Evidence-based Review on USC in January 2021 Gynecologic Oncology

Uterine serous carcinoma (USC) is a distinct type of uterine cancer with a poor prognosis, and is responsible for up to 40 percent of uterine cancer-related deaths. The January 2021 edition of Gynecologic Oncology features an evidence-based review, “Uterine serous carcinoma: Molecular features, clinical management, and new and future therapies,” which outlines the molecular characteristics of USC as well as the development of promising therapeutic strategies.

According to the article, molecular features of USC include TP53 mutation, cell cycle changes, ERBB2 amplification, and changes in PI3K signaling. “It is important to understand USC as a distinct type of endometrial cancer, not only clinically, given its aggressive nature and disproportionately high mortality, but also histologically and molecularly,” said first author Elizabeth Lee, MD.

Dr. Lee also explained why USC is so difficult to diagnose. “Uterine serous carcinoma may be less likely to present with typical post-menopausal bleeding symptoms,” she said. “Due to early distant spread, it is more difficult to diagnose at an early stage and patients may present with symptoms that are not typically associated with endometrial cancers, such as cough from distant pulmonary spread.”
The authors noted several recent advances in therapies for USC, such as the addition of trastuzumab to chemotherapy in ERBB2-amplified cancers and the combination of pembrolizumab and lenvatinib.

“Available data supports the consideration of these therapies in women with advanced USC,” said Dr. Lee. “The PFS and OS benefit of trastuzumab added to chemotherapy was demonstrated in a randomized phase 2 trial and is considered the preferred upfront regimen for HER2-positive advanced USC. A cooperative group, randomized trial currently in development further seeks to define the benefit of a number of HER2-directed therapies in HER2-positive USC.”

Dr. Lee added that the combination of pembrolizumab/lenvatinib received accelerated FDA approval based upon the strength of a single arm phase 2 trial.  Recently, top-line results from the confirmatory randomized phase 3 KEYNOTE-775/Study 309 reported both OS and PFS benefits of pembrolizumab/lenvatinib compared to doxorubicin or paclitaxel monotherapy in women with previously-treated endometrial cancer, the majority of whom were MMR-proficient.

“We eagerly await presentation of the full data, which could support the role of pembrolizumab/lenvatinib as the new standard of care therapy for recurrent endometrial cancers, inclusive of USC,” she said.

In addition to novel therapies targeting HER2 and PI3K signaling or the DNA damage response pathway, Dr. Lee mentioned other treatments that might be on the horizon for USC. “Multiple avenues of drug development in USC are ongoing,” she said. “Promising avenues of exploration include combinatorial strategies with immunotherapy and antibody drug conjugates.

“While historically we have had limited therapies for this discrete cancer subtype, our understanding of its molecular characteristics has greatly increased in recent years, leading to the development of promising therapeutic strategies.”