ARID1A alterations in gynecological cancers as a therapeutic opportunity.

Abstract

e17044 Background: Gynecologic cancers (GC) affect women's reproductive organs and are associated with the highest mortality rates due to late stage detection and lack of effective treatments. The tumor suppressor ARID1A regulates gene expression, maintains genomic integrity by interacting with ATR and is frequently inactivated in GC. We evaluated ARID1A alterations in gynecological cancers to identify new therapeutic options. Methods: Comprehensive genomic profiling was performed in 72 GC (10 primary, 60 metastatic, 2 unknown). Targeted sequencing was performed using a 562 cancer-associated gene panel on paired FFPE tumor and blood DNA samples. Results: ARID1A alterations were noted in 21% (15/72) of GC cancers, including 6/38 ovarian (2 each clear cell and ovarian serous tumor and 1 endometrioid), 5/14 endometrial, 2/7 cervical and 2/4 carcinosarcomas/MMMT. Alterations included frameshifts, nonsense mutations and INDELs, which are predicted to cause loss of ARID1A function. Interestingly, we found that 73% (11/15) of the tumors with ARID1A alterations frequently harbored alterations that lead to activation of the PI3K/AKT signaling pathway, which may increase sensitivity to PI3K/AKT pathway inhibitors, compared to only 32% (18/57) in tumors without ARID1A alterations. Mutations in the C-terminus of ARID1A, the region that interacts with ATR, mediating its recruitment to double stranded breakpoints, was observed in 40% (6/11) of tumors. Further, deleterious events in the DNA repair pathway were found in 33% (5/15) of ARID1A mutated samples, suggesting a role for PARP inhibitor therapy. Of 41 (57%) patients with TP53 mutations, only 7% were found to have concurrent ARID1A alteration. No pathogenic changes were present in the MMR genes of ARID1A altered samples. Conclusions: Targeted sequencing demonstrated that ARID1A alterations are a frequent event in GC, particularly in endometrial cancer. These alterations lead to an activation of the PI3K/AKT pathway, which indicate therapeutic opportunities with inhibitors of the PI3K/AKT pathway. The presence of pathogenic changes in the DNA repair pathway may predict clinical utility of PARP inhibitors in gynecologic cancers.