Gene Expression Profiling in Breast Cancer and Its Effect on Therapy Selection in Early-Stage Breast Cancer.
Breast cancer is the type of cancer with the highest incidence rate among women globally and it ranks the first among reasons for death due to cancer in women (1). Appropriate selection and administration of therapies according to the patient are important for not only prolonging disease-free survival and overall survival, but also for preventing late complications (such as anthracycline-related cardiac problems, myelodysplastic syndrome, leukemia and taxane-associated neuropathy) (2).
It is a standard approach to administer adjuvant chemotherapy (CT) and/or hormonal treatment (HT) to reduce the risk for metastasis according to the histological, pathological and immunohistochemical staining characteristics of the tumor following surgical treatment of early-stage breast cancer (3-5). The strongest predictors in determining the risk for metastasis are as follows: tumor diameter, histological grade, axillary lymph nodes (ALN) metastasis and hormone receptors (HR) and HER2 status as well as Ki-67 proliferation index (6). In recent years, molecular sub-types (intrinsic sub-types) of breast cancer have been described and therapy selection is done according to these sub-types (7-10). Breast cancers are divided into four sub-groups as per their molecular characteristics (11, 12): Luminal, HER2-positive, basal and normal-like (Table 1). CT is necessary for adjuvant treatment of basal-type and HER2-positive breast cancer cases.
Luminal tumors are HR-positive breast cancers that constitute approximately 60-80% of all breast cancer cases (8, 11, 12). Luminal tumors are divided into two groups as A and B: Their characteristics are summarized in Table 2. While luminal A tumors are very sensitive to HT, it may be necessary to use CT and HT together in luminal B tumors. The above-specified classical predictors are not sufficient to distinguish between the luminal A and B sub-groups in HR-positive, HER2-negative breast cancer and does not account for different clinical progresses of luminal type breast cancer patients who are in the same stage and receive similar treatments. In order to explain this difference and better differentiate between patients who may not require chemotherapy as part of adjuvant therapy and those who need to have addition of CT to their hormone therapy, various gene expression analyses have been and are being studied retrospectively and prospectively.
Gene Expression Profiling
Amsterdam 70-gene Profile- MammaPrint dx Test (Table 3)
The first one of these tests is MammaPrint dx 70-gene expression analysis, which was developed by the Netherlands Cancer Institute. They identified 70 genes which differentiate between patients diagnosed with breast cancer as good profile and poor profile depending on the risk of developing metastasis within 5 years as of diagnosis. This gene profile was developed based on a gene study conducted with 78 ALN-negative patients below the age of 55 and diagnosed with invasive breast cancer a tumor size <5 cm (13, 14). The test is conducted using the micro-array-based gene expression profiling technique. Fresh tissue sample or frozen archival material and formalin-fixed paraffin-embedded (FFPE) material are used for the test (9, 15). Several studies have demonstrated that MammaPrint is an independent prognostic factor in patients with ALN-negative breast cancer (16-18). It has been seen that 35% of patients that seemed to have high risk disease actually had low risk and 14% of patients that seemed to be in the low risk group actually had high risk in this program as compared to the adjuvant online program (19).
The MammaPrint test is recommended for early breast cancer of all ages with tumor size <5 cm, with the ALN 0-3 positive cases, and estrogen receptor (ER)-positive or negative tumors (8). It was approved by Food and Drug Administration (FDA) in 2007 for marketing as a prognostic test, but not to select therapy or predict response to therapy (15). Results are reported as low risk (13% chance of developing distant metastases at 10 years without adjuvant treatment) or high risk (56% chance of developing distant metastases at 10 years without adjuvant treatment).
