Optimal risk assessment and management of the potential ovarian cancer case: Expert guidance on individualizing an assessment approach for the patient at risk for ovarian cancer.
Assessing the premenopausal high-risk patient with positive family history, genetic concerns
Neal M. Lonky, MD, MPH: Your patient is at high risk for ovarian cancer due to a strong family history or genomic concerns. She is premenopausal and has no symptoms. What overall management approach would you take for this patient?
Leslie M. Randall, MD: For women with true genomic concerns, prevention is far preferred to surveillance. The specific high-risk genes are BRCA1, BRCA2, RAD51C, RAD51D, and BRIP1, plus Lynch syndrome (MLH1, MSH2, MSH6, PMS1, and EpCAM), and the minimum surgery for these women is a risk-reducing salpingo-oophorectomy (RRSO). RRSO is recommended between 30 and 35 years of age for BRCA1 mutation carriers, and between 40 and 45 years for carriers of the other mutations listed, regardless of menopausal status. This is true for all age groups and in both symptomatic and asymptomatic patients.
If women have undiagnosed but suspected genetic mutations, they should be referred for genetic counseling and possible testing based on established criteria. Until better screening modalities are available, identifying these women for RRSO is our best method for improving ovarian cancer mortality. Screening, however, can be considered for mutation carriers who do not meet these age criteria, desire future childbearing, or are not yet willing to undergo RRSO, as well as for women with a strong family history who test negative for mutations in these genes.
There is no current standard recommendation for screening, but clinicians can start by educating patients regarding the symptoms of ovarian cancer and performing an annual pelvic examination. Further testing protocols include at least a yearly transvaginal ultrasound scan and a serum cancer antigen 125 (CA 125) test. This approach was not successful in the general population as reported by the Prostate, Lung, Colorectal and Ovarian (PLCO) screening project. (1) Screen-detected cancers in the PLCO were predominantly diagnosed in stages III or IV, and at the expense of false-positive results attributable to ultrasound findings that prompted unnecessary surgeries and subsequent complications.
An alternative strategy of reserving ultrasonography for women with a rising annual CA 125 level (termed "multimodal screening") was studied in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKTOCS). (2) While multimodal screening was associated with less unnecessary surgery, cancers were still diagnosed at an advanced stage. There was a trend for mortality reduction, however, for women who had normal screening for the initial 7 to 14 years of monitoring.
Finally, a third approach, the Risk of Ovarian Cancer Algorithm (ROCA), also employs a mathematical CA 125 trend model with increased frequency (measurement of CA 125 every 3 months). (3) In the high-risk, genomic concern population, this strategy showed improved sensitivity for early stage disease compared with historical methods, even before the CA 125 level was greater than 35 U/mL. The ROCA, however, requires further study in a larger cohort before it can be accepted as standard of care.
Jason D. Wright, MD: Appropriate risk assessment typically is the first step when considering screening for ovarian cancer. Women with a personal or family history of breast and ovarian cancer should undergo genetic counseling. For those who meet the criteria for genetic testing, testing for deleterious mutations of the BRCA1 and BRCA2 genes can be performed. Women with a BRCA mutation are considered at high risk and warrant heightened surveillance and consideration of risk-reducing surgery.
Many commercially available genetic tests now evaluate a panel of genes in addition to BRCA1 and BRCA2. While those genes are associated with ovarian cancer, the risk is generally lower than that associated with BRCA1 and BRCA2. Data on how best to manage patients with abnormalities in these lower-penetrance genes are more limited.
For a premenopausal woman who has not completed childbearing, transvaginal ultrasonography with serum CA 125 testing can be considered. The National Comprehensive Cancer Network currently endorses such screening in women with a BRCA1 or BRCA2 mutation starting at age 30 to 35 years. (4) It should be noted that the benefit of such screening is uncertain, and screening has not been shown to reduce mortality in these women. The frequency of screening is at the discretion of the clinician, but it is often performed at an interval of every 6 months.
Devansu Tewari, MD: The most important thing always to consider in someone presumed to have a high risk of ovarian cancer is the accuracy of their family history. Clearly a first-degree relative, such as a mother, daughter, or sister with ovarian cancer, or someone who has tested positive for a genetic mutation needs to be confirmed.
If the patient is considered at high risk based on family history alone, a referral to a geneticist is warranted to determine if testing is needed. Unfortunately, screening opportunities--other than routine gynecologic examinations--outside of a clinical trial are limited.
The postmenopausal high-risk patient with no symptoms of ovarian cancer
Dr. Lonky: What is your approach for a postmenopausal patient who has no symptoms?
Dr. Randall: My approach in the asymptomatic, postmenopausal patient is much like that for the premenopausal one: RRSO for known genetic mutation carriers, genetic testing for potential carriers, and the option to use ultrasound and CA 125 monitoring in the rest.
