Linda Mileshkin

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.

Impact of chemotherapy on patients with mismatch repair deficient advanced endometrial carcinomas—a meta-analysis

Abstract Background Chemo-immunotherapy is standard of care for women with recurrent or advanced mismatch repair deficient endometrial carcinoma. However, it is uncertain whether patients with mismatch repair deficient advanced or recurrent endometrial carcinoma derive less benefit from chemotherapy than those with mismatch repair proficient endometrial carcinoma. Methods We performed a meta-analysis of randomized controlled trials (RCTs) in advanced or recurrent endometrial carcinoma to determine the difference in the benefit of chemotherapy in mismatch repair deficient vs mismatch repair proficient endometrial carcinoma. Data on chemotherapy outcomes including objective response rate, progression-free survival (PFS), and overall survival were retrieved. We pooled these data using the inverse variance method and examined subgroup difference by mismatch repair status. We also compared differences in PFS and overall survival outcomes by creating individual patient data from the Kaplan–Meier curves of trial publications for sensitivity analyses. Results A total of 5 RCTs with 1137 participants (mismatch repair deficient, 26%; mismatch repair proficient, 74%) were included. All participants were treated with carboplatin-based chemotherapy. There was no difference between the mismatch repair deficient and mismatch repair proficient subgroups for objective response rate (66.5% vs 64.0%; P = .20 for subgroup difference), PFS (hazard ratio [HR] = 0.93, 95% confidence interval [CI] = 0.77 to 1.12; P = .44; median PFS = 7.6 vs 9.5 months) or overall survival (HR = 1.03, 95% CI = 0.73 to 1.44; P = .88; median overall survival = not reached vs 28.6 months). Conclusions Objective response rate, PFS, and overall survival were similar among those with mismatch repair deficient vs mismatch repair proficient endometrial cancer treated with front-line, platinum-doublet chemotherapy in RCTs. These findings reinforce the importance of combining chemotherapy together with immune checkpoint inhibitors until the results of trials comparing immune checkpoint therapy alone with combination therapy are available.

Prediction of recurrence risk in endometrial cancer with multimodal deep learning

AbstractPredicting distant recurrence of endometrial cancer (EC) is crucial for personalized adjuvant treatment. The current gold standard of combined pathological and molecular profiling is costly, hampering implementation. Here we developed HECTOR (histopathology-based endometrial cancer tailored outcome risk), a multimodal deep learning prognostic model using hematoxylin and eosin-stained, whole-slide images and tumor stage as input, on 2,072 patients from eight EC cohorts including the PORTEC-1/-2/-3 randomized trials. HECTOR demonstrated C-indices in internal (n = 353) and two external (n = 160 andn = 151) test sets of 0.789, 0.828 and 0.815, respectively, outperforming the current gold standard, and identified patients with markedly different outcomes (10-year distant recurrence-free probabilities of 97.0%, 77.7% and 58.1% for HECTOR low-, intermediate- and high-risk groups, respectively, by Kaplan–Meier analysis). HECTOR also predicted adjuvant chemotherapy benefit better than current methods. Morphological and genomic feature extraction identified correlates of HECTOR risk groups, some with therapeutic potential. HECTOR improves on the current gold standard and may help delivery of personalized treatment in EC.

Survival and patterns of failure in small cell neuroendocrine carcinoma of the cervix treated with definitive chemoradiotherapy

To evaluate survival outcomes and patterns of failure in small cell neuroendocrine carcinoma of the cervix treated with curative-intent chemoradiotherapy at a tertiary referral center. Patients with International Federation of Gynecology and Obstetrics 2009 stage IB to IIIB small cell neuroendocrine carcinoma of the cervix treated between 1996 and 2017 were retrospectively reviewed. All underwent baseline magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT). Definitive chemoradiotherapy consisted of pelvic external-beam radiotherapy (45 Gy/25 fractions) with high-dose-rate brachytherapy (Equivalent Dose in 2Gy fractions (EQD2) >85 Gy) and concurrent platinum-etoposide chemotherapy, followed by 2 sequential cycles. Patients who underwent primary surgery followed by adjuvant chemoradiotherapy were analyzed separately. Survival outcomes were estimated using Kaplan-Meier analysis. Thirty-two patients were included; 26 received definitive chemoradiotherapy and 6 underwent surgery followed by adjuvant radiotherapy. Median follow-up was 48 months (interquartile range; 12-213). Five-year overall survival and progression-free survival were 54.6% and 49.7%, respectively. Pelvic control was high (88%), with no local relapses in patients with stage ≤IIA disease. Distant relapse occurred in 44% of patients, predominantly para-aortic (57%) and visceral (lung, liver, bone). Node-negative patients achieved significantly higher 5-year overall survival (70.6% vs 31.3%, p = .04) and progression-free survival (66.9% vs 22.4%, p = .01). Definitive chemoradiotherapy achieves excellent loco-regional control and durable survival in small cell neuroendocrine carcinoma of the cervix, particularly in early-stage and node-negative disease. Distant relapse remains the predominant failure pattern, highlighting the need for improved systemic approaches. These results support omission of radical surgery in well-staged early-stage patients managed with modern chemoradiotherapy.

Clinical Trial Protocol for ROSELLA: a phase 3 study of relacorilant in combination with nab-paclitaxel versus nab-paclitaxel monotherapy in advanced platinum-resistant ovarian cancer

Ovarian cancer has the highest mortality among gynecologic cancers, primarily because it typically is diagnosed at a late stage and because of the development of chemoresistance in recurrent disease. Improving outcomes in women with platinum-resistant ovarian cancer is a substantial unmet need. Activation of the glucocorticoid receptor (GR) by cortisol has been shown to suppress the apoptotic pathways used by cytotoxic agents, limiting their efficacy. Selective GR modulation may be able to counteract cortisol's antiapoptotic effects, enhancing chemotherapy's efficacy. A previous phase 2 study has shown that adding intermittently dosed relacorilant, a selective GR modulator, to nab-paclitaxel improved outcomes, including progression-free survival (PFS) and overall survival (OS), with minimal added toxicity, in women with recurrent platinum-resistant ovarian cancer. The ROSELLA study aims to confirm and expand on these findings in a larger population. ROSELLA is a phase 3, randomized, 2-arm, open-label, global multicenter study in women with recurrent, platinum-resistant, high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. Eligible participants have received 1 to 3 lines of prior systemic anticancer therapy, including ≥1 prior line of platinum therapy and prior treatment with bevacizumab, with documented progressive disease or intolerance to the most recent therapy. There is no biomarker-based requirement for participant selection. Participants are randomized 1:1 to receive intermittently dosed relacorilant in combination with nab-paclitaxel or nab-paclitaxel monotherapy. The study's primary efficacy endpoint is PFS as assessed by blinded independent central review. Secondary efficacy endpoints include OS, investigator-assessed PFS, objective response rate, best overall response, duration of response, clinical benefit rate at 24 weeks, and cancer antigen 125 response. The study is also evaluating safety and patient-reported outcomes. ClinicalTrials.gov Identifier: NCT05257408; European Union Drug Regulating Authorities Clinical Trials Database Identifier: 2022-000662-18.

PARP inhibition with rucaparib alone followed by combination with atezolizumab: Phase Ib COUPLET clinical study in advanced gynaecological and triple-negative breast cancers

Abstract Background Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC). Methods After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy. Results The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab. Conclusions In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens. Clinical trial registration ClinicalTrials.gov (NCT03101280).