752P - Clinical and molecular predictors of outcome in patients with tubo-ovarian high-grade serous carcinoma and exceptional survival

Background

Predictive markers of therapy response in BRCA-deficient tubo-ovarian high-grade serous carcinoma (HGSC) are poorly defined, especially in patients with a particularly unfavorable outcome. Our study seeks to uncover factors associated with exceptionally poor clinical outcomes, and identify therapeutic vulnerabilities.

Methods

Primary tumors from patients with advanced-stage HGSC with (n=105) or without (n=49) BRCA deficiency were analyzed using whole-genome sequencing, RNA-sequencing, and DNA methylation profiling. Clinicopathological features and tumor immune markers were assessed by multiplex immunofluorescence in 1389 patients with HGSC, including 282 with pathogenic germline BRCA variants (gBRCApvar). Key features were validated in an independent HGSC cohort (n=5875) from the Ovarian Tumor Tissue Analysis consortium.

Results

Suboptimal primary debulking surgery was associated with poor overall survival (OS) in non-carriers (p<0.001, HR 2.10) but was not significant in gBRCApvar-carriers with or without residual disease (p=0.188 and 0.221, HR 1.17 and 0.8, respectively). Patients with gBRCApvar located in the BRCA1 RING or C-terminal domains or BRCA2 DNA-binding domain did not have a favorable OS compared to non-carriers. HGSC patients with a homologous recombination deficiency (HRD) score ≥63 had significantly longer OS compared to those with HRD scores of 42-63 and <42, regardless of BRCA status. HGSC with clonal NF1 loss were associated with favorable outcome (median OS 12 years). Amplification of PIK3CA was associated with an exceptionally poor outcome in BRCA2-deficient HGSC (median OS 2.9 years). Patients with CCNE1 and AKT2 co-amplification (amp) had a significantly worse OS compared to unaltered HGSC (p=0.016, HR 2.50), and OS in those with CCNE1amp alone was not inferior to unaltered HGSC patients (p=0.698, HR 1.10).

Conclusions

The adverse effect of residual disease is diminished in gBRCApvar-carriers compared to non-carriers. HRD score correlated with survival but most poor survival carriers exceeded established HRD classification thresholds. NF1 loss and co-amp of AKT2 and CCNE1 appear to be associated with differential therapy response and survival.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

David Bowtell.

Funding

The National Health and Medical Research Council (NHMRC) of Australia, the National Institutes of Health (NIH) / National Cancer Institute and the U.S. Army Medical Research and Materiel Command Ovarian Cancer Research Program.

Disclosure

T.A. Zwimpfer: Financial interests, Personal, Research grant: Swiss National Foundation Postdoc Mobility Fellowship (P500PM_20726/1), Bangerter-Rhyner grant (0297), Freie Gesellschaft Basel. E.L. Christie: Financial interests, Personal, Research grant: Victorian Cancer Agency Mid-Career Fellowship (MCRF21004); Financial interests, Personal, Research grant, Funding of the Gynaecological Oncology Biobank at Westmead: National Health and Medical Research Council (NHMRC) of Australia (ID310670, ID628903), The Cancer Institute NSW (12/RIG/1-17, 15/RIG/1-16), Department of Gynaecological Oncology, Westmead Hospital, and the Sydney West Translational Cancer Research Centre (Cancer Institute NSW 15/TRC/1-01). G. Au-Yeung: Financial Interests, Institutional, Funding: AstraZeneca, Roche-Genentech. S. Ramus: Financial interest, Personal, Research grant: National Health and Medical Research Council (NHMRC) of Australia: 2009840. A. DeFazio: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca. D.D.L. Bowtell: Financial Interests, Institutional, Funding: AstraZeneca, Roche-Genentech, BeiGene; Financial Interests, Personal, Speaker, Consultant, Advisor: Exo Therapeutics. Financial interests, Personal, Research grant: National Health and Medical Research Council (NHMRC) of Australia: 1092856, 1117044 and 2008781. D.W. Garsed: Financial interests, Personal, Research grant: National Health and Medical Research Council (NHMRC) of Australia: 1186505 and 2029088, Victorian Cancer Agency / Ovarian Cancer Australia Low-Survival Cancer Philanthropic Mid-Career Research Fellowship: MCRF22018. All other authors have declared no conflicts of interest.