Faculty Bibliography

Endometrial cancer (EC) is now the leading cause of gynecologic cancer death in the United States. Recognizing the urgent need to improve outcomes for patients diagnosed with EC, The National Cancer Institute (NCI) Gynecologic Cancer Steering Committee (GCSC) convened a Clinical Trials Planning Meeting (CTPM) on January 8th and 9th 2024, "Refining the Approach to Endometrial Cancer in the Immunotherapy Era." Multi-disciplinary experts were charged with addressing critical challenges, to optimize treatment of EC in the new immunotherapy landscape. As part of the CTPM working groups were assembled to address several important aspects of clinical trial design. Working Group 1 (WG1) focused on translational science and was tasked with reviewing the scientific literature for data on validated discriminants of response to immunotherapy to inform trial concept development by the therapy-focused groups. The WG established that molecular subtyping of EC is now the standard approach for classifying endometrial tumors. Molecular subtyping for both prognostic and predictive applications should be considered when assessing biomarkers as well as therapeutic targets. Additionally, strategies to improve immune response like incorporation of radiation as well as therapy sequencing considerations should continue to be explored. A major key observation from WG1 was lack of validated discriminants for immunotherapy response beyond mismatch repair status and tumor mutational burden and exploration of additional discriminants of response and resistance will be critical with the increasing use of immunotherapy in EC.

This article highlights the gender data gaps in clinical trial inclusion and funding, with a particular focus on gynecologic oncology. Female patients have historically been excluded from clinical trials across all medical domains. Despite recent improvements, female patients remain underrepresented in key diseases, including several cancer types, despite experiencing increased burden of disease. Lack of representation is particularly stark for patients in racial, ethnic, and gender minoritized populations, including in gynecologic cancer trials. Furthermore, female health conditions receive disproportionately small amounts of funding relative to their disease burden. Despite their high lethality, gynecologic cancers, including ovarian, cervical, and uterine malignancies, rank among the lowest funded cancer sites from the National Cancer Institute. Likewise, there is significant bias against female investigators with regard to funding, publication, and academic advancement, which affects the prioritization of women's health. In combination, gender disparities at multiple steps along the research pathway from investigator and disease funding to trial inclusion to publication and dissemination of research perpetuate a significant data gap in the diagnosis, treatment, and prevention of diseases affecting female patients, including gynecologic cancers. Strategies to improve this gender gap and prioritize women's health funding include increasing female representation in clinical trials with a specific focus on inclusion of patients from historically marginalized backgrounds, considering disease burden-based funding policies, and prioritizing female academic leadership opportunities.

OBJECTIVE:We sought to determine the association between platinum-free interval (PFI) and response to retreatment with platinum-based chemotherapy vs lenvatinib/pembrolizumab in patients with recurrent endometrial cancer. METHODS:Endometrial Cancer Molecularly Targeted Therapy (ECMT2) Consortium patients with recurrent disease were included in this retrospective analysis if they received first-line treatment with platinum-based chemotherapy (adjuvant or first recurrence), followed by second-line re-treatment with platinum or lenvatinib/pembrolizumab. PFI was defined as time between date of last platinum to start date of second-line therapy. Patients were stratified according to PFI ≤12 months or > 12 months. Overall response rate (ORR) to second-line treatment was estimated after stratification by PFI. RESULTS:Of 217 patients, 146 (67 %) underwent retreatment with platinum and 71 (33 %) were treated with lenvatinib/pembrolizumab. 127 (59 %) had PFI ≤12 months, and 84 (39 %) patients had PFI >12 months. Patients treated with platinum had longer PFI than those treated with lenvatinib/pembrolizumab (median PFI 12.9 vs 4.6 months; p < 0.001). ORR was 58 % vs 49 % for platinum vs lenvatinib/pembrolizumab (p = 0.27). For all patients, ORR was 68 % vs 47 % with PFI >12 months and ≤ 12 months, respectively (p = 0.002). At each PFI, ORR was similar regardless of treatment with platinum or lenvatinib/pembrolizumab (PFI ≤12 months ORR 49 % vs 44 % respectively, p = 0.75; PFI >12 months ORR 67 % vs 75 % respectively, p = 0.74). CONCLUSION/CONCLUSIONS:Longer PFI is associated with improved response to second-line treatment in patients with recurrent endometrial cancer. Despite utilization of PFI for real-world treatment decisions, it was not found to predict response between regimens at any given PFI.

