NGS-based molecular profiling (a multi-center collaborative, observation study in Japan) highlights pathogenic variants of DNA-repair genes in advanced or recurrent endometrial cancer.

Abstract

e13510 Background: Although tumor molecular profiling has now become prevalent, next-generation sequencing (NGS)-based molecular profiling with adequate annotation is limited in recurrent endometrial cancers. We investigated the frequency of alterations in cancer-related genes in a Japanese cohort of incurable endometrial cancer patients. Methods: We enrolled 102 endometrial cancer patients, who had discontinued standard therapy, and extracted tumor DNA from their formalin-fixed paraffin-embedded specimens. Oncomine Comprehensive Assay v3 (ThermoFisher), which covers 161 cancer genes, was used as a comprehensive NGS assay. We only defined variants with the annotations “pathogenic” or “likely pathogenic.” Oncogenicity and actionability were defined with the Oncomine Knowledgebase and “Chrovis database” ( https://chrov.is/ ). The protocol was approved by the institutional ethics committee at each institute, and written informed consent was obtained from all patients before enrollment. Results: The ratios of pathogenic mutations in the PI3K-AKT pathway were 34.3%, 15.7%, and 3.9% for PIK3CA, PTEN, and AKT1, while those in the receptor tyrosine kinase-RAS-MAPK pathway were 3.9%, 2.0%, 3.9%, and 1.0% for FGFR2, KRAS, NF1, and BRAF, respectively. The pathogenic mutation ratios of TP53, ATM, CTNNB1, and FBXW7 were 21.6%, 3.9%, 10.8%, and 9.8%, respectively. In addition to 5.9% of MSH2 variants (five patients with 5-20% and one patient with 56% variant allele frequency (VAF)), pathogenic variants of BRCA1 and/or BRCA2 were identified in 7.8% (seven patients with 5-20% and one with 40% VAFs). Three fusion genes were identified in three patients ( TPR- NTRK1, ESR1- CCDC170, and TBL1XR1- PIK3CA). “Actionable” gene variants (applicable for clinical trials or approved drug available in Japan) were identified in 49.0% of patients. Candidate drugs for patients with actionable variants included ROS1/TRK, AKT, immune checkpoint, and PARP inhibitors. Conclusions: Molecular profiling in poor-prognostic endometrial cancer highlighted the significance of DNA-repair related genes ( TP53, ATM, BRCA1, and BRCA2) and Wnt-beta catenin signaling pathway, and the infrequent alterations in PTEN and KRAS genes, although PIK3CA was frequently mutated. Our data suggest that targeting DNA repair pathway (including PARP inhibitors), may be a treatment option in certain endometrial cancer patients. Clinical trial information: UMIN000027294.

Phase II study of niraparib in recurrent or persistent rare fraction of gynecologic malignancies with homologous recombination deficiency (JGOG2052)

“…Especially, uterine serous carcinoma is morphologically and biologically similar to ovarian serous carcinoma [ 17 ], and the mutation rate of BRCA1/2 in uterine serous carcinoma has been reported to be 9.1% and 6.3% [ 18 ]. Moreover, clinical studies that searched for cancer-related gene mutations in recurrent endometrial cancer in Japan were conducted in the medical institutions of the Japanese Gynecologic Oncology Group (JGOG), and the results were announced at American Society of Clinical Oncology in 2020 [ 19 ]. Among 102 cases of recurrent endometrial cancer, pathogenic or likely pathogenic variants of BRCA1/2 were detected in 8 cases (7.8%) (6 cases of the BRCA1 mutation, 2 cases of the BRCA2 mutation, and 2 duplicate cases).…”