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

Stronach, E. A. et al. (2018) Biomarker assessment of HR deficiency, tumor BRCA1/2 mutations and CCNE1 copy number in ovarian cancer: associations with clinical outcome following platinum monotherapy. Molecular Cancer Research, 16(7), pp. 1103-1111. (doi: 10.1158/1541-7786.MCR-18-0034) (PMID:29724815)

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

• Item Type: Articles
• Additional Information: Support for this study was provided by Cancer Research UK (A13086), Ovarian Cancer Action, Imperial Biomedical Research Centre, and CRUK/NIHR Imperial Experimental Cancer Medicine Centre.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Paul, Mr James and Lewsley, Ms Liz-Anne
• Authors: Stronach, E. A., Paul, J., Timms, K. M., Hughes, E., Brown, K., Neff, C., Perry, M., Gutin, A., El-Bahrawy, M., Steel, J. H., Liu, X., Lewsley, L.-A., Siddiqui, N., Gabra, H., Lanchbury, J. S., and Brown, R.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Molecular Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1541-7786
• ISSN (Online): 1557-3125
• Published Online: 03 May 2018
• Copyright Holders: Copyright © 2018 American Association for Cancer Research
• First Published: First published in Molecular Cancer Research 16(7): 1103-1111
• Publisher Policy: Reproduced in accordance with the publisher copyright policy