Abstract P3-05-59: ER+ HER2-negative mBRCA1/2 carriers breast cancer patients (n=81): Clinical outcomes and molecular characterization via the 21-gene Breast Recurrence Score (RS) test vs the general RS-tested population (799,986 samples)
Authors: Yerushalmi Rinat , Pomerantz Adi , Lewin Ron , Paluch-Shimon Shani , Soussan-Gutman Lior , Baehner Frederick , Voet Hillary , Bareket-Samish Avital , Kedar Inbal , Goldberg Yael , Peretz-Yablonski Tamar , Kadouri Luna 
Published: March 2023

Abstract
Background: The RS assay is a validated prognosticator/predictor of chemotherapy (CT) benefit in ER+ HER2-negative early-stage breast cancer (BC). It is offered to pts irrespective of BRCA1/2 status. We compared RS results, single-gene expression and gene group scores, between pts with germline BRCA1/2 mutations and the general BC pt population undergoing RS testing. Treatments/outcomes in the mBRCA1/2 cohort were also examined.
Methods: This real-life retrospective cohort study included consecutive ER+ HER2-negative mBRCA1/2 female carriers BC pts who had RS testing in 2004-2015. RS and gene expression data were compared to a previously described commercial use database (DB) (J Surg Oncol. 2020;122:611). Chi-square test and 1-sample t-test were used to compare RS distribution and single gene/gene group scores, respectively, between the cohort and the DB. Independent sample t-test was used to compare gene expression/gene group scores across pt subgroups within the mBRCA1/2 cohort. Fisher’s test/logistic regression were used to identify variables associated with distant recurrence in the mBRCA1/2 cohort.
Results: The analysis included 81 pts in the mBRCA1/2 cohort and 799,986 BC samples in the DB. Age at diagnosis was younger in the mBRCA1/2 pts vs the DB (median [IQR], 56 [47-61.5] vs 60 [51-67] yrs; P&lt;.001). In mBRCA1 and mBRCA2 pts (32 and 48 pts, respectively; for 1 pt, the BRCA gene involved was unknown), RS distribution shifted towards the high RS category when compared to the DB (Table). Comparing single-gene expression and gene group scores in mBRCA1 pts vs the DB, revealed statistically significant differences in 12 of the 16 cancer genes in the RS assay, and in 2 gene group scores, all in a direction contributing to higher RS results. Similar analysis with mBRCA2 pts, revealed significant differences in expression of 10 genes and 3 gene group scores, all in a direction contributing to higher RS results. The only statistically significant difference in gene expression between the mBRCA1 and mBRCA2 pts was in the ESR (higher in mBRCA2 pts; P=.0407) and MYBL2 gene (higher in mBRCA1 pts; P=.0365) (Table). Of the 32 mBRCA1 pts, 18 (56%) received CT (RS 0-25, 1/14 [7%]; RS 26-100, 17/18 [94%]; treatment information was unavailable for 1 pt). Of the 48 mBRCA2 pts, 19 (40%) received CT (RS 0-25, 5/27 [19%]; RS 26-100, 14/21 [67%]). With a median (IQR) follow up of 8.2 (5.6-9.7) yrs from diagnosis, 9 pts had distant recurrence (1 mBRCA1 pt, 8 mBRCA2 pts). Their median RS result was 25 (range, 16-41), and 4 received adjuvant CT. No statistically significant differences were observed between these 9 pts and the 72 non-recurring pts in terms of pt/disease characteristics and CT treatment. A trend towards significance was observed with respect to the BRCA gene involved (recurrence rate of 3.1% in mBRCA1 pts vs 16.7% in mBRCA2 pts, P=.078). A statistically significant association was found between the proliferation and invasion gene group scores and the odds of having distant recurrence (proliferation group score: odds ratio [OR], 23.60 [95% CI, 1.4-397], P=.0281; invasion group score: OR, 5.1 [95% CI, 1.1-23], P=.0339). The ER and HER2 gene groups scores were not associated with distant recurrence.
Conclusions: Both mBRCA1 and mBRCA2 carriers are characterized by higher RS results that stem from a distinct gene expression profile of most genes in the RS assay.
Single Gene Expression and Gene Group Scores vs the Commercial Use DB
Citation Format: Rinat Yerushalmi, Adi Pomerantz, Ron Lewin, Shani Paluch-Shimon, Lior Soussan-Gutman, Frederick Baehner, Hillary Voet, Avital Bareket-Samish, Inbal Kedar, Yael Goldberg, Tamar Peretz-Yablonski, Luna Kadouri. ER+ HER2-negative mBRCA1/2 carriers breast cancer patients (n=81): Clinical outcomes and molecular characterization via the 21-gene Breast Recurrence Score (RS) test vs the general RS-tested population (799,986 samples) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-59.