For the prospective validation of the test, an international, randomized, Phase-3 MINDACT study (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy-EORTC 10041/BIG 3-04 study) has been scheduled (20). In this study, 6693 patients with early-stage breast cancer (HR+, Nod 1-3 positive or negative, HER2-) were recruited. The genomic risks (using the 70-gene signature) and clinical-pathological risks (using a modified version of Adjuvant Online) of the patients were identified and the aim has been set as comparing their effectiveness in the adjuvant therapy selection. CT was not provided for the group with low genomic and clinical risk. CT was provided for the group with high genomic and clinical-pathological risk. In patients with discordant risk results, either the genomic risk or the clinical-pathological risk was used to determine the use of chemotherapy and hormone therapy or only hormone therapy. The primary aim of the study was to determine whether patients with high clinical risk and low genomic risk had requirement for CT. According to the assessment of 1550 patients with high clinical risk and low genomic risk, metastasis-free survival rate was found to be 94.7% in patients not receiving CT, which was 1.5% lower than the patients that were on CT. The rates of distant metastasis-free survival were found to be similar among patients that were node-negative or positive, ER-positive and HER2-. Based on these results, the researchers concluded that 46% of the patients with low genomic risk and high clinical risk did not require CT.
MammaPrint is featured as a prognostic parameter in the St Gallen and ESMO (European Society of Medical Oncology) guidelines (3, 21).
In the 8th Breast Cancer Staging System of American Joint Committee on Cancer (AJCC), which is to be published in 2018, gene expression profiling is included in breast cancer staging as a prognostic panel (22).
One of these panels is MammaPrint (when available as stage modifiers): For patients with HR-positive, HER2 negative , and ALN negative tumors, a MammaPrint low-risk score, regardless of T size, places the tumor in the same prognostic category as T1a-T1b N0M0 (Level of Evidence II).
21-Gene Recurrence Score assay (Oncotype DX) (Table 3)
The Oncotype DX Breast Cancer Assay is a commercially available reverse transcriptase-polymerase chain reaction (RT-PCR) based signature. It evaluates the mRNA levels of 21 genes (16 cancer-related genes and 5 reference genes) (8, 9, 15). The expression of these 21 genes is reported as a single Recurrence Score (RS), which ranges between 0 and 100. The test is routinely performed on FFPE tissue specimens.
Patients are divided into 3 risk groups depending on the risk for distant metastasis in ten years: 1- Low risk (RS<18) 2- Intermediate risk (RS 18-30) 3- High risk (RS>30)
The clinical validation of Oncotype DX was originally completed in 2 retrospective studies (National Surgical Adjuvant Breast and Bowel Project-NSABP B-14 and B-20 studies) (23, 24): In the NSABP B-14 study, patients (HR-positive disease with negative axillary nodes) were randomized to the tamoxifen versus placebo arms for 5 years (23). The distant metastasis-free survival rates of the patients as per their risk groups were as follows: Low risk group (RS<18; 10-year risk for distant metastasis: 6.8%); intermediate risk group (RS:18-30; 10-year risk for distant metastasis: 14.3%) and high risk group (RS>30; 10-year risk for distant metastasis: 30.5). In conclusion, Oncotype DX was interpreted as being a 'predictor of distant relapse in ER+ node negative disease.' These results were also tested in the NSABP B-20 study (HR positive disease with negative axillary nodes; adjuvant tamoxifen versus CMF + tamoxifen) and the contribution of CT as per the risk groups was investigated (24): It was seen that the addition of CT to tamoxifen for patients in the low risk group decreased the 10-year risk for distant metastasis by only 1.1% while the addition of CT to tamoxifen for patients in the high risk group reduced the 10-year risk for distant metastasis significantly by 27.6%. The benefit of the addition of CT to hormonal therapy in the intermediate risk group was not showed to be clinically significant.
The action to be taken for patients in the intermediate risk group could not be completely elucidated. Should it be only HT or CT and HT? In order to shed light onto this question, a prospective randomized study was initiated in the year 2006 (Trial Assigning Individualized Options for Treatment-TAILORx; prospective clinical validation study) (25). In this study, 10.253 patients (HR-positive and HER2-negative with negative axillary nodes) from 6 countries and 900 study sites were included between the years 2006 and 2010. The patients were divided into groups as follows: RS<11 low risk group (only endocrine treatment), RS 11-25 intermediate risk group (divided into two arms: only HT and CT + HT) and RS>25 high risk group (CT and HT). As part of HT, tamoxifen or aromatase inhibitor (AI) or tamoxifen followed by AI were administered for 5 years and tamoxifen or AI along with ovarian suppression were used in 3% of the patients. During the ESMO 2015 meeting, the results of the low-risk group (15.9% of all patients;-1626 patients) were presented as follows: 5-year invasive disease free survival: 93.8%; recurrence-free survival: 98.7%; distant recurrence-free survival: 99.3% and overall survival: 98%. Recurrence events were uncommon regardless of the histologic grade, tumor size and were not significantly affected by younger age at diagnosis in this low risk group.
