HER2+ endometrioid endometrial cancer possesses distinct molecular and immunologic features associated with a more active immune microenvironment and worse prognosis.

OBJECTIVE: HER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies. METHODS: 2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis. RESULTS: HER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival. CONCLUSIONS: HER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population.

GAS6-AXL Inhibition by AVB-500 Overcomes Resistance to Paclitaxel in Endometrial Cancer by Decreasing Tumor Cell Glycolysis.

Chemotherapy is often ineffective in advanced-stage and aggressive histologic subtypes of endometrial cancer. Overexpression of the receptor tyrosine kinase AXL has been found to be associated with therapeutic resistance, metastasis, and poor prognosis. However, the mechanism of how inhibition of AXL improves response to chemotherapy is still largely unknown. Thus, we aimed to determine whether treatment with AVB-500, a selective inhibitor of GAS6-AXL, improves endometrial cancer cell sensitivity to chemotherapy particularly through metabolic changes. We found that both GAS6 and AXL expression were higher by immunohistochemistry in patient tumors with a poor response to chemotherapy compared with tumors with a good response to chemotherapy. We showed that chemotherapy-resistant endometrial cancer cells (ARK1, uterine serous carcinoma and PUC198, grade 3 endometrioid adenocarcinoma) had improved sensitivity and synergy with paclitaxel and carboplatin when treated in combination with AVB-500. We also found that in vivo intraperitoneal models with ARK1 and PUC198 cells had decreased tumor burden when treated with AVB-500 + paclitaxel compared with paclitaxel alone. Treatment with AVB-500 + paclitaxel decreased AKT signaling, which resulted in a decrease in basal glycolysis. Finally, multiple glycolytic metabolites were lower in the tumors treated with AVB-500 + paclitaxel than in tumors treated with paclitaxel alone. Our study provides strong preclinical rationale for combining AVB-500 with paclitaxel in aggressive endometrial cancer models.

The Use of Targeted Agents in the Treatment of Gynecologic Cancers.

OPINION STATEMENT: Patients with advanced and recurrent ovarian, uterine, and cervical cancers have limited efficacious treatment options and poor outcomes. The development of agents that target DNA repair mechanisms, angiogenesis, immune checkpoints, and hormone receptor expression provides additional options for these patients. Many available targeted therapies have limited efficacy as single agents, so clinical trials investigating combination therapies as well as continued identification and validation of predictive biomarkers are critical. Many novel small molecule therapies, antibody drug conjugates, and therapeutic vaccines are also in development. This review will focus on recent evidence supporting the use of clinically available targeted therapies for gynecologic cancer.

Impact of the COVID-19 pandemic on referral to and delivery of gynecologic oncology care.

OBJECTIVE: To evaluate the impact of the COVID-19 pandemic on referral to and delivery of gynecologic oncology care at a National Cancer Institute-designated Comprehensive Cancer Center. METHODS: We conducted a retrospective cohort study of patients referred for evaluation by a gynecologic oncologist at Washington University in St. Louis from October 2019 - February 2020 (pre-COVID-19), and April - August 2020 (COVID-19). The primary outcome, time from referral to evaluation by a gynecologic oncologist, was compared between the two time periods. Secondary outcomes included time from initial evaluation to treatment and delays/interruptions in care due to the pandemic. Sub-group analyses were performed on patients with a cancer diagnosis to evaluate the impact of COVID-19 on treatment decision making. RESULTS: 884 patients were referred during the study period. Total referrals fell by 32% (526 to 358 patients, p < 0.001) and referrals for cancer fell by 18% (228 to 188 patients, p = 0.049). The pandemic did not impact time from referral to initial gynecologic oncology appointment overall (pre-COVID-19: 19.1 vs. COVID-19: 17.4 days, p = 0.315) or among patients with cancer (14.4 vs. 13.9 days, p = 0.662). Time from initial appointment to cancer treatment decreased by 9 days (34 days to 25 days, p = 0.001). CONCLUSION: Referrals to gynecologic oncology decreased significantly during the early months of COVID-19. Though time from referral to evaluation was not impacted by the pandemic, time to treatment initiation decreased despite institutional changes related to COVID-19.

Inhibition of AXL and VEGF-A Has Improved Therapeutic Efficacy in Uterine Serous Cancer.

Endometrial cancer remains the most prevalent gynecologic cancer with continued rising incidence. A less common form of this cancer is uterine serous cancer, which represents 10% of endometrial cancer cases. However, this is the most aggressive cancer. The objective was to assess whether inhibiting the receptor tyrosine kinase AXL with AVB-500 in combination with bevacizumab would improve response in uterine serous cancer. To prove this, we conducted multiple angiogenesis assays including tube formation assays and angiogenesis invasion assays. In addition, we utilized mouse models with multiple cells lines and subsequently analyzed harvested tissue through immunohistochemistry CD31 staining to assess microvessel density. The combination treatment arms demonstrated decreased angiogenic potential in each assay. In addition, intraperitoneal mouse models demonstrated a significant decrease in tumor burden in two cell lines. The combination of AVB-500 and bevacizumab reduced tumor burden in vivo and reduced morphogenesis and migration in vitro which are vital to the process of angiogenesis.

