Molecular targeting of low-grade serous and mucinous carcinomas of the ovary or peritoneum

Over the past decade, the strategy for clinical trial design in making progress against epithelial cancers of the ovary/peritoneum/fallopian tube has changed dramatically. The NRG [the Gynecologic Oncology Group (GOG)] Rare Tumor Committee has been a leader in this transformation. No longer does “one size fit all.” Rather, separate clinical trials for rare subtypes have been developed, and, in some cases, completed. An enhanced understanding of their pathologic diagnosis, molecular biology, and clinical behavior has galvanized this change. Pathology studies have led to replacement of the International Federation of Gynecology and Obstetrics (FIGO) grading system of low-grade serous carcinoma to the binary grading system, and immunohistochemical studies have assisted in distinguishing mucinous carcinoma of the ovary from colorectal cancer. Historically, conventional chemotherapy has demonstrated very limited activity in both histologic subtypes. Preclinical studies have identified and elucidated genes and pathways in both—MAP kinase pathway, IGF1-R, the angiogenesis pathway, and possibly, the PI3K/AKT/mTOR pathway in low-grade serous carcinoma, and KRAS, HER-2/neu amplification, src, and the angiogenesis pathway in mucinous carcinoma—that may serve as targets for novel therapies. MEK inhibitor (MEKi) therapy has shown promising activity in patients with recurrent low-grade serous carcinoma, and the current emphasis is focused on the second generation of MEKi trials and combinations of MEKi and inhibitors of the PI3K/ AKT/mTOR pathway. For mucinous carcinoma, mEOC/GOG 0241 was designed to test both a colorectal cancer-type chemotherapy regimen and anti-angiogenesis therapy but closed prematurely due to slow accrual related to the rarity of this subtype. The experience with targeted therapy is otherwise extremely limited to date. The hope is that lessons learned from the failure of the mEOC/GOG 0241 trial will inform future trials. In summary, there is tremendous potential for progress against these two rare histologic subtypes by leveraging our knowledge of their molecular biology and translating this understanding into improved, novel therapeutics.