRT's benefits without an increase in breast cancer).

(373) Women with BRCA mutations can take hormone-replacement therapy safely after ovary removal\ supra note 365 (advocating women with BRCA1/2 mutations have ovaries removed after bearing children).

(374) Id. See also Marchetti et al., supra note 371, at 764 (stating bilateral prophylactic salpingooophorectomy significantly reduces breast cancer risks).

(375) Timothy R. Rebbeck et al., Effect of Short-Term Hormone Replacement Therapy on Breast Cancer Risk Reduction After Bilateral Prophylactic Oophorectomy in BRCA 1 and BRCA2 Mutation Carriers: The PROSE Study Group, 23(31) J. OF CLINICAL ONCOLOGY, 7804, 7807 (2005). See also C.A. Gabriel et al., Use Of total abdominal hysterectomy and hormone replacement therapy in BRCA 1 and BRCA2 mutation carriers undergoing risk-reducing salpingo-oophorectomy, 8 FAMILIAL CANCER 23, 26 (2009) (suggesting HRT reduces the risk of breast cancer).

(376) See Rebbeck, supra note 375, at 7805 (stating no significant increase in risk of cancer after HRT).

(377) Prophylactic oophorectomy: Preventing cancer by surgically removingyour ovaries, supra note 359 (explaining risks associated with surgery).

(378) Id.

(379) See Lynne T. Schuster et al., Prophylactic bilateral oophorectomyjeopardises long-term health, 18 Menopausal Medicine S1 (Oct. 2010) (elaborating on such risks); Lynne T. Schuster et al., Prophylactic oophorectomy in pre-menopausal women and long term health, 14 MENOPAUSE INTERNATIONAL 111, 114 (Sept. 2008) (discussing such risks).

(380) See supra note 379 and accompanying text (weighing the risk of surgery and its potential outcomes before and after menopause).

(381) See Ellen J. Sullivan, Women with BRCA 1 Mutations May Still Be at Risk for Rare Types of Uterine Cancer After Preventive Surgery to Remove Ovaries, Tallopian Tubes, SOCIETY OF GYNECOLOGIC ONCOLOGY (Mar. 24, 2014), brcal-mutations-may-still-be-at-risk-for-rare-types-of-uterine-cancer-after-preventive-surgery/ (discussing increased risk of uterine cancer after salpingo-oophorectomy).

(382) See Charlotte Bath, 'Reasonable, But Not Required for Women With BRCA Mutations to Have Hysterectomy Concurrent With Salpingo-Oophorectomy, AMERICAN SOCIETY OF CLINICAL ONCOLOGY (Dec. 1, 2013), -mutations-to-have-hysterectomy-concurrent-with-salpingo oophorectomy/ (evaluating risk of uterine cancer in women with BRCAl mutation); Roxanne Nelson, BRCA1 linked to Higher Risk for Aggressive Uterine Cancer, MEDSCAPE (Mar. 25, 2014) (explaining advantages and disadvantages of undergoing a hysterectomy).

(383) See Birrer et al, supra note 372 (advocating use of estrogen drugs as part of post hysterectomy treatment).

(384) Abdominal Hysterectomy Risks, MAYO CLINIC (Jan. 23, 2016), abdominal-hysterectomy/details/risks/cmc-20178861 (enumerating risks associated with hysterectomy)

(385) See William H. Parker, M.D., Bilateral oophorectomy: Solving the risk/benefit equation--Choosing candidates, monitoring outcomes, CONTEMPORARY OB/GYN (Jul. 1, 2011), obgyn/news/modernmedicine/modern-medicine-now/bilateral-oophorectomy-solving riskbenefi?page=full (discussing risks of preventive surgery).

(386) See Gina Kolata, Hormone Studies: What Went Wrong? N.Y. TIMES (Apr. 22, 2003), http://www.nytimes.eom/2003/04/22/science/hormone-studies-what-went-wrong.html (detailing Women's Health Initiative's decision to stop using HRT drugs).

(387) Questions and Answers for Estrogen and Estrogen and Progestin Therapies for Post-Menopausal Women, FDA, (last updated April 13, 2016). The FDA confirms that estrogen and estrogen with progestin drug products are still the most effective treatment for providing women relief from hot flashes and other symptoms of menopause. Id.

(388) Id.

(389) See e.g., About Women's Health Initiative, WOMEN'S HEALTH INITIATIVE, (last visited Jun. 20, 2017) (discussing various studies conducted by WHI and their respective outcomes); Press Release, NIH Asks Participants in Women's Health Initiative Estrogen-Alone Study to Stop Study Pills, Begin Follow-up Phase, NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (March 2, 2004), nih-asks-participants-in-womens-healthinitiative-estrogen-alone-study-to-stop-study-pills-begin-follow-up-phase (instructing patients to cease use of estrogen medication due to increased risk of stroke); NH1.BI Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk, Lack of Overall Benefit, NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (July 9, 2002), releases/2002/nhlbi-stops-trial-of-estrogen-plus-progestin-due-to-increased-breast-cancer-risk lack-of-overall-benefit (reporting on WHI investigation into estrogen plus progestin studies).

