Purpose of review The Cancer Genome Atlas identified four distinct molecular subtypes of endometrial cancer (EC): POLE mutated, mismatch repair deficient (dMMR), copy number low, and copy number high. The goal of this review is to summarize the profound clinical implications of molecular subtyping, particularly in guiding treatment decisions for dMMR and microsatellite instability high (MSI-H) EC. Recent findings Clinical trials have demonstrated the remarkable efficacy of immunotherapy in dMMR/MSI-H EC tumors. Trials including GARNET, KEYNOTE-158, NRG GY-018, and RUBY have shown significant improvements in clinical outcomes for patients with advanced and recurrent disease, leading to FDA approvals for immunotherapy in both frontline and recurrent EC treatment settings. Building on these successes, recent studies, including DUO-E, are exploring combination therapies to enhance the efficacy of immunotherapy in EC. Simultaneously, trials including NRG GY-020, are investigating the potential benefits of immunotherapy in early-stage disease. Summary Immunotherapy therapy has revolutionized the treatment of endometrial cancer in both upfront and recurrent settings, with molecular subtyping identifying patients most likely to benefit, especially those with dMMR/MSI-H tumors.

BACKGROUND:Ovarian cancer remains the deadliest of the gynecologic cancers in the United States. There have been limited advances in treatment strategies that have seen marked increases in overall survival. Thus, it is essential to continue developing and validating new treatment strategies and markers to identify patients who would benefit from the new strategy. In this report, we sought to further validate applications for a novel humanized anti-Sialyl Tn antibody-drug conjugate (anti-STn-ADC) in ovarian cancer.METHODS:We aimed to further test a humanized anti-STn-ADC in sialyl-Tn (STn) positive and negative ovarian cancer cell line, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. Furthermore, we sought to determine whether serum STn levels would reflect STn positivity in the tumor samples enabling us to identify patients that an anti-STn-ADC strategy would best serve. We developed a custom ELISA with high specificity and sensitivity, that was used to assess whether circulating STn levels would correlate with stage, progression-free survival, overall survival, and its value in augmenting CA-125 as a diagnostic. Lastly, we assessed whether the serum levels reflected what was observed via immunohistochemical analysis in a subset of tumor samples.RESULTS:Our in vitro experiments further define the specificity of the anti-STn-ADC. The ovarian cancer PDO, and PDX models provide additional support for an anti-STn-ADC-based strategy for targeting ovarian cancer. The custom serum ELISA was informative in potential triaging of patients with elevated levels of STn. However, it was not sensitive enough to add value to existing CA-125 levels for a diagnostic. While the ELISA identified non-serous ovarian tumors with low CA-125 levels, the sample numbers were too small to provide any confidence the STn ELISA would meaningfully add to CA-125 for diagnosis.CONCLUSIONS:Our preclinical data support the concept that an anti-STn-ADC may be a viable option for treating patients with elevated STn levels. Moreover, our STn-based ELISA could complement IHC in identifying patients with whom an anti-STn-based strategy might be more effective.

OBJECTIVE:Artificial Intelligence (AI) systems such as ChatGPT can take medical examinations and counsel patients regarding medical diagnosis. We aim to quantify the accuracy of the ChatGPT V3.4 in answering commonly asked questions pertaining to genetic testing and counseling for gynecologic cancers. METHODS:Forty questions were formulated in conjunction with gynecologic oncologists and adapted from professional society guidelines and ChatGPT version 3.5 was queried, the version that is readily available to the public. The two categories of questions were genetic counseling guidelines and questions pertaining to specific genetic disorders. The answers were scored by two attending Gynecologic Oncologists according to the following scale: 1) correct and comprehensive, 2) correct but not comprehensive, 3) some correct, some incorrect, and 4) completely incorrect. Scoring discrepancies were resolved by additional third reviewer. The proportion of responses earning each score were calculated overall and within each question category. RESULTS:ChatGPT provided correct and comprehensive answers to 33/40 (82.5%) questions, correct but not comprehensive answers to 6/40 (15%) questions, partially incorrect answers to 1/40 (2.5%) questions, and completely incorrect answers to 0/40 (0%) questions. The genetic counseling category of questions had the highest proportion of answers that were both correct and comprehensive with ChatGPT answering all 20/20 questions with 100% accuracy and were comprehensive in responses. ChatGPT performed equally in the specific genetic disorders category, with 88.2% (15/17) and 66.6% (2/3) correct and comprehensive answers to questions pertaining to hereditary breast and ovarian cancer and Lynch syndrome questions respectively. CONCLUSION:ChatGPT accurately answers questions about genetic syndromes, genetic testing, and counseling in majority of the studied questions. These data suggest this powerful tool can be utilized as a patient resource for genetic counseling questions, though more data input from gynecologic oncologists would be needed to educate patients on genetic syndromes.