The results of the study also prospectively showed that only adjuvant HT was sufficient for patients with low risk according to the 21 gene expression analysis (Level IA evidence). It is expected that the results of the intermediate risk group will be announced within the year 2017.
The prognostic and predictive validity of Oncotype DX was also retrospectively evaluated in 4 randomized phase-3 studies [SWOG 8814, ATAC (Adjuvant Tamoxifen or Anastrozole), NSABP-B28 and ECOG 2197 studies] including ALN positive and HR-positive cases (26-30). It was seen that CT was beneficial in distinguishing node-positive patients who would benefit from CT (Predictor of likelihood of chemotherapy benefit in ER+ Node positive disease). Its prospective validation in the node-positive patients was demonstrated in the West German Study Group Plan B Randomized Phase-3 study, the Clalit Registry study conducted in Israel and the SEER real-life observational study (31-33). In all these studies, the 5-year survival rate of patients in the low risk group is >95%.
Other ongoing trials (RxPONDER and OPTIMA) are evaluating whether adjuvant CT is beneficial in patients with HR-positive, HER2-negative breast cancer with 1 to 3 positive ALNs and a RS of 25 or less (7, 8).
Oncotype DX is included as a prognostic and predictive tests in the ESMO, St Gallen, NCCN (National Comprehensive Cancer Network; includes 1 to 3 positive nodes) and ASCO (American Society of Clinical Oncology; node negative only) guidelines (3, 4, 21, 34).
The Oncotype DX staging system has been included in the 8th breast staging system by AJCC (when available as stage modifiers) (22): For patients with HR-positive, HER2-negative and ALN-negative tumors, Oncotype DX recurrence score less than 11, regardless of T size, places the tumor in the same prognostic category as T1a-T1b N0M0, and the tumor is staged using the AJCC prognostic stage group table as stage I (Level of Evidence I).
Predictor analysis of microarray 50 risk of recurrence score (PAM50-ROR) (Table 3)
The PAM50 is a test that uses 50 classifier genes and 5 control genes. The microarray technique is employed and study is done on FFPE tissues with quantitative RT-PCR technology (8, 9, 15). Along with the tumor diameter and four main intrinsic sub-types are provided along with the risk of recurrence (ROR). The PAM50 score is reported on a 0-100 scale (ROR score of risk of recurrence), which is correlated with the probability of distant recurrence at ten years for women with HR positive, early-stage node-negative or node 1-3 positive breast cancer. Patients are divided into high (>20%), intermediate (10 to 20%) and low (<10%) risk groups. It was retrospectively tested in the ATAC and ABCSG-8(Austrian Breast Cancer Study Group 8) studies and demonstrated to be an important prognostic indicator for both ALN-negative and ALN-positive patients in all sub-groups (35, 36). It is an FDA-approved test (9, 34).
It has been included in the 8th breast cancer staging system by the AJCC (when available as stage modifiers) (22): For patients with HR-positive, HER2-negative and ALN-negative tumors, a PAM50 ROR score in the low-range, regardless of T size, places the tumor in the same prognostic category as T1a-T1b N0M0 (Level of Evidence II).
Breast Cancer Index (BCI) (Table 3)
Breast Cancer Index is a combination of molecular grade index (MGI) and HOXB13-to-IL17BR expression ratio (H:I ratio). Studies conducted have shown that it is effective in anticipating treatment response and prognosis in ER-positive tumors (37, 38). Three risk groups are identified: low, intermediate and high risk. Its clinical usability is still being investigated. ASCO states that it can be used in making a decision for adjuvant therapy in HR-positive, HER2-negative and node-negative disease while it is not recommended to be used in node-positive disease (34).
