Targeted Therapies in Low-Grade Serous Ovarian Cancers.

OPINION STATEMENT: Low grade serous carcinoma of the ovary has been delineated as a separate entity from its counterpart high grade serous carcinoma of the ovary. Molecular profiling has helped to further characterize this disease process and has led to new and exciting treatment options. Surgery has always been a cornerstone of management both in primary and recurrent disease settings. Chemotherapy has been a long-standing backbone of adjuvant treatment, but its efficacy continues to be questioned. Hormonal therapy for upfront and recurrent disease is an effective treatment option with a high response rate and minimal side effects. Newer therapies including MEK, CDK 4/6, and PI3KCA inhibitors have emerged as exciting options for recurrent disease. Ongoing clinical trials will hopefully lead to additional therapeutic opportunities based on novel biomarkers in this disease.

RETRACTED: Cost-effectiveness of chemotherapy and dostarlimab for advanced or recurrent endometrial cancer.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of the Authors. The authors have independently identified an error in the formula that was utilized to calculate the Quality Adjusted Life Years which invalidates the data and the conclusion of the paper. The authors have contacted the journal requesting to retract the article. Apologies are offered to the readers of the journal for any confusion or inconvenience that may have resulted from the publication of this article.

Learning to lead: The evolution of a pilot leadership curriculum for gynecologic oncology fellows at the Ohio State University.

•Leadership training is under-emphasized in traditional medical education.•An effective leadership curriculum must be dynamic and requires genuine investment from participants.•Through didactic education, self-reflection, and real-world perspective we can actively mold future leaders in gynecologic oncology.

Characterization of mismatch-repair/microsatellite instability-discordant endometrial cancers.

BACKGROUND: Mismatch-repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity. METHODS: Six hundred sixty-six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut-L homolog 1 (MLH1) methylation. Select samples underwent whole-transcriptome analysis and next-generation sequencing. MMR expression of metastatic/recurrent sites was evaluated. RESULTS: MSI testing identified 27.3% of cases as MSI-high (n = 182), MMR IHC identified 25.1% cases as MMR-deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut-S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6-associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR-deficient cases and 9% in MMR-proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial-mesenchymal transition. CONCLUSIONS: Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR-deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker-directed therapy. PLAIN LANGUAGE SUMMARY: Endometrial cancer is the most common gynecologic cancer, and 20%-40% of tumors have a defect in DNA proofreading known as mismatch-repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR-deficient cells may drive tumor behavior and the risk of spreading cancer.

The impact of antibiotic and proton pump inhibitor use at the time of adjuvant platinum-based chemotherapy on survival in patients with endometrial cancer.

OBJECTIVE: We sought to assess the impact of antibiotic (ABX) and proton-pump inhibitor (PPI) use on progression-free (PFS) and overall survival (OS) in patients treated with adjuvant platinum-based chemotherapy (PC) for endometrial cancer (EC). METHODS: A retrospective, single-institution cohort study of EC patients treated with ≥four cycles of adjuvant PC following surgical staging from 2014 to 2020. Demographics and clinicopathologic features, including ABX and PPI use, were compared using χ2 and Fisher's exact tests. Univariate and multivariable analyses were performed, and survival outcomes were compared using the log-rank test. RESULTS: Of 325 patients, 95 (29%) received ABX, and 80 (24.6%) received PPI. ABX were associated with decreased 3-year PFS (49.9% vs. 66%; p = 0.0237) but not 3-year OS (68.9% vs. 79.9%; p = 0.0649). ABX targeting gram-positive bacteria were associated with decreased 3-year PFS (21.2% vs. 66.0% vs. 55.4%; p = 0.0038) and 3-year OS (36.5% vs. 79.9% vs. 75.6%; p = 0.0014) compared to no ABX and other ABX, respectively. PPI use was associated with decreased 3-year PFS (46.9% vs. 66.0%; p = 0.0001) and 3-year OS (60.7% vs. 81.9%; p = 0.0041) compared to no PPI. On multivariable regression analysis controlling for confounders including stage, histology, grade, radiation, and co-morbidities, PPI use was independently associated with worse PFS (HR 1.96, 95% CI 1.25-3.08; p = 0.0041) and OS (HR 2.06, 95% CI 1.01-4.18, p = 0.04). CONCLUSION: In this retrospective cohort study, we demonstrate that PPI use is independently associated with worse PFS and OS in patients with EC treated with PC. ABX use was associated with worse PFS on univariate analysis only. There is an unmet need to understand how PPI, ABX, and, potentially, the microbiome impact the effectiveness of chemotherapy in EC patients.

