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 ( = 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. .

Primary platinum resistance and immune exclusion in ovarian carcinomas with high expression of the homologous recombination mediator RAD51

“…A cohort of HGSOC was obtained from British Columbia Cancer (BCC TMA, n=308, SuppTable-1); samples of EOC from the SCOTROC4 clinical trial (n=309, SuppTable-2), chosen based on sample availability and divided equally between both study arms (23), were used as a tissue microarray (TMA). HRD score from the Myriad genomic scar assay was available for 240/309 cases on this TMA (24). Gene expression analysis, was performed on HGSOC and high grade endometrioid samples from the TCGA (n=566) (22), Australian Ovarian Cancer Study (AOCS, GSE9891; n=267) (25), Massachusetts General Hospital (MGH, GSE26712; n=185) (26) and Duke University Hospital (Duke, GSE3149; n=146) (27), which were extracted from CSIOVDB (28).…”

“…SCOTROC4 was a phase III clinical trial performed to assess two different dosing schedules of single agent carboplatin in EOC (23). While the trial showed no difference between the two arms, it represents a unique cohort of single agent platinum treated ovarian cancer with well-annotated survival data and HRD scores (24). Finally, we Confidential, Hoppe et al 8/6/2020 5 use a combination of in-vitro experiments and RNA expression data from four independent ovarian cancer datasets to demonstrate that the effect of RAD51 overexpression on survival is potentially mediated through an altered immune microenvironment in RAD51-High EOC.…”

Upregulated LncRNA‐CCAT1 promotes hepatocellular carcinoma progression by functioning as miR‐30c‐2‐3p sponge

“…A recent report found that the copy number variation of CCNE1 is a biomarker for ovarian tumours. 22 Ehedego et al found that the downregulation of CCNE1 markedly reduced the hepatitis and hepatocarcinogenesis. 29 Therefore, the investigation of the regulating network of CCNE1 in HCC is urgent.…”

“…19,20 CCNE1, a kind of cyclins, is required for cell cycle G1/S transition. 22 In spite of a study demonstrated that the down expression of CCNE1 reduced the liver tumorigenesis significantly in a mouse model, 23 the function of CCNE1 in human HCC is poorly understood. 22 In spite of a study demonstrated that the down expression of CCNE1 reduced the liver tumorigenesis significantly in a mouse model, 23 the function of CCNE1 in human HCC is poorly understood.…”

“…21 The abnormal expression of CCNE1 was reported in ovarian cancer. 22 In spite of a study demonstrated that the down expression of CCNE1 reduced the liver tumorigenesis significantly in a mouse model, 23 the function of CCNE1 in human HCC is poorly understood.…”