miRNA(s) expression as predictive biomarkers in recurrent/metastatic cervical cancer: The NRG Oncology/GOG-0240 NIH Cancer Moonshot.

Abstract

5523 Background: Chemotherapy + pembrolizumab +/- bevacizumab (BEV) is the standard treatment for recurrent/metastatic (R/M) cervical cancer (CC). GOG-0240 was a predecessor registration trial demonstrating survival benefit with incorporation of BEV with chemotherapy in R/M CC. In the wake of KEYNOTE A18, prior exposure to immunotherapy (I-O) via incorporation of pembrolizumab with ChemoRT for frontline therapy (FIGO stage III-IVA) may limit I-O use in 1st-line R/M CC. The need for new agents and predictive biomarkers to guide BEV use is implicit. Aberrant expression of miRNAs in CC can drive oncogenic pathways and/or suppress tumor suppressor genes, highlighting their potential as therapeutic targets. Here we present miRNA differential expression from the NIH Cancer Moonshot, which aims to identify biomarkers and predictors of survival outcomes in R/M CC through evaluation of miRNA differential expression among patients treated with Chemotherapy +/- BEV. Methods: miRNA-sequencing of R/M CC tumors from GOG-0240 was performed. miRNA expression was profiled and correlated with overall survival across all cohorts and differentials among tumors treated with ChemoRx+BEV or ChemoRx-alone were compared. Results: In the ChemoRx-alone group, lower expression of miR443 was associated with improved survival. miR-4443 may play a role in modulating tumor progression and metastasis through its impact on cell migration/invasion mechanisms. In the ChemoRx+BEV group, lower miR-196b-3p was associated with better overall survival. MiR-196b-3p has been implicated in the progression of various cancers, acting as an oncogene by regulating gene expression pathways that promote cell proliferation, inhibit apoptosis, and enhance metastatic potential. In the overall study population, higher expression of miR-10a and miR-1307 was associated with better survival. miR-1307 is thought to down-regulate ING5, which in turn may regulate the PIK3A pathway. In contrast, higher expression of several miRNAs, notably miR-584, mi-223, miR-144 was associated with worse survival. Multiple miRNAs that interact with ARID1A, VEGFA, and PIK3A were implicated. Higher expression of miR-223-5p was associated with worse outcomes. miR-223-5p is hypothesized to inhibit ARID1A expression and has been suggested to affect inflammatory response. Similarly, miR-144-5p and miR-144-3p are thought to affect both ARID1A and VEGFA. expression. Higher miR-144-3p expression was associated with lower survival, which may imply that more suppression of ARID1A expression by miR-144-3p results in a worse outcome. Finally, miR-193-5p negatively effects survival and is suggested to affect PIK3CA. Conclusions: Low expression of miR443 (ChemoRx-alone group) and miR196b-3p (ChemoRx+BEV group) track with survival in R/M CC and may serve as biomarkers to guide bevacizumab use in this orphan disease.