(390) See Wyeth v. Roivatt, supra note 17, 771-772 (discussing the history of Wyeth's interaction with the FDA during the approval for Prempro).

(391) See supra note 389 and accompanying text (examining various studies performed on effects of estrogen and progestin).

(392) NHLBI Stops Trial of Estrogen Plus Progestin, supra note 389.

(393) Id.

(394) Menopausal Hormone Therapy and Cancer, NATIONAL CANCER INSTITUTE, (last updated Dec. 5, 2011).

(395) Id.

(396) Id.

(397) Id.

(398) Premarin, WYETH PHARMACEUTICALS, INC. 8, /004782sl62sl 64sl67Ibl.pdf (last updated Jun. 2011).

(399) Id.

(400) See NI H Asks Participants in Women's Health Initiative Estrogen-Alone Study to Stop Study Pills, supra note 389 (discussing the risks of Premarin); The Estrogen Alone Study, NAT'L HEART, LUNG, AND BLOOD INST., (last visited Jun. 20, 2017) (providing another study by NHLBI highlighting this issue); Sally Shumaker et al., Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women, 291 JAMA 2947 (2004) (discussing how estrogen alone increases the risk for dementia and cognitive impairment).

(401) Barbara Atwell, Mainstreaming Complementary and Alternative Medicine in the Tace of Uncertainty, 72 UMKC LAW REVIEW 593, 602 (2004).

(402) See id. (discussing the associated, increased risks). See also Gina Kolata, In Public Health, Definitive Data Can be Elusive, N.Y. TIMES, (Apr. 23, 2002), http://www.nytimes.eom/2002/04/23/science/in-public-health-definitive-data-can-be-elusive.html (referring to a study that found HRT benefits are much more limited than doctors believed).

(403) See Alexandra Sifferlin, Hormone-Replacement Therapy: Could Estrogen Have Saved 50,000 Uves?, Time, (July 20, 2013), http://healthland.time.eom/2013/07/20/ hormone-replacement-therapycould-estrogen-have-saved-50000-lives/(cautioning against use of estrogen pills after a hysterectomy). A study published in the Journal of the American Medical Association found that women who took estrogen only after a hysterectomy had a slightly lower risk of breast cancer than women who took a placebo after a hysterectomy. Id. After a 2002 Women's Health Initiative ("WHI") study found that women who were taking a combination of estrogen and progestin had a higher rate of breast cancer, stroke, and heart disease, the percentage of women using estrogen therapy after a hysterectomy dropped by 80%. Id. Yale scientists found that these women died prematurely, but Andrea LaCroix, the co-project director of the Clinical Coordinating Center for WHI, warned that the study's results should not "drive all women who have had a hysterectomy to take estrogen pills" because more research is needed. Id. See also Getting Answers After HRT linked to High Cancer Risk, ABC NEWS, (Oct. 28, 2010), cancer/story?id=l 1994959 (discussing that daily use of synthetic progestin after hysterectomy contributes to breast cancer risk).

(404) Shulkin, supra note 368, at 81. See also Wyeth v. Rowatt, 244 P.3d 765, 771-73 (Nev. 2010) (example of a case litigating the adverse effects of HRT). But see Bailey v. Wyeth, 37 A.3d 549 (N.J. Super. Ct. Law Div. 2008). Plaintiffs alleged Wyeth ghostwrote articles but the court held there was insufficient proof to demonstrate those articles delayed a new warning label or diluted the subsequent warning of an increased risk of breast cancer. Id.; Torkie-Tork v. Wyeth, 739 F. Supp. 2d 895 (F.D. Va. 2010) (example of a case litigating the adverse effects of HRT). The court held Wyeth did not fraudulently misrepresent risks because its studies were inconclusive and there was merely a battle of scientific evidence. Id. at 907. Plaintiffs would need to show Wyeth knowingly concealed material information to demonstrate fraudulent concealment. Id. This holding is consistent with the holding in Rowatt, where plaintiffs did provide evidence to show Wyeth knowingly concealed material information. Rowatt, 244 P.3d at 782.

(405) See Rowatt, 244 P.3d at 769 (stating causes of action).

(406) See id. at 770 (listing respondent's theories of liability).

(407) See id. at 781 (summarizing jury's verdict). The jury awarded $134.6 million in compensatory damages and found that respondents proved by clear and convincing evidence that Wyeth acted with malice or fraud, giving rise to a second trial for punitive damages. Rowatt, 244 P.3d at 781.