Assessment of the feasibility of same-day discharge following minimally invasive hysterectomy in the elderly population.

Objective: To determine the safety and feasibility of same-day discharge (SDD) following minimally invasive hysterectomy (MIH) for elderly patients and to evaluate associations between age, frailty, and postoperative outcomes. Methods: Retrospective review was conducted of patients aged ≥ 70 who underwent MIH within a single gynecologic oncology institution from 2018 to 2020. Demographics, peri-operative factors, postoperative complications, and 30-day readmission rates were collected. Frailty was determined by an 11-point modified frailty index ≥ 2. Outcomes were compared between SDD and observation groups using Fisher's exact and Wilcoxon rank-sum tests. Results: Of 169 patients included in the analysis, 8.9% (n = 15) underwent SDD, and 91.1% (n = 154) were admitted for OBS following MIH. Demographics, peri-operative factors, and frailty rates (33% SDD vs 43.5% observation; p = 0.59) were similar between groups. 86.7% (n = 13) of SDD cases were completed before 12PM, and none were completed after 6PM. No SDD patients had early post-operative complications or hospital readmissions. Early postoperative complications were diagnosed in 9 (5.8%) patients admitted for OBS, and the 30-day hospital readmission rate for patients who underwent OBS was 8.4% (n = 13). While elderly patients who met objective frailty criteria (n = 72) did not have a higher likelihood of early post-operative complications (44.4% vs 55.6%; p = 0.909), they did have a higher likelihood of ED visit within 30 days of discharge (15.3 vs 3.1%; p = 0.009), and a trend was noted toward a higher rate of 30-day hospital readmission (12.5% vs 4.1%; p = 0.080). Conclusions: Elderly patients undergoing SDD following MIH did not have increased morbidity or mortality. Elderly patients who meet objective criteria for frailty, however, represent a more vulnerable population.

The right time for change: A report on the heterogeneity of IVB endometrial cancer and improved risk-stratification provided by new 2023 FIGO staging criteria.

OBJECTIVE: We sought to provide a contemporary report on stage IVB endometrial carcinoma (2009 FIGO criteria) and applied the 2023 FIGO staging criteria to this population. METHODS: Retrospective review of patients who underwent cytoreduction for stage IVB endometrial carcinoma (2009 FIGO criteria) from 2014 to 2020 was performed. Demographics, clinicopathologic factors, and outcomes were recorded. Disease burden and distribution were determined by imaging, operative notes, and pathology reports. Patients were re-staged according to 2023 FIGO staging criteria. Categorical variables were compared using χ2 or Fisher's exact test, and Kaplan-Meier curves compared survival outcomes using the log-rank test. RESULTS: Eighty-eight cases were included. Most patients (63.6%) were not suspected to have stage IVB (2009 FIGO criteria) disease prior to surgery. Seventy-two percent of patients underwent primary cytoreduction, and 12 (19%) were suboptimal. Median progression-free survival (PFS) was 12 months (95% CI 10-16 months), and median overall survival (OS) was 38 months (95% CI 19-61 months). Degree of cytoreduction (p = 0.0101) and pelvic-confined metastatic disease (p = 0.0149) were significant prognostic factors, while distant metastases were not associated with worse outcomes. For those patients who underwent primary cytoreduction, number (p = 0.0453) and diameter (p = 0.0192) of tumor deposits were associated with PFS. When 2023 FIGO staging criteria were applied, 58% of patients underwent change in stage, and 8% did not meet criteria for complete staging. PFS was significantly different based on 2023 FIGO staging (p = 0.0307); a trend in OS was also noted (p = 0.0550). CONCLUSION: Stage IVB endometrial carcinoma (2009 FIGO criteria) encompasses a diverse cohort of patients, where certain clinicopathologic features, tumor burden, and degree of cytoreduction are associated with outcomes. The 2023 FIGO staging criteria significantly improves our ability to risk-stratify patients.