In women with significant family history (ovarian cancer in more than 1 first-degree relative), RRSO might be considered in those who are medically fit for surgery. Hysterectomy could be considered for women with indications such as high-grade cervical dysplasia, postmenopausal bleeding, or the need for tamoxifen therapy. (5) In addition, women with BRCA1 mutations might be at higher risk for serous uterine cancers, and this should be discussed during surgical planning for RRSO. (6) Hysterectomy increases the risks of surgery, but these risks can be minimized by using a minimally invasive surgical approach.
Dr. Wright: Postmenopausal women with a BRCA mutation who have not undergone oophorectomy should strongly consider prophylactic RRSO. RRSO typically is recommended between the ages of 35 and 40 after the completion of childbearing. Since women with BRCA2 mutations have later onset of ovarian cancer, RRSO can be delayed until 40 to 45 years of age in these patients.
Dr. Tewari: An asymptomatic patient without a genetic mutation should undergo routine annual gynecologic examinations. Screening outside of a clinical trial is not recommended. Women carrying a known genetic mutation, such as a BRCA1 or BRCA2 mutation, should have undergone risk-reducing surgery to remove the tubes and ovaries; those who have not already had RRSO should be counseled to do so. The issue related to hysterectomy needs to be discussed with these patients, given studies showing increased rates of uterine papillary serous cancers, (6) and if a personal history of breast cancer exists this may need to be factored in as well.
Suspicious symptoms in a premenopausal high-risk patient
Dr. Lonky: Please describe your management approach for a premenopausal patient who has current symptoms.
Dr. Randall: According to Goff and colleagues, symptoms that are concerning for ovarian cancer include pelvic and abdominal pain, urinary urgency and/or frequency, increased abdominal size and bloating, and early satiety present for less than 1 year and occurring more than 12 days per month. (7) Although not always specific to ovarian cancer, the presence of these symptoms increases the performance of diagnostic testing.
Dr. Wright: Yes, clinicians should have a heightened suspicion in women who have persistent symptoms that have been associated with ovarian cancer. This is particularly true for high-risk women with a BRCA mutation or those with a family history of ovarian cancer. These patients should undergo pelvic examination, transvaginal ultrasonography, and assessment of serum CA 125.
Dr. Randall: For these women, I start with abdominal and pelvic examinations, followed by abdominal and vaginal ultrasound with serum markers based on the presence and appearance of a pelvic mass. If the mass is large (>10 cm) and/or complex, in this age group I consider tumors of both epithelial and nonepithelial ovarian origin, in addition to colorectal cancer, and perform tests for CA 125, carcinoembryonic antigen (CEA), germ cell markers (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), and sex cord/ stromal markers (inhibin B and testosterone).
Large masses will need to be managed surgically, and unless they appear purely simple on ultrasound and all serum markers are normal, these should be managed by a gynecologic oncologist, especially in the setting of genomic concerns. If imaging shows a smaller mass or ascites alone, CA 125 and CEA typically are adequate markers, and the patient should be referred for gynecologic oncology evaluation and consideration for surgery. Benign diagnoses, such as endometriosis, pelvic abscess, and ectopic pregnancy, should not be excluded in this age group for fear of cancer.
Dr. Tewari: Any symptoms such as worsening abdominal or pelvic pain, bloating, urinary frequency, or gastrointestinal changes that do not improve should trigger a gynecologic examination followed by a transvaginal ultrasound to rule out a pelvic mass. If the patient carries a genetic mutation, I would include a CA 125 test to correlate with the imaging findings.
For known BRCA1 and BRCA2 genetic carriers, I would recommend prophylactic removal of both the tubes and the ovaries if childbearing has been completed (ages 35 to 40 years), and I would consider extending the age limit into the mid-40s for BRCA2 carriers, given the later age of presentation.
Suspicious symptoms in a postmenopausal high-risk patient
Dr. Lonky: And how would you manage a postmenopausal patient who reports having current symptoms?
Dr. Tewari: I would follow the same approach for a symptomatic postmenopausal patient as for a premenopausal patient.
Dr. Wright: I agree. As with symptomatic premenopausal patients, we should be suspicious of ovarian cancer-related persistent symptoms in postmenopausal women, especially high-risk women who have a BRCA mutation or family history of ovarian cancer. Pelvic examination, transvaginal ultrasonography, and assessment of serum CA 125 are warranted.
Dr. Randall: I would mention that, in postmenopausal women, the risk of malignancy is greater for epithelial ovarian and nongynecologic primaries, such as colon and breast cancer. In addition, the risk for germ cell tumors is much lower than in premenopausal women, and that for sex cord stromal tumors is somewhat equivocal. Therefore, patients should have up-to-date breast and colon screening, and serum studies can be limited to CA 125 and CEA. In these patients, the threshold for gynecologic oncology referral and surgical evaluation should be low.
