BRCA Mutation Association with Recurrence Score and Discordance in a Large Oncotype Database

Abstract

<b><i>Background:</i></b> The Oncotype DX Breast Cancer Assay is a 21-gene assay used to predict the likelihood of distant recurrence and the benefit of chemotherapy in patients with node-negative, tamoxifen-treated breast cancer. Prior studies demonstrated 7–19% discordance, or a difference between the recurrence score (RS) and tumor grade (TG) in breast cancer patients. BRCA mutated tumors (BRCA+) have been shown to be associated with higher RS as compared to BRCA-negative patients (BRCA–). <b><i>Objectives:</i></b> We developed a large Oncotype RS database to determine if the BRCA mutation status is associated with discordance. <b><i>Methods:</i></b> We identified 723 patients (32 [4%] mutation-positive and 691 [96%] mutation-negative patients) with early-stage, hormone-positive breast cancer treated between 2006 and 2018, with tumor characteristics available for analysis. Discordance was defined as one- or two-step difference between RS (low, intermediate, high risk) and TG (well [WD], moderately [MD], and poorly [PD] differentiated). Mutation positive was defined as BRCA1 deleterious mutation, BRCA2 deleterious mutation, BRCA mutation of unknown type, BRCA variant of undetermined significance (VUS) or other mutation (classified as other VUS). Number (%) or median were used to describe patient characteristics between groups and were compared by the Kruskal-Wallis test at a significance level of 5%. <b><i>Results:</i></b> Among these patients, there were 32 (4% of total) who were identified as mutation-positive. Of those patients, 16% had a documented deleterious mutation in BRCA1, 22% in BRCA2, 6% had a BRCA mutation of unknown type (either 1 or 2), 25% were BRCA VUS, and 31% other VUS (most commonly CHEK2 and ATM). The median RS was 23.5 in patients with deleterious BRCA mutations (1, 2 or unknown) versus 16 in patients in the BRCA-negative database, which was statistically significant (<i>p</i> < 0.01). One- and two-step discordance was present in 46 and 8%, respectively, of patients with deleterious BRCA mutations versus 53 and 11%, respectively, in the BRCA-negative database. <b><i>Conclusions:</i></b> Patients with deleterious BRCA mutations demonstrated no difference in rates of discordance as compared to BRCA-negative patients. We further demonstrated that patients with BRCA-positive tumors display higher RS than patients with BRCA-negative tumors.

Clinical outcomes and Oncotype DX Breast Recurrence Score® in early‐stageBRCA‐associated hormone receptor‐positive breast cancer

“…Even with the limitations of a small BRCAm cohort, a statistically significant and clinically relevant increase in RS was detected in patients with BRCA1 / BRCA2 mutations compared to those without and is substantiated by other reports. 17 , 18 , 19 This consequential finding should be further evaluated in larger studies. Given the biological differences between BRCAm and BRCAwt breast cancers, there is also concern that BRCAm patients may have a worse prognosis without chemotherapy even with a low RS, but currently, available data do not clearly validate this theory.…”

“…We demonstrated that BRCAm breast cancers are associated with higher Oncotype DX Breast Recurrence Scores ® , which is consistent with other reports. 17 , 18 , 19 To our knowledge, this is the first report that also includes survival data. In the overall population, lower RS is associated with improved OS.…”

“…Given the biological differences between BRCAm and BRCAwt breast cancers, there is also concern that BRCAm patients may have a worse prognosis without chemotherapy even with a low RS, but currently, available data do not clearly validate this theory. 17 , 23 Larger studies to evaluate if RS in BRCAm patients provides prognostic and predictive value similar to that observed in the general population are needed to further optimize therapy.…”

Stress, anxiety, and health-related quality of life in BRCA1/2-positive women with and without cancer: A comparison of four US female samples

“…Women with BRCA1/2 live with a 69–72% increased risk of breast cancer and 11–39% of ovarian cancer by the age of 70 ( BeBRCAware.org, 2022 ). The rate of breast cancer recurrence, estimated to be between 25 and 30%, is also elevated among BRCA1/2 -positive cancer survivors compared with cancer survivors without a BRCA1/2 genetic mutation ( Blanter et al, 2020 ). Depending on preventive treatment the risk for breast cancer recurrence varies, leading oncologists to recommend prophylactic mastectomy and salpingo-oophorectomy procedures once determined to be BRCA1/2 -positive ( Nilsson et al, 2014 ).…”