Management Of Uterine Serous Carcinoma Research Articles

Monitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers.

Uterine serous carcinoma (USC) and carcinosarcomas (CSs) are rare, highly aggressive variants of endometrial cancer. No reliable tumor biomarkers are currently available to guide response to treatment or detection of early recurrence in USC/CS patients. Circulating tumor DNA (ctDNA) identified using ultrasensitive technology such as droplet digital polymerase chain reaction (ddPCR) may represent a novel platform for the identification of occult disease. We explored the use of personalized ctDNA markers for monitoring USC and CS patients. Tumor and plasma samples from USC/CS patients were collected at the time of surgery and/or during the treatment course for assessment of tumor-specific somatic structural variants (SSVs) by a clinical-grade next-generation sequencing (NGS) platform (i.e., Foundation Medicine) and a droplet digital PCR instrument (Raindance, ddPCR). The level of ctDNA was quantified by droplet digital PCR in plasma samples and correlated to clinical findings, including CA-125 serum and/or computed tomography (CT) scanning results. The genomic-profiling-based assay identified mutated "driver" target genes for ctDNA analysis in all USC/CS patients. In multiple patients, longitudinal ctDNA testing was able to detect the presence of cancer cells before the recurrent tumor was clinically detectable by either CA-125 or CT scanning. Persistent undetectable levels of ctDNA following initial treatment were associated with prolonged progression-free and overall survival. In a USC patient, CA-125 and TP53 mutations but not PIK3CA mutations become undetectable in the plasma at the time of recurrence, suggesting that more than one customized probe should be used for monitoring ctDNA. Longitudinal ctDNA testing using tumor-informed assays may identify the presence of residual tumors, predict responses to treatment, and identify early recurrences in USC/CS patients. Recognition of disease persistence and/or recurrence through ctDNA surveillance may allow earlier treatment of recurrent disease and has the potential to change clinical practice in the management of USC and CS patients. CtDNA validation studies in USC/CS patients prospectively enrolled in treatment trials are warranted.

ADAGIO: a phase IIb international study of the Wee1 inhibitor adavosertib in women with recurrent or persistent uterine serous carcinoma

BackgroundUterine serous carcinoma is a distinct histologic subtype of endometrial cancer with an aggressive phenotype, poor prognosis, and limited therapeutic options. A previous proof-of-concept phase II trial of the Wee1...

ADAGIO: A phase IIb, open-label, single-arm, multicenter study assessing the efficacy and safety of adavosertib (AZD1775) as treatment for recurrent or persistent uterine serous carcinoma.

TPS5612 Background: There is a high unmet medical need for therapies treating uterine serous carcinoma (USC), an aggressive type of endometrial carcinoma with an increased likelihood of recurrence and limited therapeutic options. 5-year overall survival (OS) for USC is estimated to be 35–50% for women with stage I–II disease and 0–15% for women with stage III–IV disease (Acharya et al. Lancet Oncol 2005). USC exhibits high rates of mutation in TP53 ( > 90% of cases), as well as mutations or amplifications in other cell-cycle regulators or oncogenes, including CCNE1, FBXW7, MYC, RB1, and KRAS/ NRAS (Zhao et al. PNAS 2013; Levine DA et al. Nature 2013), which may contribute to increased replication stress and susceptibility to inhibition of the tyrosine kinase WEE1. WEE1 inhibition is expected to release a tumor cell from DNA-damage-induced arrest at the G2/M boundary, so that unrepaired DNA damage may be taken into mitosis, leading to cell death. A Phase II study of the WEE1 inhibitor adavosertib in 34 women with recurrent or persistent USC reported an objective response rate (ORR) of 29.4% and a median duration of response (DoR) of 9.0 months; further correlative analysis and a translational biopsy cohort are planned (Liu et al. J Clin Oncol 2020). This Phase IIb study, ADAGIO, a single-arm, multicenter, global study (NCT04590248), aims to expand on these findings and will evaluate the efficacy and safety of adavosertib in women with recurrent or persistent USC who have previously received platinum-based chemotherapy. Methods: Women aged ≥18 years with histologically confirmed recurrent or persistent USC who have previously received at least one platinum-based chemotherapy regimen for the management of USC and have evidence of measurable disease according to RECIST v1.1 are eligible for this study. Participants with carcinosarcomas are not eligible. Prior receipt of immune checkpoint inhibitors, vascular endothelial growth factor inhibitors and human epidermal growth factor receptor 2 targeted therapy is permitted, with no restriction on the number of prior lines of systemic therapy a participant may have previously received. Approximately 120 eligible participants will receive oral adavosertib 300 mg qd on days 1–5 and 8–12 of a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. The primary outcome measure is ORR, defined as the percentage of patients with measurable disease at baseline who have a confirmed complete or partial response, as determined by blinded independent central review (RECIST v1.1 assessment every 6 weeks for the first 48 weeks, then every 9 weeks). Secondary outcome measures include DoR, depth of response, progression-free survival, OS, disease control rate, biomarkers, safety, tolerability, and pharmacokinetics. Clinical trial information: NCT04590248.

Pathogenesis and Clinical Management of Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer–related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC.

Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Promotes Uterine Serous Cancer Cell Proliferation and Cell Cycle Progression.

Uterine serous carcinoma (USC) is the most aggressive form of endometrial cancer, with poor survival rates and high recurrence risk. Therefore, the purpose of this study was to identify therapeutic targets that could aid in the management of USC. By analyzing endometrial cancer samples from The Cancer Genome Atlas (TCGA), we found Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be highly expressed in USC and to correlate with poorer overall survival. UCHL1 silencing reduced cell proliferation in vitro and in vivo, cyclin B1 protein levels and cell cycle progression. Further studies showed that UCHL1 interacts with cyclin B1 and increases cyclin B1 protein stability by deubiquitination. Treatment of USC-bearing mice with the UCHL1-specific inhibitor reduced tumor growth and improved overall survival. Our findings suggest that cyclin B1 is a novel target of UCHL1 and targeting UCHL1 is a potential therapeutic strategy for USC.