Abstract 2473: Breast cancer whole genomes link homologous recombination deficiency (HRD) with therapeutic outcomes
Authors: Zhao Eric Y. , Shen Yaoqing , Pleasance Erin , Kasaian Katayoon , Jones Martin R. , Ch'ng Carolyn , Reisle Caralyn , Eirew Peter , Mungall Karen , Thiessen Nina , Ma Yussanne , Fok Alexandra , Mungall Andrew J. , Zhao Yongjun , Moore Richard , Villa Diego , Shenkier Tamara , Lohrisch Caroline , Chia Stephen , Yip Stephen , Gelmon Karen , Lim Howard , Sun Sophie , Schrader Kasmintan A. , Young Sean , Karsan Aly , Roscoe Robyn , Laskin Janessa , Marra Marco A. , Jones Steven J. 
Published: July 2017

Abstract
Background: Homologous recombination deficiency (HRD) is common in cancer - germline BRCA1 & BRCA2 mutations account for 5-10% of breast cancers and confer 85% lifetime risk. HRD cancers exhibit genomic instability and sensitivity to platinum-based therapy and PARP inhibitors. While not all causes of HRD are known, recent sequencing efforts have revealed genome-wide somatic mutation signatures that characterize the HRD genomic instability phenotype, also known as “BRCA-ness”. This provides a promising new assay to predict sensitivity to platinum-based therapy. Here, we integrate two whole-genome sequencing metrics to assess their association with therapeutic outcomes in a breast cancer cohort.
Methods: Whole-genome sequencing of 47 breast cancer tumors (100x coverage) and matched normals (60x) was performed on an Illumina HiSeq. Alignment, assembly, SNV calling, and loss of heterozygosity (LOH) detection were performed with BWA, ABySS, Strelka, and APOLLOH respectively. SNV signatures were deciphered by non-negative matrix factorization with Monte Carlo resampling. An HRD score comprised of LOH, telomeric allelic imbalance (TAI), and large scale transition (LST) counts was computed. Clinical endpoints were obtained by retrospective review of treatment and imaging reports. Analysis is ongoing in an independent validation cohort of 62 sequenced cases.
Results: The HRD-linked SNV signature was significantly associated with radiographic clinical response (CR) to platinum-based therapy (p=0.015). Logistic regression demonstrated a 59% improved odds of CR to platinum-based therapy per 1000 somatic SNVs attributed to HRD (odds ratio 1.16-2.50). Tumors carried up to 10,246 such SNVs and all patients with CR were among the top quartile. The LOH-TAI-LST score was correlated with SNV signature (r=0.6, p=7×10-6) and associated with CR (p=0.025). Notably, elevated HRD signatures associated with CR were identified in tumors with wild-type BRCA1/BRCA2 or variants of unknown significance. Tumors with above median HRD signatures were associated with a 69-day longer time to treatment failure and an 18% daily decreased probability of treatment failure per 1000 HRD-attributed SNVs (hazard ratio 0.71-0.95, p = 0.007).
Discussion: We found that HRD mutation signatures are associated with clinical response and longer time to treatment failure with platinum-based therapy. While similar benefits were observed in patients with somatic bi-allelic loss of BRCA1/BRCA2, such cases are less common (8% of our cohort) compared to those with elevated HRD signature. Thus, mutation signature methods may identify patients who stand to benefit from platinum-based therapy missed by BRCA screening alone.
Citation Format: Eric Y. Zhao, Yaoqing Shen, Erin Pleasance, Katayoon Kasaian, Martin R. Jones, Carolyn Ch'ng, Caralyn Reisle, Peter Eirew, Karen Mungall, Nina Thiessen, Yussanne Ma, Alexandra Fok, Andrew J. Mungall, Yongjun Zhao, Richard Moore, Diego Villa, Tamara Shenkier, Caroline Lohrisch, Stephen Chia, Stephen Yip, Karen Gelmon, Howard Lim, Sophie Sun, Kasmintan A. Schrader, Sean Young, Aly Karsan, Robyn Roscoe, Janessa Laskin, Marco A. Marra, Steven J. Jones. Breast cancer whole genomes link homologous recombination deficiency (HRD) with therapeutic outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2473. doi:10.1158/1538-7445.AM2017-2473