Supplementary Figure 3. Mouse weight changes over the course of each four-arm treatment study. In all experiments, lapatinib and trastuzumab treatments did not significantly affect mouse weights. Mice were weighed weekly, and the percent changes in weight compared to baseline weights (100%) are shown. Error bars represent the standard error of the mean.

Supplementary Table S2: p-values of RT-PCR analysis of RAD51 gene family in CD133+ cells and CD133- CD117- cells FACS purified (Figure 6A and 6B).

Supplementary Table 1. Clinical characteristics of the 42 USC patients whose tissue specimens were utilized for HER2 immunohistochemical and FISH analyses.

Radiation Recall encompasses an array of inflammatory reactions, most commonly dermatitis, that occurs in response to a systemic medication with distribution in a previously irradiated field. While historically cytotoxic chemotherapy was a major culprit, this case report describes radiation recall dermatitis in response to pembrolizumab and lenvatinib in a 62-year old female with ongoing advanced endometrial cancer and history of breast cancer. Discontinuation of lenvatinib alone lead to complete resolution of the dermatitis, and she ultimately resumed her previous lenvatinib dose without recurrent symptoms. This case represents an important possible adverse effect of a commonly used targeted therapy, particularly in a population likely to have a history of prior radiation exposure.

Objective. To evaluate utilization of sentinel lymph node biopsy (SLNB) for early-stage vulvar cancer at minority-serving hospitals and low-volume facilities.Methods. Between 2012-2018, individuals with T1b vulvar squamous cell carcinoma were identified using the National Cancer Database. Patient, facility, and disease characteristics were compared between patients undergo-ing SLNB or inguinofemoral lymph node dissection (IFLD). Multivariable logistic regression, adjusted for patient, facility, and disease characteristics, was used to evaluate factors associated with SLNB. Kaplan-Meier survival analysis using log rank test and Cox regression was performed.Results. Of the 3,532 patients, 2,406 (68.1%) underwent lymph node evaluation, with 1,704 (48.2%) undergo-ing IFLD and 702 (19.8%) SLNB. In a multivariable analysis, treatment at minority-serving hospitals (OR 0.39, 95% CI 0.19-0.78) and low-volume hospitals (OR 0.44, 95% CI 0.28-0.70) were associated with significantly lower odds of undergoing SLNB compared to receiving care at non-minority-serving and high-volume hospitals, respectively. While SLNB utilization increased over time for the entire cohort and stratified subgroups, use of the procedure did not increase at minority-serving hospitals. After controlling for patient and tumor characteristics, SLNB was not associated with worse OS compared to IFLD in patients with positive (HR 1.02, 95% CI 0.63-1.66) or negative (HR 0.92, 95% CI 0.70-1.21) nodal pathology.Conclusions. For patients with early-stage vulvar cancer, treatment at minority-serving or low-volume hospitals was associated with significantly decreased odds of undergoing SLNB. Future efforts should be concentrated toward ensuring that all patients have access to advanced surgical techniques regardless of where they receive their care.(c) 2022 Elsevier Inc. All rights reserved.