Implementation of an enhanced recovery protocol in gynecologic oncology.

Enhanced Recovery after Surgery (ERAS) is an evidence-based approach that aims to reduce narcotic use and maintain anabolic balance to enable full functional recovery. Our primary aim was to determine the effect of ERAS on narcotic usage among patients who underwent exploratory laparotomy by gynecologic oncologists. We characterized its effect on length of stay, intraoperative blood transfusions, bowel function, 30-day readmissions, and postoperative complications. A retrospective cohort study was performed at Abington Hospital-Jefferson Health in gynecologic oncology. Women who underwent an exploratory laparotomy from 2011 to 2016 for both benign and malignant etiologies were included before and after implementation of our ERAS protocol. Patients who underwent a bowel resection were excluded. A total of 724 patients were included: 360 in the non-ERAS and 364 in the ERAS cohort. An overall reduction in narcotic usage, measured as oral morphine milliequivalents (MMEs) was observed in the ERAS relative to the non-ERAS group, during the entire hospital stay (MME 34 versus 68, p < 0.001 and within 72 h postoperatively (MME 34 versus 60, p < 0.005). A shorter length of stay and earlier return of bowel function were also observed in the ERAS group. No differences in 30-day readmissions (p = 0.967) or postoperative complications (p = 0.328) were observed. This study demonstrated the benefits of ERAS in Gynecologic Oncology. A significant reduction of postoperative narcotic use, earlier return of bowel function and a shorter postoperative hospital stay was seen in the ERAS compared to traditional perioperative care.

Disparities Among Cervical Cancer Patients Receiving Brachytherapy.

OBJECTIVE: To evaluate the effects of race and insurance status on the use of brachytherapy for treatment of cervical cancer. METHODS: This is a retrospective cohort study of the National Cancer Database. We identified 25,223 patients diagnosed with stage IB2 through IVA cervical cancer who received radiation therapy during their primary treatment from 2004 to 2015. A univariate analysis was used to assess covariate association with brachytherapy. A multivariable regression model was used to evaluate the effect of race and insurance status on rates of brachytherapy treatment. The Cox proportional hazards model and the multiplicative hazard model were used to evaluate overall survival. P<.05 indicated a statistically significant difference for comparisons of primary and secondary outcomes. RESULTS: Non-Hispanic black patients received brachytherapy at a significantly lower rate than non-Hispanic white patients (odds ratio [OR] 0.93; 95% CI 0.86-0.99; P=.036); Hispanic (OR 0.93; 95% CI 0.85-1.02; P=.115) and Asian (OR 1.13; 95% CI 0.99-1.29; P=.074) patients received brachytherapy at similar rates. Compared with patients with private insurance, those who were uninsured (OR 0.72; 95% CI 0.65-0.79; P<.001), had Medicaid (OR 0.83; 95% CI 0.77-0.89; P<.001) or Medicare insurance (OR 0.85; 95% CI 0.78-0.92; P<.001) were less likely to receive brachytherapy. Brachytherapy was not found to be a mediator of race and insurance-related disparities in overall survival. CONCLUSION: Racial and insurance disparities exist for those who receive brachytherapy, with many patients not receiving the standard of care, but overall survival was not affected.

Implementation of an abdominal closure bundle to reduce surgical site infection in patients on a gynecologic oncology service undergoing exploratory laparotomy.

OBJECTIVE: Surgical site infections (SSI) are associated with increased morbidity, mortality, and healthcare costs. This study investigated whether implementation of an abdominal closure bundle reduces surgical site infection rates. We aimed to identify sub-populations that would benefit the most from this intervention. METHODS: We conducted a retrospective cohort study of all patients that underwent exploratory laparotomy by a Gynecologic Oncologist from January 1, 2011 to April 1, 2017. The abdominal closure bundle was implemented on May 6, 2014. SSI rates were assessed overall and within subgroups. RESULTS: 875 patients were included in the analysis. Overall, SSI rate was reduced, albeit not significantly, from 48/471 (10.2%) to 32/404 (7.9%) (p=0.148) with implementation of the closing bundle. In patients that underwent a tumor debulking procedure, SSI was noted in 36/277 (13.0%) in the pre-bundle group and 14/208 (6.7%) in the post-bundle cohort (p=0.017). In patients with malignant pathology, the pre-bundle cohort had an SSI rate of 38/282 (13.5%), which reduced to 18/215 (8.4%) in the post-bundle group (p=0.049). In patients with FIGO stage III or IV disease, the SSI rate was reduced from 21/114 (18.4%) to 8/87 (8.4%) with implantation of the closure bundle (p=0.028). In patients with intra-operative ascites, SSI rate decreased from 19/119 (15.9%) pre-bundle to 4/104 (3.8%) in the post-bundle group (p=0.002). CONCLUSIONS: Implementation of an abdominal closure bundle was not associated with a significant reduction in overall SSI rate. However, multiple subpopulations associated with advanced gynecologic cancer benefited from this intervention.