Treatment Strategies for ARID1A-Deficient Ovarian Clear Cell Carcinoma

SIMPLE SUMMARY: Deleterious mutations in SWI/SNF chromatin remodeling genes, such as ARID1A, are present in more than 50% of cases of ovarian clear cell carcinoma (OCCC), a histological subtype of ovarian cancer prevalent in Asian countries. To efficiently treat OCCC, which is refractory to conventional platinum-based chemotherapy, several therapeutic strategies based on SWI/SNF deficiency have been proposed, including gemcitabine-based chemotherapy, synthetic lethal therapy, and immune checkpoint blockade therapy. Implementation of these strategies would improve the prognosis of patients with this disease. ABSTRACT: Ovarian clear cell carcinoma (OCCC) is a histological subtype of ovarian cancer that is more frequent in Asian countries (~25% of ovarian cancers) than in US/European countries (less than 10%). OCCC is refractory to conventional platinum-based chemotherapy, which is effective against high-grade serous carcinoma (HGSC), a major histological subtype of ovarian cancer. Notably, deleterious mutations in SWI/SNF chromatin remodeling genes, such as ARID1A, are common in OCCC but rare in HGSC. Because this complex regulates multiple cellular processes, including transcription and DNA repair, molecularly targeted therapies that exploit the consequences of SWI/SNF deficiency may have clinical efficacy against OCCC. Three such strategies have been proposed to date: prioritizing a gemcitabine-based chemotherapeutic regimen, synthetic lethal therapy targeting vulnerabilities conferred by SWI/SNF deficiency, and immune checkpoint blockade therapy that exploits the high mutational burden of ARID1A-deficient tumor. Thus, ARID1A deficiency has potential as a biomarker for precision medicine of ovarian cancer.