Supplementary Table 1. Clinical characteristics of the 42 USC patients whose tissue specimens were utilized for HER2 immunohistochemical and FISH analyses.

3023 Background: DB-1303 is an antibody-drug conjugate (ADC) consisting of a humanized anti-HER2 IgG1 monoclonal antibody, covalently linked to proprietary DNA topoisomerase I inhibitor (P1003) via a maleimide tetrapeptide-based cleavable linker, with a high drug-to-antibody ratio (~8). Methods: This is a global first-in-human, dose-escalation and -expansion study in patients (pts) with advanced/metastatic solid tumors. Pts (ECOG 0-1) with HER2 – (high or low) expressing or mutant cancers who failed previously systemic therapies were recruited and received DB-1303 intravenously Q3W as monotherapy. The objectives were safety, tolerability, maximum tolerated dose (MTD) or recommended phase 2 dose (PR2D), pharmacokinetics (PK), and preliminary antitumor activity. Here we report the results from dose-escalation. Results: As of Jan 13, 2023, 85 pts received DB-1303 at 6 dose levels (2.2, 4.4, 6.0, 7.0, 8.0, and 10.0 mg/kg) and received a median of 7 (range, 1-27) prior lines of therapy, including previous anti-HER2 ADC therapy in 32.9% of pts. The median duration of treatment was 63.0 (range, 21-211) days, and 68 pts (80.0%) remained on treatment. Treatment-emergent adverse events (TEAEs) and ≥ grade (G) 3 TEAEs occurred in 74 pts (87.1%) and 18 pts (21.2%), respectively; the most common TEAEs were nausea (51.8%, 3.5% ≥ G3), vomiting (43.5%, 1.2% ≥ G3), platelet count decreased (35.3%, 3.5% ≥ G3), and anemia (29.4%, 5.9% ≥ G3). Few pts experienced neutropenia (10 [11.8%]) and alopecia (3 [3.5%]). There was no DLT or TEAEs leading to death. Interstitial lung disease occurred in 2 pts (2.4%, G1), without any ≥ G2. The exposure parameters (C max and AUC) of DB-1303 ADC increased with ascending doses from 2.2 to 10.0 mg/kg. The half-life of DB-1303 ADC is approximately 6-7 days for 6.0-8.0 mg/kg dose cohorts. The exposure of serum release payload was magnitudes lower than that of DB-1303 ADC, demonstrating stability of the ADC in systemic circulation. A total of 52 pts had undergone at least one post-baseline tumor scan. Twenty-three pts (44.2%, 23/52) had objective partial tumor response per RECIST 1.1: Thirteen HER2+ breast cancer (BC) (50.0%, 13/26, including 5 pts with brain metastases [55.6%, 5/9]), 5 HER2 low BC (38.5%, 5/13), 2 colorectal cancer (66.7%, 2/3), 1 endometrial carcinoma (33.3%, 1/3), 1 esophageal cancer (50.0%, 1/2), and 1 ovarian cancer (50.0%, 1/2). Among all the pts, the DCR was 88.5% (46/52); for pts with HER2+ BC and HER2-low BC, the DCRs were 96.2% (25/26) and 84.6% (11/13), respectively. Conclusions: DB-1303 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2+ BC and brain metastasis as well as in HER2-low BC. Expansion is ongoing in selected tumor pts treated at the RP2D. Clinical trial information: NCT05150691 .

Supplementary Figure Legends. The supplementary figure legends are in this document as requested.

Supplementary Figure 2. Anti-tumor activity of single agent lapatinib treatment was observed in HER2 amplified ARK2 xenografts (p = 0.02), while no response was seen in non-HER2 amplified SPEC2 xenografts. Mice harboring tumors derived from ARK2 or SPEC2 cell lines were treated with either vehicle or lapatinib. Tumors were measured twice weekly, and the percent change in tumor volume compared to baseline volume (100%) is shown. Error bars represent the standard error of the mean.

