Abstract 5427: Genomic prevalence analysis in TNBC patients in the Phase 2 VIOLETTE study
Authors: Armenia Joshua , Lai Zhongwu , Tutt Andrew , Dean Emma , Loembe Bienvenu , McGarvey Hannah , Edgington Sarah , Barrett J Carl , Pierce Andrew J. , Harrington Elizabeth A. , Lukashchuk Natalia 
Published: September 2020

Introduction: Triple-negative breast cancer (TNBC) accounts for ~15-20% of all breast carcinomas. VIOLETTE is a global, multicentre, open-label, randomized phase 2b study (NCT03330847), recruiting patients with metastatic TNBC to 2 treatment arms: olaparib and olaparib + ceralasertib (ATR inhibitor AZD6738). Patients are prospectively tested for mutations in genes involved in homologous recombination repair (HRR) by tumor DNA sequencing for stratification into BRCA mutated (BRCAm), non-BRCA HRR mutated (HRRm), and HRR wild-type (HRRwt) strata in each treatment arm. Patients can also be recruited as a result of a local test and tumor sample for those patients is analysed retrospectively.

Methods: Sequencing of VIOLETTE tumor samples (prospective and retrospective) (n=518; DCO Sep 2019) using the FoundationOneCDx Clinical trial assay (CTA) test (Foundation Medicine [FMI]) was conducted to detect deleterious/suspected deleterious alterations, classified using AstraZeneca rules. Mutational zygosity and germline vs somatic status were assessed by a Somatic/ Germline/ Zygosity (SGZ) algorithm at FMI (Sun et al., 2018) and genome-wide LOH (loss of heterozygosity - gLOH) scores were generated.

Results: The most prevalent alterations were in TP53 (86%) and MYC (25%). Alterations in main cancer signaling pathways included the HRR pathway (23%: BRCA1, BRCA2, ATM, RAD51B, RAD51C, RAD54L, RAD51D, BRIP1, FANCL, PALB2, BARD1, CHEK1, CHEK2, CDK12, PPP2R2A), the PI3K pathway (39%; (PIK3CA - 17.8%; PTEN - 20.1%; AKT1 - 5%)), cell cycle (37%: RB1, CDKN2A, CCNE1, CCND1) and RTK/RAS (22%: NF1, KRAS, FGFR1, FGF19/FGF3/FGF4). Preclinical and clinical data suggest that alterations in HRR pathway genes are associated with sensitivity to PARP inhibitors including olaparib. The most prevalent HRR gene alterations were BRCA1 (9.5%) and BRCA2 (3%) and non-BRCAm HRRm prevalence was 11%. Out of 96 patients with reported zygosity, 81% (44/54) of BRCAm and 64% (27/42) of non-BRCAm HRRm tumors had biallelic inactivation. Consistent with gLOH being a measure of HRR deficiency, gLOH scores were significantly higher in BRCAm patients compared to HRRwt patients (mean BRCAm 28, mean HRRwt 19, P=2.1E-08). Interestingly, we observed a significant mutual exclusivity between alterations in the HRR pathway and activating PIK3CA variants (P=0.01), suggesting distinct disease segments within TNBC.

Conclusions: The genomic prevalence of breast cancer related alterations in VIOLETTE is as expected for TNBC, excepting HRRm, which was lower than anticipated from the TCGA dataset (23% VIOLETTE vs 35% TCGA). This may reflect the specific eligibility criteria for VIOLETTE. This is the largest dataset of genomic prevalence in TNBC reported, providing a deeper understanding of the prevalence of potentially actionable alterations to guide clinical development of targeted therapies.

Citation Format: Joshua Armenia, Zhongwu Lai, Andrew Tutt, Emma Dean, Bienvenu Loembe, Hannah McGarvey, Sarah Edgington, J Carl Barrett, Andrew J. Pierce, Elizabeth A. Harrington, Natalia Lukashchuk. Genomic prevalence analysis in TNBC patients in the Phase 2 VIOLETTE study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5427.