Masanori Yasuda

New clinicopathological concept of endometrial carcinoma with integration of histological features and molecular profiles

AbstractThe dual‐stratified pathway of endometrial carcinomas (ECs) has long been dominant. However, in 2013, The Cancer Genome Atlas (TCGA) defined four EC subgroups with distinctive prognoses. Inspired by TCGA, in 2018, the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) provided four pragmatic molecular classifiers to apply surrogate immunohistochemical markers to TCGA subgroup categorization. These trends prompted the revision of 2020 WHO Classification of Female Genital Tumors, 5th edition (2020 WHO classification), in which four molecular subtypes are recognized: POLE‐ultramutated; mismatch repair‐deficient; p53‐mutant; and no specific molecular profile. In the 2020 WHO classification, the diagnostic algorithm is characterized by prioritizing POLEmut over other molecular abnormalities. Following the 2020 WHO classification, Federation of International Gynecology and Obstetrics (FIGO) proposed a new staging system in 2023. The updated system focuses on diagnostic parameters, such as histological type and grade, lymphovascular space invasion, and molecular alterations. These new histomolecular diagnostic concepts of ECs are being accordingly introduced into the routine pathology practice. For the first time, the 2020 WHO classification includes mesonephric‐like adenocarcinoma (MLA) as a novel histological entity, mimicking the conventional mesonephric adenocarcinoma, but is considered of Müllerian ductal origin.

Histological classification of uterine cervical adenocarcinomas: Its alteration and current status

AbstractAdenocarcinomas (ADCs) of the uterine cervix are relatively minor compared to squamous cell carcinomas. However, ADCs are histologically and histogenetically unique, especially because they can be with or without human papillomavirus (HPV) infection. At present, ADCs are divided into tumors as HPV‐associated ADCs (HA‐ADCs) and HPV‐independent ADCs (HI‐ADCs), including adenocarcinomas in situ (AIS) as their precursor, both of which consist of variable histological types. The usual‐type accounts for the majority of HA‐ADCs, and the gastric‐type is a representative of HI‐ADCs. Notably, it is clinicopathologically significant to differentiate between HA‐ADCs and HI‐ADCs because of the discrepancy in prognosis between them. Although relatively rare in comparison with HPV‐associated AIS (HA‐AIS), HPV‐independent AIS (HI‐AIS) has gradually attracted attention since gastric‐type ADC (g‐ADC) was introduced in the World Health Organization Classification 4th ed. (2014). Occasional HA‐ADCs and HI‐ADCs, including HA‐AIS and HI‐AIS, require p16 immunostaining, in situ hybridization, or HPV testing to differentiate between them because morphological features alone cannot often be conclusive for the diagnosis. A system focusing on the infiltrative pattern has been introduced due to its clinicopathological value. Staging criteria of HA‐ADCs with polypoid/exophytic growth, recommended by the International Collaboration on Cancer Reporting, may supplement the International Federation of Gynecology and Obstetrics staging system for clinical management and treatment.

HER2-negative or low expression as an unfavorable prognostic factor in patients with stage I/II uterine carcinosarcoma

Uterine carcinosarcoma (UCS) is uncommon high-grade endometrial cancer with limited treatment options. We evaluated the prognostic significance of human epidermal growth factor receptor 2 (HER2) expression and HER2 gene amplification within large cohorts of UCS, and clarify clinicopathologic characteristics of HER2-low UCS. We examined HER2 protein expression in 148 patients of UCS using in vivo diagnostic HER2 immunohistochemistry (IHC) kits and HER2 gene amplification using fluorescence in situ hybridization (FISH) in 72 patients. HER2 IHC score was evaluated according to the latest American Society of Clinical Oncology/College of American Pathologists criteria for gastric cancer, which was negative in 41 patients, low expression of 1+ was observed in 57 patients, and HER2 high expression was observed in 50 patients (2+ in 38 and 3+ in 12 patients). There was no significant statistical difference in clinicopathological characteristics based on HER2 protein expression status. HER2 negative and low expression compared to high expression revealed poor overall survival in stage I/ II. The concordance between IHC and FISH results were relatively low compared to other cancer types (HER2 IHC score 1+, 2+, and 3+ were 5%, 15%, and 50%), and combining these results was not efficient as a prognostic factor in UCS. In contrast, the HER2 IHC score alone was a prognostic factor in stage I/II UCS. HER2 low group did not show specific clinicopathologic features. Since the HER2 IHC score low in advanced UCS is a predictive factor, stratification of UCS using HER2 IHC score for HER2 IHC score low group and developing adjuvant therapy may be proposed in the near future.

