Uterine serous carcinoma: key advances and novel treatment approaches

Abstract

The incidence and mortality rates from endometrial cancer continue to increase worldwide, while rates in most other cancers have either plateaued or declined considerably. Uterine serous carcinoma represents a fraction of all endometrial malignancies each year, yet this histology is responsible for nearly 40% of all endometrial cancer-related deaths. These deaths disproportionately affect black women, who have higher rates of advanced disease at diagnosis. Molecular genetic analyses reveal major alterations including TP53 mutation, PIK3CA mutation/amplification, ERBB2 amplification, CCNE1 amplification, FBXW7 mutation/deletion, PPP2R1A mutation, and somatic mutations involving homologous recombination genes. Clinical risk factors for uterine serous carcinoma include advancing age, a history of breast cancer, tamoxifen usage, and the hereditary breast–ovarian cancer syndrome. Surgery remains the cornerstone of treatment. Recent advances in our understanding of uterine serous carcinoma molecular drivers have led to development of targeted therapeutics that promise improved outcomes for patients. Overexpression or amplification of HER2 in uterine serous carcinoma carries a poor prognosis; yet this actionable target has led to the incorporation of several anti-HER2 therapies, including trastuzumab which, when added to conventional chemotherapy, is associated with improved survival for women with advanced and recurrent HER2-positive disease. The combination of pembrolizumab and lenvatinib is also a promising targeted treatment strategy for women with uterine serous carcinoma, with a recent phase II study suggesting a 50% response rate in women with recurrent disease. Several trials examining additional targeted agents are ongoing. Despite years of stalled progress, meaningful, tailored treatment options are emerging for patients with this uncommon and biologically aggressive endometrial cancer subtype.

Evaluation of a Patient With Non-Myoinvasive Uterine Serous Carcinoma Confined to a Polyp and Positive Peritoneal Washings With Somatic ARHGAP35 and KRAS Mutations

“…This patient also had TP53 and PIK3CA mutations with a low mutation frequency and microsatellite stable. These results are not unusual for this patient population but do have implications on prognosis and treatment [ 28 ]. In one study it was found that individuals with both TP53 and PIK3CA mutations had worse survival prognoses than those with only TP53 mutation [ 29 ].…”

Neural plasticity of the uterus: New targets for endometrial cancer?

“…However, a recent phase-II trial for the study of pembrolizumab in combination with lenvatinib (a multi-kinase inhibitor) has shown a 50% response rate in women with advanced serous endometrial disease. 64 The progression-free survival (7.2 vs 3.8 months; HR 0.56) and the overall survival (OS: 18.3 vs 11.4 months; HR 0.62) were significantly improved with the combination of both versus pembrolizumab monotherapy. 65 Based on this study, pembrolizumab with lenvatinib was also approved in an accelerated manner by the FDA for patients with previously treated metastatic EC whose tumors were not MSI-H/dMMR.…”

Sentinel lymph node biopsy in high-risk endometrial cancer: performance, outcomes, and future avenues

“…Previously, hysteroscope-guided peritumoral injection of ICG administered to >200 patients from a single center showed a para-aortic SLN detection rate of >50% [49]. However, a multicenter prospective randomized study of 165 patients who were administered hysteroscopeguided injection alone versus those administered cervical injection reported better pelvic SLN identification and a higher bilateral detection rate with the cervical injection method [50]. Another alternative is the fundal injection of ICG using a laparoscopic approach, which is usually performed sequentially with cervical ICG injection and pelvic SLN sampling.…”