Germline genetic testing reveals pathogenic variants in uterine serous carcinoma patients.

An increase in the risk of developing uterine serous carcinoma (USC) has been observed among BRCA1 and BRCA2 germline pathogenic variant carriers in the published literature. However, routine germline genetic testing is not currently incorporated into USC management guidelines. The primary objective of this study is to define the incidence of germline pathogenic variants identified through genetic counseling referrals for USC patients at our institution. A retrospective cohort study was performed of patients diagnosed with USC at a single institution over a seven-year interval. A total of 91 patients with uterine serous carcinoma were identified. Almost half of the patients were referred to genetic counseling, and just over half of referred patients (24/43, 56%) ultimately underwent germline genetic testing. Pathogenic variants were noted in 12.5% (3/24) of the patients who were tested. Pathogenic mutations were found in BRCA1, BRCA2, and MSH6. Variants of unknown significance (VUS) were seen in 16.6% (4/24) of patients. Based on our findings, we recommend integration of germline testing into the standard management of patients with USC.

Implementation of routine venous thromboembolism prophylaxis during neoadjuvant chemotherapy for patients with ovarian cancer.

OBJECTIVE: To compare the venous thromboembolism (VTE) rate in patients with ovarian cancer undergoing neoadjuvant chemotherapy before and after implementing routine thromboprophylaxis. METHODS: This is a quasi-experimental pre-post study evaluating the VTE rate in patients with ovarian cancer who received neoadjuvant chemotherapy following a quality improvement initiative of routine thromboprophylaxis within a single healthcare system that started in January 2017. Patients were excluded if VTE was diagnosed before initiating chemotherapy. Patient factors and perioperative variables of interest were investigated for their association with VTE through univariate and multivariate models. RESULTS: Of the 136 patients in the pre-implementation group, 3.7% (n = 5) received thromboprophylaxis. Of the 154 patients in the post-implementation group, 65.6% (n = 101) received thromboprophylaxis. Provider compliance varied from 51% in 2019 to 79.3% in 2021. The overall rate of VTE, from the start of chemotherapy to the end of treatment, was 21.3% (n = 29) pre- and 8.4% (n = 13) in the post-implementation group (p < 0.01). There was no difference in major bleeding events between groups (0% vs. 0.68%, p = 0.63). On univariate analysis, thromboprophylaxis (OR 0.19; 95% CI 0.07-0.52) and post-implementation period (OR 0.34; 95% CI 0.17-0.69) were associated with a decreased risk of any VTE during primary treatment. On multivariate analysis, only thromboprophylaxis remained significantly associated with reduced VTE rates (aOR 0.19; 95% CI 0.07-0.53). CONCLUSION: Routine thromboprophylaxis during neoadjuvant chemotherapy is associated with reduced risk of VTE throughout primary treatment and is not associated with increased bleeding events.

Provider compliance with a tailored opioid prescribing calculator in gynecologic surgery.

OBJECTIVE: To evaluate the impact a tailored opioid prescription calculator has on meeting individual patient opioid needs while avoiding opioid over prescriptions. METHODS: Our group previously developed and published an opioid prescribing calculator incorporating patient risk factors (history of depression, anxiety, chronic opioid use, substance abuse disorder, and/or chronic pain) and type of surgery (laparotomy or laparoscopy). This calculator was implemented on 1/1/2021 and its impact on opioid prescriptions was evaluated until 12/31/21. The primary outcome of the present study is to determine prescriber compliance with the calculator (defined as not overprescribing from the number of pills indicated by the calculator). The secondary outcome is to determine the excess prescription rate (defined as proportion of patients reporting more than 3 pills remaining at 30 days post-surgery). Refill rates and pain related patient phone calls were collected. Descriptive statistics were used to summarize the cohort. RESULTS: Of the 355 patients included, 54.7% (N = 194) underwent laparoscopy and 45.4% (N = 161) underwent laparotomy. One hundred and forty-two patients (40%) had at least one risk factor for opioid usage. The median number of opioid pills prescribed following laparoscopy was 3 (range 0-15) and 6 (0-20) after laparotomy. The prescriber compliance was 88.2% and the excess prescription rate was 25.1% (N = 89 patients). CONCLUSIONS: Our tailored opioid calculator has a high prescriber compliance. Implementation of this calculator led to a standardization of tailored opioid prescribing, while limiting the number of over prescriptions. A free web version of the calculator can be easily accessed at www.opioidcalculator.org.

Optimization of postoperative opioid prescriptions in gynecologic oncology: Striking a balance between opioid reduction and pain control.

OBJECTIVE: To implement a quality-improvement initiative to assess the impact various patient and procedural factors have on postoperative opioid use. To develop a tailored opioid prescribing algorithm for gynecologic oncology patients. METHODS: A retrospective cohort study was performed of patients who underwent a laparoscopy or laparotomy procedure for a suspected or known gynecologic malignancy between 3/2019-9/2020. Patients were assessed preoperatively for the presence of suspected risk factors for opioid misuse (depression, anxiety, chronic pain, current opioid use, or substance abuse). Patients completed a 30-day postoperative questionnaire assessing for total opioid pill use and refills requests. Multivariate models were developed to estimate the independent effect of sociodemographic characteristics, risk factors for opioid misuse and procedural factors on patient reported postoperative opioid use. RESULTS: A total of 390 patients were analyzed. Thirty-nine percent (N = 151/390) of patients reported not using opioids after discharge and 5% (N = 20/390) received an opioid refill. For both minimally invasive procedures and laparotomy procedures, body mass index, comorbidities, intraoperative or postoperative complications and final diagnosis of malignancy were not associated with the amount of opioid consumption. However, younger age and history of risk factors for opioid misuse significantly impacted postoperative opioid use. In multivariate analysis, age (p = 0.038) and risk factors (p < 0.001) remained significant after controlling for other factors. CONCLUSIONS: Two out of every five patients did not use opioids after surgery. Younger patients and those with risk factors for opioid misuse need a tailored approach to prescribing opioids to balance the need for adequate pain control with the risk of misuse.

Combined VEGFR and MAPK pathway inhibition in angiosarcoma.

Angiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.

Clinical significance of homologous recombination deficiency score testing in endometrial Cancer.

BACKGROUND: Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer. METHODS: 253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed. RESULTS: ROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using the discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4. Both cohorts were further separated into four groups according to molecular subtypes (TMB positive; MSI positive; HRD positive; all others). When grouped by molecular subtype, there was a significant difference between groups using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments. CONCLUSIONS: High HRD score was associated with worse DFS in our patient cohort. These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.