Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors.

ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium, including ovarian and uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). Loss-of-function mutations in ARID1A alter epigenetic regulation of transcription, cell-cycle checkpoint control, and DNA damage repair. We report here that mammalian cells with ARID1A deficiency harbor accumulated DNA base lesions and increased abasic (AP) sites, products of glycosylase in the first step of base excision repair (BER). ARID1A mutations also delayed recruitment kinetics of BER long-patch repair effectors. Although ARID1A-deficient tumors were not sensitive to monotherapy with DNA-methylating temozolomide (TMZ), the combination of TMZ with PARP inhibitors (PARPi) potently elicited double-strand DNA breaks, replication stress, and replication fork instability in ARID1A-deficient cells. The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A-mutated cancers to PARP inhibition, which warrants further experimental exploration and clinical trial validation. SIGNIFICANCE: The combination of temozolomide and PARP inhibitor exploits the specific DNA damage repair status of ARID1A-inactivated ovarian cancers to suppress tumor growth.

Fertility preservation for women with breast cancer before chemotherapy: a systematic review and meta-analysis.

The preservation of fertility in women of childbearing age with breast cancer is challenging because the time for ovarian stimulation is restricted and only a limited number of oocytes can be retrieved before gonadotoxic therapies. The aim of this meta-analysis was to evaluate the fertility preservation outcomes after ovarian stimulation with various protocols in women with breast cancer. PubMed, Embase and the Cochrane Library were searched. Twenty-two studies comparing the outcomes of women with breast cancer receiving random-start ovarian stimulation or conventional protocol; single or double ovarian stimulation cycles; and coadministration of aromatase inhibitors or tamoxifen were included. Random-start ovarian stimulation resulted in a comparable number of retrieved oocytes to the conventional protocol. Two ovarian stimulation cycles had significantly higher numbers of total retrieved oocytes than one cycle (mean difference 7.91, 95% confidence interval [CI] 3.42 to 12.40). Coadministration of letrozole and tamoxifen showed similar results for retrieved oocytes to those without. A significantly lower peak serum oestradiol concentration was observed in letrozole-based groups than in letrozole-free groups (mean difference -1.22; 95% CI -1.42 to -1.02). In conclusion, this study indicated that implementing random-start protocols to shorten the duration of waiting for ovarian stimulation, applying two ovarian stimulation cycles, and coadministration of letrozole can lead to more desirable outcomes.