Linda Nooij

Clinical and Molecular Characteristics of High-Risk, Recurrent, or Metastatic Endometrial Cancer That Is Human Epidermal Growth Factor Receptor 2–Low

PURPOSE Recent success of human epidermal growth factor receptor 2 (HER2)–targeted antibody-drug-conjugate trastuzumab-deruxtecan in HER2-low and HER2-positive tumors has sparked interest in examining the HER2 status of tumors not traditionally associated with HER2 amplification. Despite the increasing number of systemic treatment options, patients with advanced endometrial cancer (EC) still face a poor prognosis. This study evaluates HER2-low status in over 800 EC, correlating HER2 with both molecular and clinical features. METHODS HER2 status was determined by immunohistochemistry (IHC) and dual in situ hybridization (DISH) on four studies of previously classified high-risk EC (PORTEC-3 and Medical Spectrum Twente cohort), recurrent or metastatic EC (DOMEC), and a primary stage IV cohort. EC was classified as HER2-negative (IHC 0), HER2-low (IHC 1+/2+ without amplification), or HER2-positive (IHC 3+ or DISH-confirmed amplification). Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models assessed the independence of any prognostic impact of HER2 status. RESULTS HER2 status was determined in 806 EC: 74.8% were HER2-negative, 17.2% HER2-low, and 7.9% HER2-positive. HER2-low was found across all molecular classes and histotypes. The highest rates of HER2-low and HER2-positive tumors were in recurrent or metastatic EC (35.6% and 15.6%), followed by primary stage IV EC (29.9% and 12.4%) and high-risk EC (14.2% and 6.8%). HER2 status had no independent prognostic value. CONCLUSION A quarter of high-risk, metastatic, or recurrent EC exhibited HER2 overexpression. The presence of HER2 overexpression in all clinical and molecular categories highlights the need for broad testing and offers treatment options for a wide range of patients.

Prognostic value of molecular classification in stage IV endometrial cancer

Multiple studies have proven the prognostic value of molecular classification for stage I-III endometrial cancer patients. However, studies on the relevance of molecular classification for stage IV endometrial cancer patients are lacking. Hypothetically, poor prognostic molecular subtypes are more common in higher stages of endometrial cancer. Considering the poor prognosis of stage IV endometrial cancer patients, it is questionable whether molecular classification has additional prognostic value. Therefore, we determined which molecular subclasses are found in stage IV endometrial cancer and if there is a correlation with progression-free and overall survival. A retrospective multicenter cohort study was conducted using data from five Dutch hospitals. Patients with stage IV endometrial cancer at diagnosis who were treated with primary cytoreductive surgery or cytoreductive surgery after induction chemotherapy between January 2000 and December 2018 were included. Exclusion criteria were age <18 years or recurrent disease. The molecular classification was performed centrally on all tumor samples according to the World Health Organization 2020 classification (including 164 stage IV endometrial cancer patients were molecularly classified. Median age of the patients was 67 years (range 33-86). Most patients presented with a non-endometrioid histological subtype (58%). Intra-abdominal complete cytoreductive surgery was achieved in 60.4% of the patients. 101 tumors (61.6%) were classified as p53 abnormal, 35 (21.3%) as no specific molecular profile, 21 (12.8%) as mismatch repair deficient, and 6 (3%) as The distribution of the molecular subclasses in stage IV endometrial cancer patients differed substantially from the distribution in stage I-III endometrial cancer patients, with the unfavorable subclasses being more frequently present. Although the molecular classification was not prognostic in stage IV endometrial cancer, it could guide adjuvant treatment decisions.

Primary chemoradiation versus neoadjuvant chemotherapy followed by surgery as treatment strategy for locally advanced vulvar carcinoma (VULCANize2)

Current treatment options for patients with locally advanced vulvar cancer are limited and associated with high morbidity. Therefore, it is important to develop new and safe treatment strategies for this vulnerable patient group. To compare the efficacy and safety of neoadjuvant chemotherapy followed by surgery with definitive chemoradiation in patients with locally advanced vulvar cancer. Neoadjuvant chemotherapy followed by surgery is oncologically safe, potentially more effective than primary chemoradiation in establishing long lasting locoregional control, and associated with an improved quality of life. This study is a multicenter, prospective, phase II randomized controlled trial. Patients will be randomized 1:1 to the standard treatment arm (primary chemoradiation, consisting of a tumor dose of 64.5 Gy in 30 fractions of external beam radiotherapy with weekly cisplatin for 6 weeks) or the experimental treatment arm (neoadjuvant chemotherapy, consisting of carboplatin and paclitaxel in a 3 weekly scheme, followed by surgery). Eligible patients must have a histologically confirmed primary or recurrent locally advanced squamous cell carcinoma of the vulva (International Federation of Gynecology and Obstetrics (FIGO) stages Ib-Iva; Lesions larger than 2 cm in size or stromal invasion larger than 1 mm (T1b or higher), any status of lymph node involvement (any N), no distant metastasis including pelvic lymph nodes (M0)) with the size or localization of the tumor requiring treatment through primary chemoradiation or extensive surgery. Patients with documented metastases of the pelvic lymph nodes will be excluded from participation in this study. Locoregional control at 24 months. 98 patients will be included in the study. Expected complete accrual in 2028 with presentation of results by 2030. ClinicalTrials.gov NCT05905315.

Primary Chemoradiation VS. Neoadjuvant Chemotherapy Followed By Surgery As Treatment Strategy For LAVC

A phase 2 randomised controlled trial will be performed in which the efficacy and safety of standard treatment (primary chemoradiation; consisting of 64.5 Gy in 30 fractions of external beam radiotherapy with weekly cisplatin for six weeks) and experimental treatment (NACT; consisting of carboplatin and paclitaxel in a 3-weekly scheme) will be compared in 98 patients with LAVC, registered from eight national medical centres.