PURPOSE OF REVIEW/OBJECTIVE: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/RESULTS: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/CONCLUSIONS: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:Overcoming the heterogeneous mechanisms of metastasis and chemoresistance will improve outcomes for women with tubo-ovarian carcinomas (TOCs). CD44 expression has been shown to be associated with poor prognosis and advanced disease in TOCs. In addition, studies have shown a link between chemoresistance and CD44 pathways. Given the therapeutic implications of targeting CD44, this manuscript examines the biologic effects of a novel CD44 modulator, SPL-108, in TOCs. MATERIALS AND METHODS/METHODS:We assessed the effects of SPL-108 on chemosensitivity and migration in a panel of ovarian cancer cell lines with varied CD44 and MDR1 expression. In vitro experiments (cell viability assay, Western blot analysis, Calcein AM fluorescence assay, and migration assay) were carried out to determine the functional effects of SPL-108 in TOCs. FINDINGS/RESULTS:Ovarian cancer cell lines OVCAR5 and OVCAR8 expressed higher protein levels of CD44 as demonstrated through Western Blot analysis. SPL-108 treatment significantly decreased the number of migrating cells in OVCAR8, OVCAR5 and OVCAR3 cell lines and migratory response was independent of CD44 expression. Treatment with SPL-108 led to significant accumulation of the MDR1 substrate Calcein in OVCAR5, OVCAR8 and OVCAR3 cells lines compared to verapamil treated positive control cells. Retention of Calcein after SPL-108 treatment was seen in cell lines with high MDR1 protein expression and no Calcein retention was seen in cells lacking MDR1 expression, suggesting SPL-108 inhibits MDR1. CONCLUSIONS:SPL-108 treatment has anti-metastatic properties and may play a role in chemoresistance in preclinical models of TOCs independent of CD44 expression. Ongoing in vitro and in vivo studies will help guide further clinical development of SPL-108.

PURPOSE/UNASSIGNED:Endometrial cancer (EMCA) is the most common gynecologic malignancy, and new diagnoses are increasing in the United States. Black patients are more likely to present with advanced stage, be diagnosed with high-risk uterine serous carcinoma (USC) and die of their cancer. METHODS/UNASSIGNED:Patients with endometrial adenocarcinoma who received tumor FoundationOne CDx testing at our institution between January 2017 and August 2022 were identified. Genomic alterations, demographic and clinical characteristics were collected. Descriptive statistics and Fisher's exact test were used to analyze data. RESULTS/UNASSIGNED:amplification had significantly shorter median overall survival (97.3 months vs 44.3; HR (95%CI): 7.1 (10.03, 59.4) p< 0.05). CONCLUSIONS/UNASSIGNED:amplification had shorter overall survival. Identifying actionable mutations in this high unmet need population is crucial to improving outcomes among Black patients with uterine malignancy. Development of new targeted-therapies will need to keep these alterations at the forefront as trials are being designed.

INTRODUCTION/UNASSIGNED:Disseminated actinomyces is a rare infection that presents with subtle symptoms and radiographic findings. Patients frequently complain of pelvic pain and nonspecific gastrointestinal symptoms. Imaging can reveal a tumor-like mass and mimic malignancy. Here we discuss a patient who presented with abdominal pain, and computerized tomography (CT) imaging revealed a pelvic mass and features suggestive of carcinomatosis concerning for ovarian cancer. CASE PRESENTATION/UNASSIGNED:A 55-year-old woman presented with 1 week of abdominal pain and 5 months of increasing abdominal girth. CT imaging was concerning for an advanced ovarian cancer and demonstrated a pelvic mass, peritoneal nodularity, and omental thickening. She subsequently underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy and abdominal washout with pathology and cultures revealing disseminated actinomyces. She fully recovered after receiving a long course of antibiotics. CONCLUSION/UNASSIGNED:This case adds to the limited literature illustrating that disseminated actinomyces can present similarly to ovarian cancer. The diagnosis may only be elucidated upon histologic examination of surgical specimens. Consideration of pelvic actinomyces should be entertained in all women presenting with pelvic tumors on imaging and intrauterine devices in place.

