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

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Title: Biomarker assessment of HR deficiency, tumor BRCA1/2 mutations and CCNE1 copy number in ovarian cancer: associations with clinical outcome following platinum monotherapy
Authors: Stronach, EA
Paul, J
Timms, KM
Hughes, E
Brown, K
Neff, C
Perry, M
Gutin, A
El-Bahrawy, M
Steel, JH
Liu, X
Lewsley, L-A
Siddiqui, N
Gabra, H
Lanchbury, JS
Brown, R
Item Type: Journal Article
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. 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.
Issue Date: 1-Jul-2018
Date of Acceptance: 19-Apr-2018
URI: http://hdl.handle.net/10044/1/59251
DOI: https://dx.doi.org/10.1158/1541-7786.MCR-18-0034
ISSN: 1541-7786
Publisher: American Association for Cancer Research
Start Page: 1103
End Page: 1111
Journal / Book Title: Molecular Cancer Research
Volume: 16
Issue: 7
Copyright Statement: ©2018, American Association for Cancer Research.
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: 13086
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Cell Biology
BREAST-CANCER
PHASE-II
CHEMOTHERAPY
CARBOPLATIN
THERAPY
REPAIR
TRIAL
AMPLIFICATION
MULTICENTER
CARCINOMAS
Aged
BRCA1 Protein
BRCA2 Protein
Biomarkers, Tumor
Carboplatin
Cyclin E
DNA Copy Number Variations
Disease-Free Survival
Female
Homologous Recombination
Humans
Loss of Heterozygosity
Middle Aged
Mutation
Oncogene Proteins
Ovarian Neoplasms
Treatment Outcome
Humans
Ovarian Neoplasms
Carboplatin
Cyclin E
Oncogene Proteins
BRCA1 Protein
BRCA2 Protein
Disease-Free Survival
Treatment Outcome
Mutation
Loss of Heterozygosity
Aged
Middle Aged
Female
DNA Copy Number Variations
Homologous Recombination
Biomarkers, Tumor
Oncology & Carcinogenesis
Developmental Biology
1112 Oncology and Carcinogenesis
Publication Status: Published
Conference Place: United States
Online Publication Date: 2018-05-03
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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