(408) Id. at 783 (setting out elements for an award of punitive damages). "A defendant has a '[c]onscious disregard' of a person's rights and safety when he or she knows of 'the probable harmful consequences of a wrongful act and a willful and deliberate failure to act to avoid those consequences.'" Rowatt, 244 P.3d at 783. An award of punitive damages requires conduct in excess of mere recklessness or gross negligence. Id.

(409) Id. at 784.

(410) See id. at 771, 773 (summarizing studies' findings). Independent studies showed a relationship between estrogen-progestin hormone therapy and an increased risk of developing breast cancer. Id. at 771. The Women's Health Initiative study of 27,000 postmenopausal women found a 4.61 relative risk for women who took estrogen and progestin for more than five years. Id. at 771, 773.

(411) Id. at 771.

(412) See Rowatt, 244 P.3d. at 772 (indicating Wyeth's plan to minimize the negative study and divert attention from it).

(413) Id. at 771. FDA rejected Wyeth's application to market estrogen and progestin together, but allowed Wyeth to study the drugs' combination. Id. However, its documents showed that Wyeth had a company policy of not supporting breast cancer research and it declined a request to fund a study that would review data of women who had already been taking estrogen and progestin. Id.

(414) See id. (providing drugs to National Institutes of Health for WHI).

(415) See id. at 771-772 (discussing risks associated with Prempro). Data for the WHI study showed an "increased risk of invasive breast cancer, coronary heart disease, and stroke" as well as a decline in cognitive functioning for women 65 and older. Rowatt, 224 P.3d at 772.

(416) See Rowatt, 224 P.3d at 772 (discussing Wyeth's response to negative press about the risks of Prempro).

(417) Id. Wyeth used television advertisements, pamphlets, guides, and textbooks to promote the health benefits of Prempro. Id.

(418) Id. at 771-772.

(419) See id. at 780 (summarizing Wyeth's misleading data manipulation).

(420) Id. at 784-785.

(421) Id. at 779-781.

(422) See Rowatt, 224 P.3d at 772 (noting that Wyeth did not update its warning label). Wyeth's warning label was misleading in that it claimed they conducted their own human study, when they did not. Id. at 771-772.

(423) See Rowatt, 244 P.3d at 784 (upholding the jury's conclusion that Wyeth manipulated scientific evidence); Bailey,, 37 A.3d at 575 ("[T]here is no proof that these corporate-initiated articles in any way delayed the implementation of what FDA requested be in the Premarin or Prempro labeling or diluted the warnings on these drugs.")


(425) See supra notes 266, 268 (discussing advertising literature associated with salpingooophorectomys). See supra notes 389, 403 (discussing the scientific evidence explaining the dangers of such treatment and claims)

(426) Rowatt, 244 P.3d at 770, 772.

(427) Id. at 784.

(428) See supra note 17 and accompanying text (suppression of safety data, ghostwriting, failure to mention key risk information); supra note 301 (financial conflicts of interest).

(429) SUSAN J. RAMUS, ET AL., SCREENING FOR THE BRCA1-INS6KBEX13 MUTATION: POTENTIAL FOR MISDIAGNOSIS, 8 (Mutation in Brief 2007) (discussing the severe clinical implications of a misdiagnosis of a genetic mutation).

(430) Jorgensen, supra note 17, at 14 (discussing patient anxiety and documenting overdiagnosis); Gotzsche & Jorgensen, supra note 17, at 14-15 (discussing perceived accuracy and ongoing patient anxiety).

(431) See Breanne Sergent, Disclosing the Gray Areas of Mammography: Should Women with Dense Breast Tissue Remain in the Dark About Breast Cancer Screening Alternatives?, 34 J. LEGAL MED. 453, 472 n.176 (2013) (discussing advised alternative testing and treatment for patients based on BRCA testing). See also supra note 430 and accompanying text (discussing impact of patient anxiety on treatment).

(432) See American Medical Association, Opinion 2.07 and Opinion 2.071, 17 AM. MED. ASS'N J. OF ETHICS 1136, 1136-39 (2015), available at http://journalofethics.ama (discussing physician obligation with respect to clinical trials); American Medical Association, Opinion 8.08 and Opinion 8.082, 14 AM. MED. ASS'N J. OF ETHICS 555, 555-56 (2012), available at 1207.pdf (discussing physician obligation to ensure informed consent for treatment plan and not to withhold or omit relevant information); American Medical Association, Opinion 8.12 and Opinion 8.121,13 AM. MED. ASS'N J. OF ETHICS 626, 626-28 (2011), available at (discussing physician obligation to study and develop research mechanisms related to patient care).

(433) See Opinion 8.12 and Opinion 8.121, supra note 432 and accompanying text (discussing physician obligation to study and develop research mechanisms related to patient care).