"More than a song and dance": Exploration of patient perspectives and educational quality of gynecologic cancer content on TikTok.

OBJECTIVE: To investigate themes, quality, and reliability of gynecologic cancer-related content on the social media application TikTok. METHODS: TikTok was systematically searched for the 100 most popular posts for ovarian cancer (OC), endometrial cancer (EC), cervical cancer (CC), vulvar cancer (VC), and gestational trophoblastic disease (GTD) in August 2022. Data was collected for demographics, tone, and themes. Educational videos were rated for quality and reliability utilizing the modified DISCERN scale. Relationships between content demographics, disease sites, and themes were assessed. RESULTS: As of August 2022, the top five hashtags for each gynecologic cancer on TikTok had 466.7 million views. 430 of the top 500 posts were eligible for inclusion (OC: n = 86, CC: n = 93, EC: n = 98, GTD: n = 63, VC: n = 90). The majority of creators (n = 323, 75.1%) were White, 33 (7.7%) were Black, 20 (4.6%) were Asian/Pacific Islander (API), 10 (2.3%) were South Asian, 20 (4.7%) were Hispanic/Latino/a, 24 (5.5%) were unable to determine. Eleven central themes were identified, with significant differences when analyzed by disease site and race. The median DISCERN score for all posts was 1.0, indicating poor educational quality and reliability. When compared by race, South Asian/API posters received the highest scores (3, IQR 2.5) versus Black (2: IQR 3), Hispanic/Latino/a (2: IQR 0), and White posters (1, IQR 2) (p = 0.0013). CONCLUSION(S): Gynecologic cancer-related content on TikTok is of poor educational quality, and racial disparities in gynecologic cancer extend to social media. Opportunities exist to create more diverse content to support racial and cultural experiences in gynecologic cancer treatment.

Epigenetic MMR defect identifies a risk group not accounted for through traditional risk stratification algorithms in endometrial cancer.

Purpose: We sought to evaluate the contribution of mismatch repair (MMR) status to traditional risk stratification algorithms used to predict nodal involvement and recurrence in a large single-institution cohort. Methods: Endometrioid endometrial cancer (EC) cases from 2014-2020 were evaluated. MMR immunohistochemistry (IHC) was performed universally. Uterine factors assessed in the Mayo criteria were used to retrospectively classify patients as low or high risk for lymphatic spread. Patients were classified according to risk for recurrence using GOG 99 and PORTEC criteria. Associations were evaluated using chi-square and t-tests and contributing factors assessed using logistic regression models. Results: 1,514 endometrioid EC were evaluated; 392 (25.9%) were MMR (MMR) deficient of which 80.4% of MMR defects were associated with epigenetic silencing of MLH1. Epigenetic MMR defects were significantly more likely to be high risk for lymph node (LN) metastasis based on Mayo criteria (74.9% vs 60.6%, p=<0.001) and with the presence of LN metastasis (20.3 vs 10.5%, p=0.003) compared to MMR proficient tumors. Tumors with epigenetic MMR defects were significantly more likely to be classified as high or high intermediate risk using GOG99 and PORTEC criteria. Furthermore, cases with epigenetic MMR defects classified as low or low intermediate risk were significantly more likely to recur (GOG99 p=0.013; PORTEC p=0.008) and independently associated with worse disease-free survival (DFS). MMR status was found to be independently associated with worse DFS (HR 1.90; 95% CI 1.34-2.70; p=0.003) but not overall survival. Conclusion: While MMR deficient EC has been associated with poor prognostic features in prior reports; we demonstrate that only epigenetic MMR defects have poorer outcomes. Epigenetic MMR defect were independently associated with lymph node metastasis after controlling for risk criteria. Epigenetic MMR deficiency was found to be an independent predictor of recurrence beyond the factors considered in traditional risk stratification algorithms. Traditional uterine-based risk stratification algorithms may not fully reflect the risk for recurrence in MMR deficient tumors. Consideration should be given to implementing MMR status and MLH1 hypermethylation alongside traditional risk stratification algorithms. Performing MMR IHC on preoperative pathologic specimens may aid in risk stratification and patient counseling.

