Predictive Biomarkers and Personalized Medicine Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome

Purpose:High-grade serous cancer (HGSC) is themost common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. Experimental Design:We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). Results: LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOHandwas further divided into two subgroups. The secondgroup contained remarkably less LOH.BRCA1 promotermethylationwas associatedwith themajor group. LOHclusterswere reproduciblewhen validated in two independentHGSCdatasets. LOHburden in themajor cluster ofHGSCwas similar to triple-negative, anddistinct fromotherhigh-gradebreast cancers.Our analysis revealed anLOHclusterwith lower treatment resistance and a significant correlation between LOH burden and PFS. Conclusions: SeparatingHGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors. Clin Cancer Res; 18(20); 1–10. 2012 AACR.