The premenopausal average-risk woman with symptoms
Dr. Lonky: Consider a woman at average risk for ovarian cancer who is premenopausal and has current symptoms. Please describe your management approach for this patient.
Dr. Wright: While ovarian cancer is often considered the "silent killer," some symptoms have been associated with ovarian cancer. As mentioned, women with ovarian cancer frequently describe symptoms of abdominal and pelvic pain, early satiety, bloating, and urinary urgency and frequency. Although these symptoms are common in the general population, women with ovarian cancer tend to experience them more frequently as well as persistently. An ovarian cancer symptom index has been developed; it includes pelvic and abdominal pain, urinary urgency and frequency, increased abdominal size, bloating, and difficulty eating or feeling full, with symptoms present for less than 1 year and for more than 12 days per month. While some studies have found that these symptoms are useful in detecting ovarian cancer, others have questioned the overall value of symptomatology.
Patients and clinicians should have a heightened suspicion for ovarian cancer when these symptoms are noted. When they do occur, evaluation can include pelvic and rectovaginal examination along with transvaginal ultrasound and measurement of serum CA 125. CA 125 is a nonspecific marker and is often elevated, particularly in premenopausal women. If the results of these tests raise concern for ovarian cancer, patients should be referred to a gynecologic oncologist or a physician with expertise in the diagnosis and management of ovarian cancer.
Dr. Randall: In this age group, other markers, such as human epididymis protein 4 (HE4) and a multivariate index assay (OVA1), might be helpful. HE4 is especially helpful when an elevated CA 125 is likely due to benign disease, such as endometriosis, adenomyosis, or leiomyomata. In these cases, HE4 is much less likely to be falsely elevated, and the Risk of Malignancy Algorithm (ROMA) can be used to calculate risk, but the HE4 level alone is sufficient to triage benign from malignant masses in low-risk patients. (8,9) OVA1 can be used to assist in the triage of pelvic masses planned for surgery due to size or symptomatology to benign gynecologic or gynecologic oncology surgeons. Of note, if the CA 125 is elevated, OVA1 also will be elevated and therefore less helpful than in cases where the CA 125 is normal.
Dr. Tewari: Without an abnormal finding on imaging, I would not order a CA 125 test given the high false-positive rate. If a mass is identified, its clinical features would determine if a CA 125 test is warranted as well as the next steps in surgical management.
Dr. Randall: Fortunately, premenopausal women at average risk for ovarian cancer typically have benign diagnoses, even when they are symptomatic. I would perform the same evaluation as in the high-risk patient, but I would have a higher threshold to suspect cancer, to refer to oncology, and to recommend or perform immediate surgical intervention.
The postmenopausal average-risk woman with symptoms
Dr. Lonky: Your average-risk patient is postmenopausal and has current symptoms. What is your management approach?
Dr. Randall: The approach in this age group is the same as that for the average-risk premenopausal patient with symptoms, but cancer diagnoses including ovarian, endometrial, colon, or metastatic breast cancer are higher on the differential. Again, up-to-date breast and colon screening, endometrial biopsy for postmenopausal bleeding and abnormal uterine lining thickness, ultrasonography, and serum markers are the mainstays for evaluation.
Pre- and postmenopausal average-risk patients with no symptoms
Dr. Lonky: What is your approach for women who are at average risk for ovarian cancer and have no symptoms--whether they are premenopausal or postmenopausal?
Dr. Wright: Among average-risk women--whether they are premenopausal or postmenopausal--routine screening for ovarian cancer is not recommended. Overall, the prevalence of ovarian cancer in the general population is low. Therefore, even screening tests with a high specificity have a low predictive value for the detection of ovarian cancer, and they require evaluating a large number of women without cancer. This is problematic for ovarian cancer--which requires that women undergo surgery to diagnose a cancer.
Two large screening trials, one in the United States and one in the United Kingdom, evaluated the utility of screening average-risk women with CA 125 and transvaginal ultrasonography for the detection of ovarian cancer. (1,2) Neither trial was able to demonstrate a reduction in mortality with screening. Both trials noted that a significant number of women require surgical intervention to detect 1 case of ovarian cancer, and that surgery was associated with significant morbidity. Based on these data, the US Preventive Services Task Force considers the harms of screening to outweigh the benefits and classifies ovarian cancer screening as category D.
Dr. Randall: I agree, as shown in the PLCO and UKTOCS trials, the harms of screening currently outweigh any benefit. (1,2) Therefore, aside from screening for indications for genetic testing, I do not recommend any special testing in these age groups.
Dr. Tewari: The annual gynecologic examination gives ObGyns an opportunity to ask about symptoms that may be suggestive of ovarian cancer.
