Abstract 156: Mutational signature 3 predicts responses to olaparib plus buparlisib in triple-negative breast cancer and high-grade serous ovarian cancer
Authors: Batalini Felipe , Gulhan Doga , Mao Victor , Polak Madeline , Winer Eric P. , Mayer Erica L. , Matulonis Ursula A. , Konstantinopoulos Panagiotis A. , Park Peter , Wulf Gerburg M. 
Published: July 2021

Abstract
Background: Poly (ADP-ribose) polymerase (PARP) inhibitors target cancers with homologous recombination deficiency (HRD). Preclinical data showed PI3K inhibitors impair homologous recombination (HR) pathways; exposure may sensitize HR-proficient cancers to PARP inhibition. Single-base substitution mutational signature 3 (Sig3) is strongly associated with HRD. We report correlative analysis of Sig3 as predictor of response from a Phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120) in patients (pts) with advanced high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC).
Methods The parent trial (NCT01623349) is a multicenter phase 1b trial of escalating doses of olaparib and buparlisib. Eligible pts enrolled in the trial carried a diagnosis of advanced TNBC, HGSOC, or recurrent breast cancer of any histology with a germline BRCA1 or BRCA2 (BRCA1/2) mutation. Archival tumor tissue was available from 39 pts, and was analyzed by panel sequencing and whole-exome sequencing (WES). A score for the Sig3 was calculated from panel sequencing data and WES using SigMA. Genomic Instability Score (GIS) based on copy-number variation (CNV) were also calculated from WES data using scarHRD. Survival analyses and Cox regression were performed.Results: Our cohort comprised 39 pts (28 pts with HGSOC and 11 pts with TNBC). The median age was 58 years (range 34 - 78). Pts with Sig3+ tumors had a progression-free survival (PFS) of 7.7 months vs 5.6 months for those with Sig3- tumors (log-rank test; p = 0.036). CNV+ group did not differ significantly from CNV- group (log-rank test; p = 0.18). Even though Sig3 identified the majority of cancers with BRCA1/2 mutations (18/24), the PFS for pts with BRCA1/2 mutations was not statistically different from those with BRCA wild type tumors (log-rank test; p = 0.15). In our Cox regression model, Sig3+ had a significant positive impact on PFS (HR 0.27, CI 0.092 - 0.77, p = 0.015) while GIS did not (HR 0.41, CI 0.13 - 1.3, p = 0.14). We tested the influence of copy number alterations of genes associated with PARPi resistance on PFS, and identified ATR amplification as a feature of PARPi resistance (HR 4.48, p = 0.002).Conclusions: Within a trial that combined the PARP inhibitor olaparib and the PI3K inhibitor BKM120 in advanced ovarian and breast cancer, Sig3 positivity from panel sequencing data was associated with longer PFS while the CNV-based HRD prediction score (i.e. GIS) from WES was not. SigMA identified Sig3 from readily-available clinical sequencing as a candidate biomarker to refine patient selection for therapy with PARP inhibitors. Mutational signatures may improve HRD identification compared to a selection solely based on the mutation status of BRCA1/2 genes. Clinical utility should be explored in the setting of a confirmatory clinical trial.
Citation Format: Felipe Batalini, Doga Gulhan, Victor Mao, Madeline Polak, Eric P. Winer, Erica L. Mayer, Ursula A. Matulonis, Panagiotis A. Konstantinopoulos, Peter Park, Gerburg M. Wulf. Mutational signature 3 predicts responses to olaparib plus buparlisib in triple-negative breast cancer and high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 156.