Biomarker Assessment of HR Deficiency, Tumor BRCA1/2 Mutations, and CCNE1 Copy Number in Ovarian Cancer: Associations with Clinical Outcome Following Platinum Monotherapy

• Published in: Molecular cancer research Vol. 16; no. 7; pp. 1103 - 1111
• Main Authors: Stronach, Euan A, Paul, James, Timms, Kirsten M, Hughes, Elisha, Brown, Krystal, Neff, Christopher, Perry, Michael, Gutin, Alexander, El-Bahrawy, Mona, Steel, Jennifer H, Liu, Xinxue, Lewsley, Liz-Anne, Siddiqui, Nadeem, Gabra, Hani, Lanchbury, Jerry S, Brown, Robert
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.07.2018
• Subjects: Aged; Amplification; Biomarkers; Biomarkers, Tumor - genetics; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Breast cancer; Cancer; Carboplatin; Carboplatin - administration & dosage; Copy number; Cyclin E - genetics; Disease-Free Survival; DNA Copy Number Variations - genetics; Female; Homologous recombination; Homologous Recombination - genetics; Homology; Humans; Loss of Heterozygosity; Middle Aged; Mutation; Oncogene Proteins - genetics; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Patients; Platinum; Subgroups; Survival; Treatment Outcome; Tumors
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-18-0034

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 ( = 250), with high-grade serous (HGSOC) subgroup analysis ( = 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, = 0.00015; tBRCA = 0.0096), and the HGSOC subgroup (HRD, = 0.0016; tBRCA = 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, = 0.00021; CCNE1 status = 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 ( = 0.049 and = 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. 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. .