Abstract C058: Clinical relevance of telomerase upregulation via TERT promoter mutation or TERC amplification in high-grade ovarian cancer

Abstract

Abstract Background: Increased telomerase activity confers a survival advantage to cancer cells and is considered one of the cancer hallmarks. The two main molecular mechanisms responsible for telomerase upregulation are the amplification of the telomerase RNA component gene (TERCamp) which serves as the template for telomeric repeats, and mutations in the telomerase reverse transcriptasegene promoter (TERTm), which encored the catalytic unit of telomerase. Increased telomerase activity has been detected in more than 90% of ovarian cancer (OC) but the clinical impact of this phenotype remains understudied. Methods: This retrospective analysis included all patients (pts) with high grade OC who underwent large-panel sequencing (Foundation Medicine) from National University Cancer Institute, Singapore and Institut Gustave Roussy, France. TERTm and TERCamp were correlated with clinical, pathological and molecular features as well as progression-free survival (PFS, calculated from histological diagnosis to first progression). Results: Out of the 503 pts with OC analyzed, 15 pts (3.0%) presented TERT mutation and 39 pts (7.8%) had TERC amplification. In the TERTm subgroup, only one hotspot mutation was detected (c.-124C>T). Compared to the wild-type (WT) group, there was significantly higher frequency of FIGO I/II diseases (57% vs 17%, p=0.001) and clear-cell histology (80% vs 14%, p<0.001). Consequently, there were more ARID1A and PIK3CA mutations and median loss of heterozygosity (LOH) score was significantly lower (5.3% vs 16.4%, p=0.006). Interestingly, TERTm were exclusive to P53 and BRCA1/2 mutations. With a follow-up of 64 months, the median PFS was 8.1 months, 18.7 months and 25.5 months for the TERTm, P53m and WT subgroups respectively (p=0.006). In the multivariate analysis, TERTm emerged as an independent negative prognostic biomarker. In the TERCamp subgroup, compared to WT, there was no difference in term of stage (74% of advanced stages vs 82%), or histologic type (77% of high-grade serous vs 71%). TERCamp was associated with a significantly higher tumor mutational load (6.2 mut/mbase vs 4.2, p<0.001), more P53 mutations (90% vs 72%, p=0.014), more BRCA1/2 mutations (33% vs 17%, p=0.016) and higher LOH (22% vs 15%, p=0.023). There were no statistical differences in terms of PFS. Conclusion: This study highlights intriguing heterogeneity in high-grade OC pts with telomerase upregulation. TERTm are associated with a clear-cell phenotype and TERTm and P53m define three prognostic subgroups among OC patients. On the other hand, TERCamp are detected in genomically unstable tumors presenting a higher mutational burden and copy-number alterations. These results emphasize the critical importance of the molecular mechanism underlying increased telomerase activity, which may impact the efficacy of telomerase-targeted therapy. Citation Format: Felix Blanc-Durand, Natalie Ngoi, Damien Vasseur, Patricia Pautier, Judith Michels, Kaissa Ouali, Catherine Genestie, Sophie Cotteret, Etenne Rouleau, Yi Wan Lim, Siew Eng Lim, Diana Lim, Silvana Talisa Wijaya, Alexandra Leary, David SP Tan. Clinical relevance of telomerase upregulation via TERT promoter mutation or TERC amplification in high-grade ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C058.