Molecular characterization of ovarian carcinosarcoma reveals heterogeneous oncogenic mechanisms
Gurdial Dhillon1, Cheng Han Lee2,3, Marta Llaurado Fernandez1, Basile Tessier Cloutier4, Dina Bassiouny5,6, Keiyan Sy6, Nelson Wong2, Allan Covens5,6, Martin Kobel7, Jennifer Pors2, Guangming Han8, Mark S Carey1,2.
1University of British Columbia, Vancouver, BC, Canada; 2BC Cancer Agency, Vancouver, BC, Canada; 3University of University of Alberta, Edmonton, AB, Canada; 4McGill University, Montreal, QC, Canada; 5Sunnybrook Hospital, Toronto, ON, Canada; 6University of Toronto, Toronto, BC, Canada; 7University of Calgary, Calgary, AB, Canada; 8Surrey Memorial Hospital, Surrey, BC, Canada
Objective(s): Ovarian carcinosarcoma (OCS) is a rare and lethal variant of ovarian cancer. Despite its incredibly poor prognosis, it has received little research attention. In this study, our first aim is to molecularly characterize a series of OCS cases. Additionally, in a contemporary cohort, we aimed to evaluate if any molecular features confer prognostic and/or therapeutic significance.
Study methods: For molecular characterization, we examined 30 OCS by immunohistochemistry (IHC) and by targeted panel sequencing of 26 cancer genes collected from cases from 2003-2013 at Sunnybrook Hospital in Toronto. From November 2016 to April 2023, we then collected an additional 57 ovarian carcinosarcoma cases from BC Cancer Agency (Vancouver, BC), University of Alberta (Edmonton, AB) and University of Calgary (Calgary, AB). The primary end point for overall survival (OS) was calculated as a time from the date of pathologically confirmed diagnosis till death or date of last known follow up. The Kaplan–Meier method was used to estimate overall survival, and differences in survival rates were compared using the log-rank test. All tests were two-sided. A p-value of less than 0.05 was considered statistically significant.
Results: Most OCS (82%) harbored TP53 mutations and/or exhibited abnormal pattern by p53 IHC staining concordant between the carcinomatous and sarcomatous components. All endometrioid or clear cell histologies had wildtype p53 IHC staining. Median survival of the p53 abnormal cohort (47 patients) was significantly higher (62 months) compared to the p53 wildtype cohort (10 patients/21 months; P <0.01). Remarkably, within the p53 abnormal cohort, seven patients with germline or somatic BRCA mutations were all still alive at 3 years from diagnosis compared to 51% in the BRCA wildtype cohort (33 patients; P = .022). All BRCA 1/ 2 mutated patients received PARP inhibitors as maintenance therapy.
Conclusion: Most carcinosarcomas have a morphologic and molecular profile resembling high-grade serous ovarian carcinoma, however some OCS represent a distinct metaplastic subtype that likely evolved through non-serous/endometriosis oncogenic pathway. This molecular distinction has both prognostic and treatment (predictive) implications. We also emphasize the clinical need for diagnostic testing including p53 IHC and BRCA testing.