Dr. Lonky: Are there any other special case concerns to discuss?
Dr. Tewari: A lot of focus has centered around screening, which ignores the evidence for warranting increased symptom awareness. We need to convey to women the need to be aware of ovarian cancer symptoms, especially those listed in the ovarian cancer symptom index. Use of the symptom index has been associated with identifying the disease at earlier stages, which is important because that is when response and cure rates are higher.
Dr. Randall: I would like to mention additional imaging. Computerized tomography (CT) and magnetic resonance imaging (MRI) should be reserved for cases with abnormal ultrasound findings. CT with intravenous contrast has poor sensitivity for soft-tissue definition and is best employed to detect ascites, retroperitoneal lymphadenopathy, peritoneal carcinomatosis, and gastrointestinal or urinary tract obstruction. T2-weighted MRI with gadolinium contrast has excellent soft-tissue resolution and can be particularly helpful to differentiate ovarian and uterine masses in premenopausal women faced with surgery who desire to retain fertility.
Advanced imaging techniques, such as positron emission tomography (PET), increase costs significantly and often do not change management beyond that derived from CT or MRI studies. Therefore, PET should not be used routinely in the workup of these women.
Dr. Wright: Similar to liquid biopsies, there is interest in detecting ovarian cancer cells that are exfoliated through the lower genital tract. These cells could be obtained in a manner that is similar to collecting a specimen for a Pap test. A technology currently being developed by PapGene Inc uses cells collected from the cervix and examines them for molecular abnormalities. A pilot study found that the test identified 9 of 22 (41%) ovarian cancers. These types of tests are currently being evaluated as a potential modality to aid in the detection of ovarian cancer.
Dr. Lonky: Please explain what liquid biopsies are and how can they be used in gynecology.
Dr. Wright: Liquid biopsy is a test in which a blood sample is collected and analyzed to look for tumor cells. The hope with liquid biopsies is that ovarian cancer could be detected at an earlier stage. Liquid biopsy requires that tumor cells are present in the bloodstream and that these cells have molecular abnormalities that can be used to distinguish the tumor cells from normal cells. There currently are several promising technologies available, and many are undergoing testing and evaluation. At present, this is not a test that is used routinely in practice.
Dr. Tewari: Yes, they are the newest wave in next-generation sequencing. With no effective screening strategies for ovarian cancer to date, liquid biopsies serve as a potential future option. Although the technology of next-generation sequencing is improving by the minute, its role in gynecologic cancers at this time is more one of potential and promise than widespread acceptance. However, that day may not be far off as more and more studies are showing successful comparisons.
Dr. Randall: Liquid biopsies are attractive because not only do they save the patient the inconvenience, risk, and cost of a surgical or CT-guided percutaneous biopsy but also they are associated with a very quick turnaround time (days versus 3 to 4 weeks for tissue biopsy) for timely clinical decision making. If better markers of early stage gynecologic cancers of all types are validated, this technique has significant potential for screening, diagnosis, and monitoring of response to therapy.
(1.) Buys SS, Partridge E, Black A, et al; PLCO Project Team. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011;305(22):2295-2303.
(2.) Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2016;387(10022):945-956.
(3.) Skates SJ, Greene MH, Buys SS, et al. Early detection of ovarian cancer using the Risk of Ovarian Cancer Algorithm with frequent CA125 testing in women at increased familial risk--combined results from two screening trials. Clin Cancer Res. 2017;23(14):3628-3637.
(4.) National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/familial high-risk assessment: breast and ovarian. Version 1.2018--October 3,2017.
(5.) Lu KH, Kauff ND. Does a BRCA mutation plus tamoxifen equal hysterectomy? Gynecol Oncol. 2007;104(1):3-4.
(6.) Shu CA, Pike MC, Jotwani AR, et al. Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol. 2016;2(11):1434-1440.
(7.) GoffBA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer. 2007;109(2):221-227.
(8.) Moore RG, Miller MC, Disilvestro P, et al. Evaluation of the diagnostic accuracy of the risk of ovarian malignancy algorithm in women with a pelvic mass. Obstet Gynecol. 2011;118(2 pt 1):280-288.
(9.) Anton C, Carvalho FM, Oliveira EI, Maciel GA, Baracat EC, Carvalho JP. A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses. Clinics (Sao Paolo). 2012;67(5):437-441.
Expert panel featuring Neal M. Lonky, MD, MPH, moderator; with Leslie M. Randall, MD; Devansu Tewari, MD; and Jason D. Wright, MD
Dr. Lonky reports that he has received grant or research support from Merck & Co.
Dr. Wright reports that he has served as a consultant to Clovis Oncology and Tesaro Inc.
Dr. Randall and Dr. Tewari report no financial relationships relevant to this article.
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|Date:||Jan 1, 2018|
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