775P - A gene expression signature to predict benefit from intraperitoneal (IP) carboplatin chemotherapy in ovarian carcinoma (OC): Translational research study from the intraperitoneal therapy for ovarian cancer with carboplatin (iPocc) phase II/III trial

Background

The phase 3 iPocc trial reported improved progression-free survival (PFS) in OC patients receiving IP over intravenous (IV) carboplatin with IV dose-dense paclitaxel. We sought to identify biomarkers that can predict sensitivity to IP therapy.

Methods

117 pre-treatment frozen samples were subjected to mRNA profiling (Affymetrix HTA 2.0) and ACT Genomics ACTOnco®+ next generation sequencing. Cox regression analyses were performed to identify genes significantly correlated with PFS following IP treatment (p < 0.05). Homologous recombination repair deficiency (HRD) is defined by loss-of-heterozygosity (LOH) score ≥ 0.48.

Results

Patients receiving IP (n=61) or IV (n=56) had similar clinico-pathological distributions. We identified a 72-gene signature that was significantly correlated with PFS in IP but not in IV patients. Tumors harboring a signature with reduced VEGFA/VEGFR2 and PI3K signaling had low IP resistant score (IPRS) and were associated with improved outcomes for IP therapy. There was no difference in IPRS between BRCA1/2 wildtype and mutant tumors (p = 0.55). HRD tumors had a significantly higher IPRS than non-HRD tumors (p = 0.03). A high IPRS was significantly correlated with poorer PFS after IP therapy (median: ∼18 months vs not reached/NR, p < 0.0001), with no correlation seen after IV therapy (median: 25 vs 24 months, p = 0.9). Low IPRS IP patients had improved PFS compared with low IPRS IV patients (median: NR vs 25 months, p = 0.0261). Paradoxically, when IPRS is high, IP patients have worse PFS than IV patients (median: ∼18 vs 24 months, p = 0.004). Low IPRS was also able to predict improved outcomes in appendiceal cancer patients receiving hyperthermic IP therapy with the DNA cross-linking agent mitomycin-c (median PFS: 4.4 vs 1.5 years, p = 0.01).

Conclusions

The IPRS shows promise in identifying a subset of OC patients likely to benefit from IP platinum treatment. Validation in a larger cohort is warranted.

Clinical trial identification

NCT01506856.

Editorial acknowledgement

Legal entity responsible for the study

National University of Singapore.

Funding

The National Medical Research Council Singapore; Pangestu Family Foundation Gynaecologicla Cancer Research fund.

Disclosure

D.S. Tan: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Merck Serono, Roche, Eisai, GSK, Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, MSD, Eisai, Roche, Genmab, GSK, Boehringer Ingelheim; Financial Interests, Personal, Stocks/Shares: Asian Microbiome Library (AMiLi); Financial Interests, Institutional, Research Grant: Roche, Bayer, Karyopharm Therapeutics, AstraZeneca; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Bergen Bio; Financial Interests, Institutional, Local PI: Zeria Pharmaceutical Co Ltd., Bayer, Byondis B.V.; Financial Interests, Leadership Role, Ex society president: Gynecologic Cancer Group Singapore; Financial Interests, Member of Board of Directors: Gynaecologic Cancer Intergroup (GCIG); Financial Interests, Leadership Role, Ex- Chair: Asia-Pacific Gynecologic Oncology Trials Group (APGOT); Financial Interests, Institutional, Product Samples, Research Study: MSD, Eisai, AstraZeneca. N.Y.L. Ngoi: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck, Pfizer; Financial Interests, Personal, Other, honoraria: MSD. K. Yamamoto: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, CMIC holdings, Johokiko, Triceps, Kanagawa Medical Practitioners Association; Financial Interests, Personal, Other, Statistical analysis: Otsuka Pharmaceutical; Financial Interests, Personal, Other, Statistical consultation: J-Pharma, Craif, Kanagawa Prefectural Hospital Organization; Financial Interests, Institutional, Other, unlimited grant: Taiho Pharmaceutical; Financial Interests, Institutional, Other, Unlimited grant: Boehringer Ingelheim, Ono Pharmaceutical, Takeda Pharmaceutical, Bayer Yakuhin, Daiichi Sankyo, Astellas, Kyowa Kirin, Data Vehicle Inc., EP Croit. Y. Jan, S. Chen: Financial Interests, Personal, Full or part-time Employment: ACT Genomics. K. Fujiwara: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Takeda; Financial Interests, Personal, Advisory Board: MSD, Eisai, Genmab, Nano Carrier, Daiichi Sankyo, Seagen; Financial Interests, Personal, Other, Travel Expense: Clovis; Financial Interests, Institutional, Funding: Regenerone; Financial Interests, Institutional, Research Grant: MSD, Ono, Zeria, Genmab; Financial Interests, Personal and Institutional, Coordinating PI: AstraZeneca; Non-Financial Interests, Leadership Role: GOTIC. R. Huang: Financial Interests, Personal, Research Funding: Illumina. K. Hasegawa: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Takeda, Chugai, Genmab, Kaken, Eisai, Sanofi, GSK; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Funding, contracted research: MSD, Ono, Daiichi Sankyo, Eisai, Takeda. All other authors have declared no conflicts of interest.