Molecular and immune profiling of TP53-mutated ovarian cancers with non-BRCA1/2 homologous recombination gene alterations.

Kyle C. Strickland Labcorp Oncology; Duke University Medical Center, Duke Cancer Institute, Department of Pathology, Durham, NC info_outline Kyle C. Strickland, Rebecca A. Previs, Zachary D Wallen, Mary K Nesline, Heidi Chwan Ko, Sarabjot Pabla, Stephanie Hastings, Taylor J. Jensen, Prasanth Reddy, Eric A Severson, Shakti Ramkissoon

Authors Kyle C. Strickland Labcorp Oncology; Duke University Medical Center, Duke Cancer Institute, Department of Pathology, Durham, NC info_outline Kyle C. Strickland, Rebecca A. Previs, Zachary D Wallen, Mary K Nesline, Heidi Chwan Ko, Sarabjot Pabla, Stephanie Hastings, Taylor J. Jensen, Prasanth Reddy, Eric A Severson, Shakti Ramkissoon Organizations Labcorp Oncology; Duke University Medical Center, Duke Cancer Institute, Department of Pathology, Durham, NC, Labcorp Oncology; Duke University Medical Center, Duke Cancer Institute, Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Durham, NC, Labcorp Oncology, Durham, NC Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Labcorp Background: Molecular alterations in homologous recombination (HR) pathway genes lead to HR deficiency (HRD) in ~50% of high grade serous ovarian carcinomas (HGSOC). The immune microenvironment of BRCA1/2-mutated HGSOC has been extensively characterized, in contrast to tumors with mutations in other HR genes. We evaluated a cohort of epithelial ovarian cancers (EOC) enriched for HGSOC and compared molecular and immune signatures of tumors with BRCA1/2 mutations ( BRCA m) to those with non-BRCA1/2 HR gene mutations (NBHRD). Methods: We characterized 173 EOC by comprehensive genomic and immune profiling (CGIP) using panel-based next-generation DNA (523 genes) and RNA sequencing (384 genes), respectively. We enriched for HGSOC by selecting for TP53 mutations and excluding tumors with non-serous histology or any mutation in POLE , MLH1 , PMS2 , MSH2 , MSH6 , or nucleotide excision repair genes. Tumors lacking BRCA1/2 -mutations were classified as NBHRD if a reportable mutation was present in canonical HR genes. Mutational burden (TMB, mut/Mb) was estimated from detected SNV/indels. We calculated immune-related expression signatures, including tumor immunogenicity score (TIGS), cellular proliferation (CP), and cancer testis antigen burden (CTAB). PD-L1 expression was assessed by tumor proportion score (TPS) following 22C3 immunohistochemistry. Differences in TMB, TIGS, CP, CTAB, PD-L1 and gene expression rank were tested for using Wilcoxon rank-sum test. Results: Of 173 EOC, 84 cases had complete CGIP, including 11 (13%) BRCA m, 7 (8%) NBHRD (Table), and 66 (79%) lacking HR gene alterations. On average, NBHRD tumors harbored lower TMB (4.1±2.3 vs. 6.6±2.3 vs. p=0.03) and elevated TIGS (59.1±16.2 vs. 41.7±16.2 p=0.044) compared to BRCA m tumors. We found no difference in PD-L1 (p=0.21), CP (p=0.26), or CTAB (p=0.48). Expression changes were identified in 32 immune genes, of which 31 (97%) were substantially up-regulated (1.3-3.3 fold) in NBHRD compared to BRCA m tumors. Conclusions: Our findings showed our cohort of NBHRD tumors were more immunogenic but less mutagenic than BRCA m tumors, implying enhanced immunogenicity unrelated to neoantigen load. Given that immune checkpoint inhibitors have shown limited efficacy in ovarian cancer, our data suggest NBHRD tumors may have stronger and possibly distinct immune escape mechanisms compared to BRCA m tumors. NBHRD mutations NBHRD Case Gene(s) Mutation(s) 1 ATM BRIP1 3085dupA (T1029fs) 517C>T (R173C) 2 FANCA 3494T>G (L1165*) 3 BRIP1 1871C>A (S624*) 4 BRIP1 2010dupT (E671*) 5 FANCF 388dupC (Q130fs) 6 BRIP1 1489delG (V497fs) 7 CHEK2 1100delC (T367fs)

Pre-clinical