Oncotype Dx recurrence score among BRCA1/2 germline mutation carriers with hormone receptors positive breast cancer

Abstract

Gene expression assays are widely used to predict risk of recurrence in early breast cancer (BC). We report the 21-gene expression assay (Oncotype Dx) recurrence score (RS) distribution of 27 BRCA carriers with estrogen receptor (ER) positive BCs, identified at Hadassah Medical Center, combined with 2 previous studies. Treatment decision and outcomes of the 27 BRCA carriers were compared with an Israeli cohort of 1594 patients published recently. We found Oncotype Dx RS low (<18), intermediate (18-30) and high (>30) among 12 (21.4%), 23 (41.1%) and 21 (37.5%) of 56 BRCA1 carriers compared with 15 (17.2%), 49 (56.3%) and 23 (26.4%) of 87 BRCA2 carriers (p = 0.2). The corresponding distribution in a population of 82,434 women published by Genomic Health was 53.4%, 36.3% and 10.3% for low, intermediate and high RS (p < 0.001 for BRCA1 and BRCA2). Treatment decision regarding chemotherapy according to RS was similar in BRCA1, BRCA2 and the control group. Two of 27 carriers had distant recurrence: a BRCA1 carrier with RS of 18 and a BRCA2 carrier with RS of 22; both have an excellent response to chemotherapy. We found an approximately ∼3 fold increased rate of high RS among BRCA1 and 2 carriers with ER positive BC compared with the general BC population. These data might indicate that hormone positive BC in BRCA carriers are molecularly unique. The surprisingly good response to chemotherapy in the metastatic setting in 2 patients may suggest that the predictive value of low-intermediate RS in carriers merits further studies.

Patterns of recurrence and metastasis in BRCA1/BRCA2‐associated breast cancers

“…Other groups have demonstrated differences between BRCA2-associated HR-positive tumors versus sporadic HR-positive tumors, including in the distribution of Oncotype DX (Genomic Health) recurrence scores. [53][54][55] Because of the timeframe of primary tumor diagnoses encompassed in our study, we chose not to collect information on Oncotype Dx testing, nor did we perform tissue-based assays to identify other potential molecular differences that might also explain the differences in CNS relapse risk. Methodologic differences in BRCA1/BRCA2 mutation detection may cause some under ascertainment of carriers in this older cohort.…”

Relationship Between Hereditary Cancer Syndromes and Oncotype DX Recurrence Score

“…The RS is used to stratify early-stage hormone receptorepositive breast tumors into those with disease likely to respond to adjuvant cytotoxic chemotherapy. On the basis of existing cut points established by Genomic Health at the time of the study, RS was categorized into 3 risk groups: low (0-17), intermediate (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and high (! 31).…”

“…Studies have shown that patients with BRCA-associated breast cancers may have enhanced sensitivity to cytotoxic chemotherapy. [19][20][21][22] Although BRCA-associated tumors may have more aggressive features than sporadic breast cancers as a whole, more recent data suggest individuals with BRCA-associated breast cancers tend to have similar outcomes to those with sporadic cancers. 19,23e25 Additional studies of BRCA carriers have illustrated that they have a higher median RS, more high RS disease, more intermediate RS disease, and less low RS disease compared to sporadic breast cancer cases.…”

“…19,23e25 Additional studies of BRCA carriers have illustrated that they have a higher median RS, more high RS disease, more intermediate RS disease, and less low RS disease compared to sporadic breast cancer cases. 22,26,27 Although data exist describing the associations between RS with pathogenic mutation status, there is no description of the use of ODX as an independent predictor of germline mutations in patients with undiagnosed hereditary cancer syndromes. Additionally, there are no other studies describing the association of ODX with hereditary mutations other than BRCA1 and BRCA2.…”

PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside

“…Breast cancer risk begins to rise at younger ages for BRCA1 mutation carriers compared with BRCA2 carriers . BRCA1 ‐mutant breast cancers are more often high grade, triple negative (TNBC) cancers (negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 [HER2]) and have a basal epithelial phenotype; whereas BRCA2 ‐mutant breast cancers more often exhibit a luminal B phenotype with expression of hormone receptors that have higher Oncotype Dx recurrence scores compared with sporadic tumors . The National Comprehensive Cancer Network guidelines recommend genetic testing for all patients aged ≤60 years who have TNBC, because 15% to 33% of these individuals will have an abnormal gene mutation …”