Antitumor Effect of Farletuzumab Ecteribulin in Molecular Subtypes of Endometrial Cancer Patient-Derived Xenograft Models

Abstract Endometrial cancer represents a significant health burden globally, particularly in postmenopausal women. Current treatment options for advanced-stage endometrial cancer remain limited, emphasizing the need for novel therapeutic strategies. This study aimed to investigate farletuzumab ecteribulin (FZEC), an antibody–drug conjugate targeting folate receptor α (FRα), as a potential new therapeutic agent for endometrial cancer. We utilized a panel of 22 patient-derived xenograft (PDX) models, representing various histologic and molecular subtypes of endometrial cancer with different levels of FRα expression, to evaluate the antitumor effect of FZEC. FZEC was administered intravenously at doses of 5 and 12.5 mg/kg on day 0. Intratumoral accumulation of eribulin, the payload of FZEC, was visualized using phosphor-integrated dot imaging. FZEC demonstrated dose-dependent antitumor effects across the endometrial cancer–PDX panel. At 5 mg/kg, the FZEC efficacy was associated with FRα expression, with 100% of FRα 3+ models exhibiting tumor shrinkage compared with 33.3% of FRα-negative models. FZEC also demonstrated broad activity across both histologic and molecular subtypes. Intratumoral eribulin accumulation was highly correlated with antitumor effects, even in models with low FRα expression. Follow-up studies confirmed FRα-dependent antitumor effects while also indicating potential FRα-independent mechanisms of action. FZEC demonstrated a robust antitumor effect against the FRα-high endometrial cancer–PDX models with significant antitumor effects also observed, even in FRα-low or FRα-negative models. Notably, intratumoral eribulin accumulation exhibited a stronger correlation with efficacy than with FRα expression alone. These findings support further clinical development of FZEC for endometrial cancer treatment and highlight the complexity of the mechanisms of action of antibody–drug conjugates.

Establishing a comprehensive panel of patient-derived xenograft models for high-grade endometrial carcinoma: molecular subtypes, genetic alterations, and therapeutic target profiling

High-grade endometrial cancer (EC) has a poor prognosis, but molecular classification-based treatments present new therapeutic opportunities. Antibody-drug conjugates (ADC) emerge as promising tools, yet a deeper understanding of antigen dynamics, optimal therapeutic sequencing, and resistance mechanisms is essential. This study investigates the utility of patient-derived xenograft (PDX) models for EC as preclinical platforms, evaluating molecular subtypes and the ADC targets expression of patient and PDX tumors. We developed a comprehensive panel of molecularly characterized PDX models from patients with EC representing various histological types. Molecular subtypes and gene alterations were analyzed using sequencing and immunohistochemistry. ADC targets, including human epidermal growth factor receptor 2, trophoblast cell-surface antigen 2, B7-H4, folate receptor alpha, and cadherin-6, were profiled. Thirty-one EC-PDX models were successfully established, maintaining histological fidelity and 93.1 % molecular subtype consistency with the patient tumors. Notably, 80.6 % of the PDX models exhibited high expression (2+/3+) of at least one ADC target, and 54.8 % displayed high expression of multiple targets. Remarkably, 9.7 % showed high expression of all targets, with gene mutations also characterized. Meanwhile, patient tumors, 78.8 % showed high expression (2+/3+) of at least one ADC target, and 63.6 % showed high expression of multiple targets. The molecularly classified EC-PDX panel, enriched with detailed antigen profiles and genetic data, provides a robust platform for investigating novel ADC therapies and precision treatment strategies for high-grade EC.

Human epidermal growth factor receptor 3 expression in patients with epithelial ovarian cancer: a potential target for ovarian mucinous and clear cell carcinoma

Human epidermal growth factor receptor 3 (HER3), a tyrosine kinase belonging to the HER family, is a known target for cancer therapy; recently, an anti-HER3 antibody-drug conjugate (ADC) is developing. To understand HER3 expression in epithelial ovarian cancer (EOC), this study was conducted. We investigated the expression of HER3 in 202 patients with EOC using immunohistochemistry (IHC), and the association between HER3 expression, clinicopathological features, prognosis, and treatment timing. Of all the cases, 55.4% had a HER3 IHC score ≥ 1 + . In particular, 78.0% of the patients with clear cell carcinoma (CCC) and 87.9% of the patients with mucinous carcinoma (MC) had a HER3 IHC score ≥ 1 + . Regarding clinicopathological features, early disease stage, feasibility of primary debulking surgery, no residual tumor, and low CA125 levels were more frequently observed in patients with a HER3 IHC score ≥ 1 + . Furthermore, a HER3 no-expression showed a significant association with a relatively short progression-free survival (PFS). And, for patients with mucinous carcinoma, those with a HER3 IHC score ≥ 1 + had poorer PFS and overall survival than those with a HER3 no-expression (no statistically significant difference). In addition, we analyzed HER3 expression at primary tumor and recurrence tumor in same patients. Thus, we observed the HER3 IHC score tended to change from 0 to ≥ 1 + in recurrence cases compared with primary cases. These observations suggested that patients with MC, CCC and recurrence of all histological type may potentially benefit from future clinical trials of HER3-directed therapies.