The Cancer Genome Atlas publication first described the genomic landscape of endometrial cancer and characterized these cancers into four molecular subtypes with different prognoses. The Proactive Molecular Classifier for Endometrial Cancer was developed to more easily and inexpensively classify endometrial cancers into four similar molecular subtypes which are termed POLE, mismatch repair deficient, p53 abnormal and no specific molecular profile. Beyond these four subtypes, other molecular biomarkers may influence clinical behavior and response to targeted therapies and include beta-catenin, Her2 amplification, PI3K/mTOR/AKT alterations, L1CAM, hormone receptor expression, tumor mutational burden, and ARID1A. There are numerous clinical trials exploring treatment escalation and de-escalation within the four molecular subtypes as well as matching targeted therapies to specific mutational or biomarker profiles. All endometrial cancers should undergo basic molecular classification that includes assessment of mismatch repair status. POLE and p53 status are prognostic and may become actionable in the future. Clinicians who treat patients with endometrial cancer should understand the role of molecular classification in guiding treatment. The goal of this practice statement is to guide appropriate testing, interpretation, and application of molecular information in endometrial cancer.

Purpose: Locally advanced cervical cancer was defined by an international consensus panel as a high priority malignancy during the COVID-19 pandemic, recommending prompt initiation of definitive treatment and completion of treatment (PMID 32563593). The objective of this study was to study the clinical outcomes of patients (pts) with cervical cancer treated with definitive chemoradiation (CRT) and brachytherapy (BT) at our institution in 2019 (pre-COVID) and in 2020 (peri-COVID).
Material(s) and Method(s): This was a retrospective cohort study of pts with FIGO Stage IB2-IVA cervical cancer at our institutions from 1/1/2019 to 12/31/2020. Pts received CRT followed by intracavitary brachytherapy (IC) with two operative insertions one week apart, or interstitial (IS) BT with one operative insertion. BT treatment was planned using image-guided CT or MR delineation. Pre-COVID was defined by initiation of CRT in 1/2019-12/2019, and peri-COVID was defined by initiation in 1/2020-10/2020. Process changes peri-COVID included limited on-site staff (e.g., minimal OR staff, no trainees, remote physics team), universal implementation of COVID-19 testing prior to surgery, and CT instead of MR-delineation based treatment. Outcomes of interest were time to treatment initiation and completion and differences in treatment planning modality or dosimetry. Fisher's exact and Mann Whitney U tests were used with significance p<0.05.
Result(s): Thirty-one pts were included, with 18 patients undergoing treatment pre-COVID and 13 peri-COVID. The median age at diagnosis pre-COVID was 57.7 (range 23-77) and for peri-COVID, 45.5 (range 28-62, p=0.06). There were no differences in non-English speaking pts (44% vs 59%, p=0.71) or uninsured pts (11% vs 33%, p=0.184) between the two cohorts. Median time to initiation of treatment from biopsy diagnosis was 52 days (range 13-209) in 2019 and for peri-COVID, 55.5 (range 20-173, p=0.71). During COVID, four pts had delayed initiation to treatment >100 days: two related to fertility, and one due to fear of COVID-19. For this pt, tumor size progressed from 2.3 cm to 4.2 cm maximal dimension. One pt treated in 2020 tested positive following treatment and did not require hospital admission. All pts except one completed CRT with RT: 25 pts pelvic RT (45 Gy), 3 pelvic and para-aortic RT (45 Gy with 57.5 Gy concomitant boost to nodes), 8 pts pelvic RT (45Gy) with sequential parametrial boost (50.4-59.4 Gy) using IMRT with no dose differences between pre and peri-COVID (Table 1). No pts required treatment breaks and the median overall treatment time was 50 days (range 31-85) in 2019 vs 50 days (range 43-63) in 2020 (p=0.710).
Conclusion(s): Despite the significant burden of the COVID-19 pandemic on our health care system, all cervical cancer pts receiving CRT met standard of care including CRT and BT within the recommended time frame with no significant differences in dosimetric treatment parameters pre- and peri-COVID. Delays in treatment initiation of treatment initiation were seen in 30% of pts in the peri-COVID period, suggesting that patients may have had increased barriers to access care. More follow-up is needed to determine how the Covid pandemic impacted cervical cancer outcome measures.
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