EndoPredict (Table 3)
It involves RNA-based analysis of 11 genes (8 cancer related and 3 reference genes). Its prognostic value was validated using the data from ABCSG-6 and ABCSG-8 trials (39). ASCO states that it can be used in making a decision for adjuvant therapy in HR-positive, HER2-negative and node-negative disease while it is not recommended to be used in node-positive disease (34). It is a test which can also be used to make a decision for prolonged adjuvant therapy.
Breast Cancer Index and EndoPredict (when available as stage modifiers) tests are also included as part of the prognostic panel in the 8th staging booklet (Level of evidence II) (22) (Table 3).
Other assays include the Rotterdam 76-gene signature, genomic grade index, molecular grade index, etc. There are not sufficient data about the prognostic significance of these arrays (9, 15, 34, 40, 41). Further studies are needed.
Gene expression analyses are beneficial in determining the prognosis and selecting therapy for luminal type breast cancers (HER2-negative, HR-positive). Even though these tests are costly, studies performed have shown that they are actually cost-efficient (42, 43). They are included in reimbursement schemes in the USA and Europe whereas they are not included in the reimbursement program in Turkey and many other countries. Therefore, studies can be conducted only on a limited group of patients. Studies conducted in Turkey have demonstrated that Oncotype DX has significantly correlated with PR and Ki-67 score of the tumor, and has a significant contribution to determining the therapy selection (44, 45). In another study from Turkey, Oncotype DX test was found as cost-effective in patients with early stage breast cancer (46).
It should also be kept in mind that gene expression analyses may yield false results in rarely seen tumors such as breast cancers showing neuroendocrine differentiation and in mixed morphologies (47). Furthermore, the stromal cells and inflammatory cells around the tumor tissue and the normal breast tissue are not included in the analysis. The ratio of non-neoplastic cells in the analysis may change the expression profile and the prognostic signature. In the second-generation gene expression analyses, myoepithelial and stromal cells are also assessed in addition to the epithelial cancer cells (8).
There are no gene expression tests available yet to determine the therapy selection for other intrinsic types of breast cancers. Various gene expression analyses and second generation gene expression analysis studies are ongoing with the aims of determining the drug selection in endocrine treatment, selecting the agent to be used in chemotherapy and predicting treatment to neoadjuvant therapy (8). Technological advancements and developments in the field of molecular biology and genetics will enable us to provide individualized therapies for our patients.
Peer-review: Externally peer-reviewed.
Conflict of Interest: No conflict of interest was declared by the author.
Financial Disclosure: The author declared that this study has received no financial support.
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E. Nilufer Guler
Department of Medical Oncology, Hacettepe Cancer Institute, Ankara, Turkey
Address for Correspondence: E. Nilufer Guler, e-mail: firstname.lastname@example.org
Cite this article as: Guler N. Gene Expression Profiling in Breast Cancer and Its Effect on Therapy Selection in Early-Stage Breast Cancer. Eur J Breast Health 2017; 13: 168-174.
