Michael Toboni

Updates and controversies in the management of uterine serous carcinoma and uterine carcinosarcoma

Uterine serous carcinoma and uterine carcinosarcoma are among the rarest but most lethal endometrial cancer sub-types, accounting for 15% of all cases, and are responsible for more than 50% of related deaths. These malignancies are distinguished by a high likelihood of metastasis and multisite recurrence, making them biologically different from other endometrial cancer sub-types. This review aims to analyze the existing evidence regarding molecular classification, new biomarkers, and innovative treatment approaches for these high-risk tumors. Herein, we explored the role of biomarkers, including HER2, TP53, and mismatch repair deficiency/microsatellite instability hypermutated and their influence on treatment strategies, surveillance approaches, the potential role of circulating tumor deoxyribonucleic acid, novel precision-based treatment options, and disparate survival outcomes for non-Hispanic Black and other underserved minority patients, along with strategies to improve outcomes for these patients. Substantial progress has been made in the last 5 years, prompting the following question: What lies ahead in the next 5 years? Our current understanding of uterine serous carcinoma and carcinosarcoma underscores the necessity of continuing to prioritize biomarker-driven therapies and the development of novel treatments through clinical trials while integrating these new strategies with traditional approaches, such as surgical resection and cytotoxic chemotherapy.

Sociodemographic characteristics and cervical cancer survival in different regions of the United States: a National Cancer Database study

To determine how sociodemographic factors impact cervical cancer survival in different geographic locations in the USA. A retrospective cohort of patients with cervical cancer from January 1, 2004 to December 31, 2015 in the National Cancer Database (NCDB) was identified. Tumor characteristics as well as race, income, insurance type, and treating facility types were compared among nine geographic regions. χ A total of 48 787 patients were included. Survival was inferior in seven of nine regions for underinsured patients. In six regions survival was inferior for Medicaid and Medicare patients, respectively: Middle Atlantic: hazard ratio (HR) 1.25 and 1.22; South Atlantic: HR 1.41 and HR 1.22; East North Central: HR 1.36 and HR 1.25; East South Central: HR 1.37 and HR 1.25; West North Central: HR 1.67 and HR 1.42; West South Central: HR 1.44 and HR 1.46. In the Pacific region survival was inferior for Medicare patients (HR 1.35) but not inferior for Medicaid patients. Being uninsured was associated with worse survival in the South Atlantic (HR 1.23), East North Central (HR 1.23), East South Central (HR 1.56), and West South Central (HR 1.31) regions. Annual income level under $38 000 was associated with worse survival in the Middle Atlantic (HR 1.24), South Atlantic (HR 1.35), and East North Central (HR 1.49) regions. Lastly, when compared with academic research institutions, comprehensive community cancer centers had significantly worse survival in four of the nine regions. Cervical cancer mortality is higher for women with a low income, underinsured (Medicaid or Medicare) or uninsured status, and decreased access to academic institutions in most US regions. An increase in cervical cancer mortality was associated with underinsured or uninsured populations in regions mainly located in the South and Midwest.

Using Circulating Tumor DNA–Based Molecular Residual Disease Detection for Postoperative Monitoring in Early-Stage Uterine Cancer

PURPOSE Clinical decision making for adjuvant treatment in early-stage uterine cancer (UC) following surgery is typically directed by clinicopathological risk factors. There is an unmet need for a clinically relevant biomarker to improve individualized risk stratification and help monitor response to adjuvant therapy. Here, we sought to analyze circulating tumor DNA (ctDNA) as a prognostic biomarker in patients with early-stage UC. METHODS Retrospective analysis of ctDNA results from real-world data was performed for 61 patients (233 plasma time points) diagnosed with early-stage UC. ctDNA status and dynamics were assessed using a clinically validated, personalized, tumor-informed ctDNA assay (Signatera), and its association with recurrence-free survival (RFS) was evaluated. RESULTS ctDNA positivity was associated with significantly reduced RFS postoperatively (hazard ratio [HR], 7.6; P = .003) and postdefinitive therapy (HR, 25.4; P = .0009) and was the most significant factor associated with recurrence when compared with other clinicopathological and molecular risk factors. Notably, of patients who recurred and for whom clinical outcomes were available, 100% were ctDNA-positive before or at the time of recurrence, whereas none of the serially ctDNA-negative patients experienced relapse. CONCLUSION Our data demonstrate the feasibility of monitoring ctDNA in the postoperative and adjuvant settings in early-stage UC. Analysis of ctDNA, in addition to other risk factors, may help identify patients at the highest risk of recurrence, inform surveillance strategies, and support treatment decision-making for these patients.

Differential Responses to Immune Checkpoint Inhibitors are Governed by Diverse Mismatch Repair Gene Alterations

Abstract Purpose: The response to immune checkpoint inhibitors (ICI) in deficient mismatch repair (dMMR) colorectal cancer and endometrial cancer is variable. Here, we explored the differential response to ICIs according to different mismatch repair alterations Experimental Design: Colorectal cancer (N = 13,701) and endometrial cancer (N = 3,315) specimens were tested at Caris Life Sciences. Median overall survival (mOS) was estimated using Kaplan–Meier. The prediction of high-, intermediate-, and low-affinity epitopes by tumor mutation burden (TMB) values was conducted using R-squared (R2). Results: Compared with mutL (MLH1 and PMS2) co-loss, the mOS was longer in mutS (MSH2 and MSH6) co-loss in all colorectal cancer (54.6 vs. 36 months; P = 0.0.025) and endometrial cancer (81.5 vs. 48.2 months; P < 0.001) patients. In ICI-treated patients, the mOS was longer in mutS co-loss in colorectal cancer [not reached (NR) vs. 36 months; P = 0.011). In endometrial cancer, the mOS was NR vs. 42.2 months; P = 0.711]. The neoantigen load (NAL) in mutS co-loss compared with mutL co-loss was higher in colorectal cancer (high-affinity epitopes: 25.5 vs. 19; q = 0.017, intermediate: 39 vs. 32; q = 0.004, low: 87.5 vs. 73; q < 0.001) and endometrial cancer (high-affinity epitopes: 15 vs. 11; q = 0.002, intermediate: 27.5 vs. 19; q < 0.001, low: 59 vs. 41; q < 0.001), respectively. R2 ranged from 0.25 in mutS co-loss colorectal cancer to 0.95 in mutL co-loss endometrial cancer. Conclusions: Patients with mutS co-loss experienced longer mOS in colorectal cancer and endometrial cancer and better response to ICIs in colorectal cancer. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.