Germline BRCA screening for locally advanced breast cancer treated by neoadjuvant chemotherapy: Defining a subgroup with high rate of mutation and local relapses

Abstract Introduction: Neoadjuvant chemotherapy (NAC) is proposed for locally advanced breast cancer (LABC) to increase the breast conservative treatment (BCT). In France, mastectomy is the risk-reducing prophylactic surgical strategy only for pre-symptomatic germline BRCA-mutated (gBRCAm) patients. On the other hand, BCT is proposed to all patients following NAC based on clinical response, even for patients do not demonstrating germline BRCA mutation. Moreover, in the case of BRCA mutation, local recurrence risk is higher in the BCT group (23%) vs mastectomy (5%). The aim of this retrospective one-institution analysis is to evaluate if the knowledge of gBRCAm status impact shared surgical decision between surgeons and patients. Patients and methods: Inclusion criteria were: (i) patients treated for unilateral LABC, T2-4, N≥0, M0 by NAC, and (ii) patients who underwent germline BRCA screening. BRCA screening, using targeted next-generation screening, was carried out either during NAC (rapid process) or after surgery. Deleterious mutations were confirmed using Sanger sequencing before passing on the results to the clinical geneticist. Some gBRCAm patients from Olympia clinical trial study were also included. Patients were followed-up over a long term for overall survival (OS), local recurrence (LR) and disease-free recurrence interval (DRFI). Chi-square, Fischer test and T-test and Wilcoxon test were used to generate statistical descriptive analysis. Results: Between 2007 and 2015, 988 women were treated for LABC at our institution. Among them, 151 patients underwent clinical genetic testing for gBRCAm based on these criteria: young age at diagnosis or familial history of breast or ovarian cancer or histological characteristics as grade 2/3, Her2-3+ or basal like. A total of 125 patients were included in the study; 27 patients had germline mutations (MT group) and no mutations were detected in 98 patients (WT). Significant differences between the two groups (MT vs WT) were observed for - Intrinsic tumor subtypes basal like (64.3% vs 42.5%, p=0.0432) - ER are more often negative (21.4% vs 46.8%, p=0.0165). Among the 29 patients who underwent germline screening during NAC and eligible for BCT, all the patients with gBRCAm choose mastectomy (100%). Among the 96 patients with screening mutation after breast cancer treatment, 6 of the 19 patients with gBRCAm had a mastectomy (28%). In the 25 gBRCAm patients, 15 had a BCT and 11 a mastectomy. In the 98 wtBRCA patients, 70 had a BCT and 28 a mastectomy. After a follow-up of 76.8 months of 83 patients with BCT, we observed 9 LR, 7% in the WT group and 30.8% in the MT group. The median delay of disease recurrence is 40.8 months [22-113]. According DRFI and OS, there is not statistically difference between the WT and the MT group, at 3 years and 5 years of follow up. Discussion: In this selected subgroup of patients, gBRCAm rate is higher (21%) than the rate based on familial criteria for BRCA testing (12%). Regarding the rationale for BCT or mastectomy procedure in LABC and pre-symptomatic gBRCAm patients, this study led us to establish mastectomy as the sole risk-reducing strategy surgery procedure for gBRCAm patients. Moreover, 100% gBRCAm patients chose mastectomy; the mastectomy rate was lower when the patient was unaware of their BRCA status (26%). The LR rate was higher in the gBRCAm vs wtBRCA with a statistical difference. In LABC patients with high genetic risk, the knowledge of mutation status could influence patients’ and surgeons’ choice of surgery. In case of gBRCAm status, mastectomy is recommended to decrease LR risk Citation Format: Nicolas Sevenet, Christine Tunon de Lara, Jeanne Leroux, Françoise Bonnet, Marc Debled, Delfine Lafon, Emmanuelle Barouk-Simonet, Marion Fournier, Adeline Petit, Virginie Bubien, Nathalie Quenel-Tueux, Véronique Brouste, Gaëtan MacGrogan. Germline BRCA screening for locally advanced breast cancer treated by neoadjuvant chemotherapy: Defining a subgroup with high rate of mutation and local relapses [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-10.