Table 1. Breast cancer molecular subtypes (Modified from 11) Intrinsic IHC (*) status Grade Prognosis Prevalence subtype Luminal A ER+/PR+;HER2-;Ki67 1/2 Good 40% low Luminal B ER+/PR+;HER2-;Ki67 2/3 Intermediate 20% high ER+/PR+;HER2+;Ki67 2/3 Intermediate any HER2 ER-/PR-;HER2+;Ki67 2/3 Poor 12 to 21% overexpression any Basal ER-/PR-;HER2-;basal 3 Poor 11 to 23% marker+ Normal-like ER+/PR+;HER2-Ki67 1/2/3 Intermediate 3 to 10% any (*) IHC: Immuno-Histo-Chemical Staining; ER: Estrogen Receptor; PR: Progesteron Receptor Table 2: Characteristics of Luminal Subtypes Breast Cancers (Modified from 8) Luminal A Luminal B Incidence % 40 20 ER-related genes High Relatively low HER2-related genes Low Variable TP53 mutation 12% 29% Proliferation-related genes Low High Prognostic significance Good Poor Prediction to endocrine Highly Relatively less therapy sensitive sensitive Prediction to cytotoxic therapy Less sensitive Less sensitive ER: estrogen receptor Table 3: Gene Expression Tests for Predicting Clinical Outcomes in Patients with HR positive, HER2 negative, Node 0-3 Positive Early Stage Breast Cancer (7, 9, 22, 34, 40) PAM50-risk of Oncotype DX MammaPrint recurrence score Manufacturer Genomic Health Agendia NanoString (Redwood City, CA) (Irvine, CA) Technologies (Seattle, WA) Tissue Sample FFPE Fresh, frozen, FFPE or FFPE No of genes 16 cancer 70 50 cancer 5 control 22 control /housekeeping + tumor size Technology Quantitative Microarrays Quantitative RT-PCR RT-PCR Predictive + - - Prognostic + + + Eligible ER+ and HER2-, Stage I-and ER+, stage patients T1/2 0-3 nodes f II breast I/II 0-3 nodes cancer Measure RS Good risk and ROR:Ten year /Categories Low <18 poor risk probability Intermediate 18-31 intrinsic of distant High subtype recurrence >31 Low <10% Intermediate 10-20% High >20% Intrinsic subtype Strength Strong for N0 Moderate for Strong for N0 of ASCO Moderate N0 and N+ Moderate for N+ recommendation for N+ 8th AJCC For patients with For patients For patients with breast cancer HR-positive, HER2 with HR-positive, staging manual negative, and ALN HR-positive, HER2 negative, (when negative tumors, HER2 negative, and ALN negative available Oncotype Dx and ALN negative tumors, a PAM50 as stage recurrence score tumors, a ROR score in the modifiers). less than 11, MammaPrint low-range, regardless of T low-risk score, regardless of T size, places the regardless of T size, places the tumor in the same size, places the tumor in the same prognostic tumor in the prognostic category as same prognostic category as T1a-T1b N0M0, category as T1a-T1b N0M0 and the tumor is T1a-T1b N0M0 (Level of Evidence staged using the (Level of II). AJCC prognostic Evidence II). stage group table as stage I (Level of Evidence I). Breast Cancer Index EndoPredict Manufacturer bioTheranostics Myriad /Sividon Diagnostics Tissue Sample FFPE FFPE No of genes MGI-5 cell cycle 8 cancer genes; H/I-Gene 3 control expression ratio Technology Quantitative Quantitative RT-PCR RT-PCR Predictive + - Prognostic + + Eligible ER+ ER+ patients HER2- HER2- Node- Measure Low, intermediate The test result is /Categories and high risk composed of the 'molecular fingerprint' of a tumor in combination with the established prognostic parameters nodal status and tumor size Strength Moderate for N0 Moderate for N0 of ASCO Strong for N+ and N+ recommendation (don't use for N+) 8th AJCC For patients with For patients with breast cancer HR-positive, HER2 HR-positive, staging manual negative, and ALN HER2 negative, (when negative tumors, and ALN negative available a BCI in the tumors, Endopredict as stage low-range, regardless low-risk score, modifiers). of T size, places regardless of T size, the tumor in the same places the tumor in prognostic category the same prognostic as T1a-T1b N0M0 category as T1a-T1b (Level of Evidence N0M0 (Level of II). Evidence II). AJCC: American Joint Committee on Cancer; ALN: axillary lymph node; ASCO: American Society of Clinical Oncology; FFPE: formaline-fixed parafine embedded; RT-PCR: reverse transcriptase-polymerase chain reaction; ER: estrogen receptor; HR: hormone receptor; BCI: Breast Cancer Index; ROR: Risk of Recurrence
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|Author:||Guler, E. Nilufer|
|Publication:||European Journal of Breast Health|
|Date:||Oct 1, 2017|
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