Supplementary Figure 5. HER2 inhibition in mice harboring non-HER2 amplified SPEC2 (A) or EnCa2 (B) xenografts did not affect tumor cell apoptosis, as shown by TUNEL analysis. Representative images of TUNEL (green) and DAPI (blue) stained sections of the differently treated xenografts are shown. Scale bars: 50 µm.

Targeted therapies for endometrial cancer are an active area of investigation. The use of antihuman epidermal growth factor receptor 2 (HER2) is expanding rapidly and confers a survival benefit in endometrial cancer. CCNE1 amplification has been associated with poor survival and can coexist with other targetable molecular alterations. The objective of this study was to determine the relationship between HER2 positivity and CCNE1 amplification in endometrial tumors to provide a rationale for novel anti-HER2 and cell cycle therapeutics. This was a retrospective multicenter study of patients in a large, urban healthcare system with advanced or recurrent epithelial endometrial cancer diagnosed between 2010 and 2022. Patients who underwent comprehensive tumor molecular profiling with next-generation sequencing (NGS) were included in this study. HER2 positivity was defined as 3+ by immunohistochemistry staining or 2+ with FISH amplification (HER2/CEN17 ratio ≥ 2.0) or ERBB2 amplifications by NGS. Associations between clinical variables and genomic findings were correlated utilizing non-parametric testing and univariate survival estimates with the Kaplan-Meier method. There were 291 patients included in this cohort. Race demographics in the overall cohort were as follows: 154 White (53%); 85 Black (29%); 25 Asian (9%); 1 Native American (0%); and 26 other (9%). There were 30 (10%) patients with CCNE1 amplification. Of Black patients, 22 of 85 (26%) were CCNE1 amplified compared to 8 of 206 (4%, P < 0.001). Forty-nine patients (17%) were HER2 positive. Of 85 Black patients, 19 (22%) were HER2 positive, and of 206 non-Black patients, 30 (15%) were HER2 positive (P = 0.106). There were ten patients with both HER2 positivity and CCNE1 amplification; in this group, Black patients were overrepresented (8 of 85, 9%) compared to non-Black patients (2 of 206, 1%, P < 0.001). Of the 10 patients with both HER2 positivity and CCNE1 amplification, 8 had serous histology, and 2 had endometrioid histology; all were P53 aberrant. This dual signature of HER2 positivity and CCNE1 amplification was associated with a median overall survival of 43 months for those with HER2 positivity and CCNE1 amplification versus 161 months for those without both molecular signatures (P = 0.05, log-rank). In this cohort, NGS and HER2 immunohistochemistry and FISH testing demonstrated that Black patients with endometrial cancer are more likely to have HER2 positivity and CCNE1 gene amplification than non-Black patients. This signature was associated with a worsened overall survival. These data suggest pairing anti-HER2 therapeutics with cell cycle disrupting agents may be rational for this group of patients that are in greatest need of novel treatment strategies.

Supplementary Figure 1. HER2 expression levels in USC models. HER2 protein expression (A) and gene amplification (B) status of the USC cell line derived and patient derived xenografts that were utilized in this study, as assessed by IHC and FISH. HER2 protein over-expression as well as HER2 gene amplification were observed in ARK1, ARK2 and EnCa1 xenografts, while low HER2 protein expression and normal HER2 gene status were found in SPEC2 and EnCa2 xenografts.

Uterine carcinosarcoma (UCS) are rare tumors with high aggressive behavior. Chemotherapy is the mainstay of treatment either in the adjuvant and the metastatic setting. Previous carcinogenetic theory considered carcinosarcoma as a biphasic tumor with an epithelial and mesenchymal component and were treated accordingly with drugs directed towards these two components (i.e. cisplatin-ifosfamide). Actually UCS are reclassified as epithelial cancers with metaplastic de-differentiated components and drugs with proven activity in epithelial tumors (i.e. carboplatin-paclitaxel) have been implemented in the treatment algorithm. The paper will review literature evidences in UCS treatment and will support the strategy which identify carboplatin-paclitaxel as the standard of care.