Biomarker assessment of HR deficiency, tumor BRCA1/2 mutations, and CCNE1 copy number in ovarian cancer: Associations with clinical outcome following platinum monotherapy

Abstract

The current study evaluated three biomarkers [homologous recombination deficiency (HRD), tumor BRCA1/2 (tBRCA) mutations, and CCNE1 copy-number variation (CNV)] in ovarian tumors from patients enrolled on the SCOTROC4 clinical trial for associations with outcome following carboplatin monotherapy. Ovarian tumors (n ¼ 250), with high-grade serous (HGSOC) subgroup analysis (n ¼ 179) were classified as HRD positive (HRD score 42 or tBRCA mutation) and as CCNE1 amplification positive (CCNE1 CNV score >2.4). Seventy-four (30%) tumors were HRD positive, including 34 (14%) with tBRCA mutations. Forty-seven (19%) were CCNE1 amplification positive, all of which were tBRCA wild-type. HRD and tBRCA, but not CCNE1 amplification, were significantly associated with CA125 complete response in the entire cohort (HRD, P ¼ 0.00015; tBRCA P ¼ 0.0096), and the HGSOC subgroup (HRD, P ¼ 0.0016; tBRCA P ¼ 0.032). HRD and lack of CCNE1 amplification were associated with improved progression-free survival (PFS) and overall survival (OS) in the full cohort and HGSOC subgroup (HRD, P ¼ 0.00021; CCNE1 status P ¼ 0.038). HRD remained significant for OS and PFS after adjusting for clinical factors, while CCNE1 status only remained significant for PFS. Patients with HRD-positive tumors had greater PFS and OS benefit from platinum dose intensification than HRD-negative tumors (P ¼ 0.049 and P ¼ 0.035, respectively). An alternative exploratory HRD score threshold (33 or tBRCA mutation) was also significantly associated with both PFS and OS in the HGSOC subset. Implications: HRD, tumor BRCA1/2 mutations, and absence of CCNE1 amplification are associated with improved survival of ovarian cancer patients treated with platinum monotherapy and HRD-positive patients may benefit from platinum dose intensification.