(434) See K H Satyanarayana Rao, Informed Cotisent: An Ethical Obligation or Ilegal Compulsion, 1 J. CUTANEOUS AND AESTHETIC SURGERY 33, 35 (2008), available at (confirming doctors have both legal and ethical obligations to provide in-depth information to patients). "Obtaining consent is not only an ethical obligation, but also a legal compulsion.... There cannot be anything called a standard consent form. No doctor can sit in comfort with the belief that the "consent" can certainly avoid legal liability." Id.
   Physicians must provide an explanation of the correlation, if
   known, between carrying a particular genetic trait and
   developing a serious illness because an assessment of this
   risk may have a significant impact on an individual's
   decision to pursue testing--particularly if treatment options
   are limited. It should also be the responsibility of the
   physician and genetic counselor to know and to describe to
   the patient the range of treatment that may be available. For
   example, the fact that there is no treatment for Huntington's
   disease contributes significantly to the low rate of testing
   among those at risk. Similarly, the lack of palatable
   treatment options may reasonably deter a woman from
   testing for the BRCA genes; alternatively, for a woman
   willing to undergo prophylactic mastectomy or
   oophorectomy, being tested either can obviate this action or
   reaffirm her decision.

Elizabeth B. Cooper, Testing for Genetic Traits: The Need for A New Legal Doctrine of Informed Consent, 58 Md. L. Rev. 346, 407 (1999). Not only is the patient in front of the physician a consideration when considering BRCA mutation, but also others in the patient's genetic line. Jacquelyn Ann K. Kegley, Genetics Decision-Making: A Template for Problems with Informed Consent, 21 MED. & L. 459, 464 (2002). See generally supra page 5, note 20 and accompanying text (identifying Unified Composite Risk Benefit Analysis as the creation of this author and defining it as "the amount of risk reduction from the proposed intervention calculated against the cumulative potential risks from all subsequent interventions related to the initial intervention"); supra notes 430-432 and accompanying text.

(435) See supra note 434 and accompanying text (discussing physician obligation to secure adequate informed consent). See also BRCA1 and BRCA2: Cancer Risk and Genetic Testing, supra note 41 (discussing harms, implications and options related to BRCA testing). See generally supra page 5, note 20 and accompanying text (identifying Unified Composite Risk Benefit Analysis as the creation of this author and defining it as "the amount of risk reduction from the proposed intervention calculated against the cumulative potential risks from all subsequent interventions related to the initial intervention").

(436) See supra note 53 and accompanying text (discussing how genetic testing focuses tone of conversation between physician and patient depending on results).

(437) See supra note 53 (discussing various BRCA tests and organizations that administer them).

(438) See Surgery to Reduce the Risk of Breast Cancer, supra note 304 (discussing potential surgery options for patients with breast cancer); Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment, supra note 357 (sharing treatment options for patients with particular types of cancer).

(439) See Surgery to Reduce the Risk of Breast Cancer, supra note 304, (discussing surgery options for patients with breast cancer); Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment, supra note 357, (discussing alternative cancer treatment options).

(440) Finch et al., supra note 357.

(441) Abdominal Hysterectomy, supra note 384.

(442) See Abdominal Hysterectomy, supra note 384. See also Wolters Kluwer, Patient education: Abdominal hysterectomy (Beyond the Basics), UPTODATE, http: //www. basics?source=search_result&search=abdominal+hysterectomy&selectedTitle=1~6 (last visited Jun. 20, 2017) (detailing complications that may result from abdominal hysterectomy).

(443) See supra note 209 and accompanying text (providing statistics surrounding oophorectomies); See also Albert Asante, MD, MPH, et al., Elective Oophorectomy in the United States: Trends and In-Hospital Complications, 116 OBSTETRICS & GYNECOLOGY 1088 (2010) (detailing information on elective oophorectomy surgery).

(444) See supra note 394 (describing health risks associated with preventive treatment).

(445) See generally Saundra Buys et al., supra note 209 (recognizing the complexity surrounding risk assessments).

(446) See O'Connor, supra note 196 (noting many patients sometimes make decisions without realizing all risks or benefits).

(447) See O'Connor, supra note 196. The word "cancer" has such a negative connotation that many patients may choose to undergo preventive interventions even if it increases their chances to suffer other serious illnesses. Id.

(448) FDA Report, supra note 6, at 3 (noting the expanded use of LDTs).

(449) See supra note 6, at 3. See also O'Connor, supra note 196 (claiming side-effects from overtreatment can be very serious as well).

(450) See O'Connor, supra note 196 (describing cancer treatment alternatives).
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Title Annotation:laboratory developed tests
Author:Drabiak, Katherine
Publication:Journal of Health & Biomedical Law
Date:Mar 22, 2017
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