Abstract PR-003: Half of CCNE1-amplified high-grade serous ovarian carcinomas are homologous recombination deficient and platinum-sensitive
Authors: Pikkusaari Sanna , Kahelin Essi , Oikkonen Jaana , Li Yilin , Micoli Giulia , Koskela Heidi , Rajavuori Anna , Hynninen Johanna , Hautaniemi Sampsa , Virtanen Anni , Kauppi Liisa 
Published: March 2024

Abstract
In ovarian high-grade serous carcinoma (HGSC), homologous recombination deficiency (HRD) sensitizes tumors to DNA-damaging platinum-based chemotherapy, as well as to poly-ADP-ribose polymerase inhibitors (PARPi), resulting in longer survival compared to HR-proficient patients. Cyclin E1 (CCNE1) amplified tumors are found in about 20% of HGSC patients and associate with poorer clinical outcomes. CCNE1 amplification is mutually exclusive with inactivating BRCA1/2 mutations, the best-established cause for HRD. This has led to the notion that CCNE1-amplified tumors are dependent on the HR pathway for viability i.e., are HR-proficient, but empirical data to demonstrate this are scarce. We set out to investigate whether in CCNE1-amplified HGSC, functional HR is indeed essential. Whole-genome sequencing (WGS) data from &gt;200 HGSOC patients has to date been produced as part of the DECIDER project (https://www.deciderproject.eu/); from this cohort, we identified 51 CCNE1-amplified cases (defined as at least 8 CCNE1 copies and 2x tumor ploidy). As expected, no BRCA1/2-mutated patients were found in this cohort. For each CCNE1-amplified patient, we aimed to assess CCNE1 protein levels by IHC from at least one tumor site, obtain genomics-based HRD estimates and quantify functional HR capacity based on positivity for RAD51, a key HR protein marker that predicts clinically relevant HRD (Pikkusaari et al. 2023, PMID 36805632). So far, we have analyzed 29 CCNE1-amplified tumor specimens from 24 HGSC patients, all FIGO stage IIIB or higher. A third of samples displayed genomic HRD, i.e., were positive for mutational signature SBS3+ and/or ovaHRDscar+ (Perez-Villatoro et al. 2022, PMID 36581696); 50% were functionally HR-deficient, as measured by the RAD51 assay. Our findings thus challenge the dogma that CCNE1 amplification is mutually exclusive with HRD. Moreover, clinical outcomes of HR-deficient vs. HR-proficient CCNE1-amplified patients were significantly better (11/12 vs. 1/12 with complete response to primary therapy, median progression-free survival of 511 days vs. 316 days, respectively), indicating that our assays are measuring clinically meaningful HRD, and that HRD is a major driver of favorable platinum response also in the CCNE1-amplified cohort. It follows that the HR-deficient CCNE1-amplified subgroup would be expected to benefit from PARPi therapy as well. Our results indicate that CCNE1 amplification alone is not a surrogate marker for HR-proficient HGSC, nor an optimal predictive biomarker of chemotherapy resistance in HGSC. Instead, HRD – which in CCNE1-amplified tumors appears to not be consistently detectable by genomics-based HRD assays and therefore necessitates functional HRD testing – should be incorporated into patient stratification within the CCNE1-amplified patient population, to identify platinum-sensitive (and presumably, PARPi-sensitive) cases.
Citation Format: Sanna Pikkusaari, Essi Kahelin, Jaana Oikkonen, Yilin Li, Giulia Micoli, Heidi Koskela, Anna Rajavuori, Johanna Hynninen, Sampsa Hautaniemi, Anni Virtanen, Liisa Kauppi. Half of CCNE1-amplified high-grade serous ovarian carcinomas are homologous recombination deficient and platinum-sensitive [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr PR-003.