Abstract P1-10-05: Evaluation of germline whole exome sequencing of early breast cancer patients with triple negative breast cancer (TNBC) included in a prospective study of neoadjuvant chemotherapy (NAC) with epirubicin and cyclophosphamide (EC) and carboplatin-paclitaxel (PC) (BSMO 2014-01)
Authors: Fontaine Christel , Renard Vincent , Van den Bulck Heidi , Vuylsteke Peter , Glorieux Philippe , Dopchie Catherine , Decoster Lore , Awada Ahmad , Wildiers Hans , De Brakeleer Sylvie , Teugels Erik , De Grève Jacques 
Published: March 2020

Abstract
Background: BSMO 2014-01 is a published prospective phase 2 study evaluating the efficacy of neoadjuvant EC and PC in the treatment of TNBC patients. (1) The addition of weekly carboplatin to neoadjuvant paclitaxel and dose-dense EC lead to a pathologic complete response (pCR) of 54%, comparable to prior studies. A secondary endpoint was to correlate pCR to homologous recombination (HR) and DNA damaging repair (DDR) deficiency due to germline mutations. Methods: Sixty-three patients (pts) of which nine already identified with a BRCA 1/2 mutation were considered. Peripheral blood was collected in 52 pts after obtaining informed consent for a broad genomic DNA analysis. Whole Exome Sequencing was performed, and only rare variants (M.A.F. &lt;0.01) with a strong impact on protein structure (nonsense, frameshift or splice-site variants) in genes involved in DNA damage repair (DDR) were further taken into consideration. The correlation between pCR rate and DDR deficiency or deficiency in Homologous Recombination repair or HR, a subclass of DDR deficiency, was analyzed using the Fisher's exact test. Results: Twenty nine out of the 52 investigated patients carried a germline mutation in a DDR gene. Twenty of these 29 pts had a pCR, while a pCR was observed in 8/23 patients without an DDR mutation (p=0.014). In 13/15 with an HR gene mutation a pCR was obtained, while the pCR was 15/37 in pts without an HR deficiency (p=0.003). DDR deficiency not involving HR genes lead to a pCR rate of 7/14, while this was 8/23 in pts without a mutation (p= 0.3). Conclusions: This is the first genomic study in early TNBC pts which demonstrates, that a germline mutation in any of the genes involved in DNA repair by homologous recombination, strongly predicts for a pCR on neoadjuvant chemotherapy with EC and PC. Other DDR gene mutations do not predict for an enhanced pCR rate compared to pts with no DDR gene mutations identified in their germline. Ref: C. Fontaine, V. Renard, H. Van den Bulk, P. Vuylsteke et al. Weekly carboplatin plus neoadjuvant anthracycline-taxane-based regimen in early triple-negative breast cancer: a prospective phase II trial by the Breast Cancer Task Force of the Belgian Society of Medical Oncology (BSMO). Breast Cancer Res Treat 2019.
Citation Format: Christel Fontaine, Vincent Renard, Heidi Van den Bulck, Peter Vuylsteke, Philippe Glorieux, Catherine Dopchie, Lore Decoster, Ahmad Awada, Hans Wildiers, Sylvie De Brakeleer, Erik Teugels, Jacques De Grève. Evaluation of germline whole exome sequencing of early breast cancer patients with triple negative breast cancer (TNBC) included in a prospective study of neoadjuvant chemotherapy (NAC) with epirubicin and cyclophosphamide (EC) and carboplatin-paclitaxel (PC) (BSMO 2014-01) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-05.