Recurrence rate in early-stage epithelial ovarian cancer: Is there a role for upfront maintenance with PARP inhibitors in stages I and II?

Objective: To determine the recurrence rate and survival among early-stage epithelial ovarian cancer cases considering homologous recombination deficiency (HRD) status. Methods: Single institution retrospective study of stage I/II EOC patients from 2017 to 2020. HRD was defined as evidence of germline or somatic BRCA mutation, or loss of heterozygosity (LOH)/genomic instability (GIS) as determined by companion diagnostic tests. Kaplan-Meier analyses were performed. Results: 89 stage I/II cases were included. 4/89 (4.5%) had a germline BRCA1/2 mutation, 8 (9%) were germline negative but had a somatic BRCA mutation, and 8 (9%) were BRCA wild-type but had evidence of LOH/GIS on somatic testing; these 20/89 (22%) cases comprised the HRD group. The remaining tumors were confirmed homologous recombination proficient (HRP, 35/89, 39%) or homologous recombination unknown (HRU, 34/89, 38%). The overall recurrence rate was 33/89 (37%). There were more recurrences among HRD cases (14/20, 70%) compared to HRP/HRU cases (19/69, 27.5%, p = 0.0012). Median Recurrence-Free Survival (RFS) was 35 months for HRD cases and 225 months for HRP/HRU cases (p = 0.001). At 2 years, there were 60% HRD cases and 88% HRP/HRU cases recurrence-free. At 5 years there were 29% HRD and 69% HRP/HRU cases recurrence-free (p = 0.001). Conclusions: Despite a high rate of complete surgical staging and six cycles of adjuvant chemotherapy, recurrence rate was high in this early-stage cohort. Higher recurrence rates were seen in the HRD group, however these data are likely biased by the clinical practice of tumor testing primarily at the time of recurrence rather than the upfront setting. RFS was significantly lower for HRD cases.

Safety and feasibility of same-day discharge following minimally invasive hysterectomy in the morbidly obese patient population.

OBJECTIVES: To determine whether morbid obesity should serve as an independent factor in the decision for same day discharge following minimally invasive hysterectomy. METHODS: Retrospective review was performed of patients with BMI ≥ 40 who underwent minimally invasive hysterectomy within a single comprehensive cancer center between January 2018 - August 2020. Demographics, perioperative factors, post-operative monitoring, complications, and readmissions were compared between patients who underwent same day discharge and overnight observation using Fisher's exact tests and Wilcoxon rank-sum tests. RESULTS: 374 patients with BMI ≥ 40 were included. Eighty-three (22.2%) patients underwent same day discharge, and 291 (77.8%) patients underwent overnight observation. Factors associated with increased likelihood of same day discharge included younger age (median age 53 vs 58; p = 0.001), lower BMI (median BMI 45 vs 47; p = 0.005), and fewer medical co-morbidities (Charlson Co-Morbidity Index 2 vs 3; p < 0.001). On multivariate regression analysis, frailty (OR 2.16 [1.14-4.11], p = 0.019) and surgical completion time after 12 PM (OR 3.67 [2.16-6.24], p < 0.001) were associated with increased risk of overnight observation. Few patients admitted for routine overnight observation required medical intervention (n = 14, 4.8%); most of these patients were frail (64.3%). The overall hospital readmission rate within 30 days of discharge was 3.2% (n = 12), with no patients discharged on the day of surgery being readmitted. CONCLUSIONS: Morbid obesity alone should not serve as a contraindication to same day discharge following minimally invasive hysterectomy. Admission for observation was associated with low rates of clinically meaningful intervention, and patients who underwent same day discharge were not at increased risk of adverse outcome.

Pembrolizumab with or without bevacizumab for recurrent or metastatic cervical cancer: A cost-effectiveness analysis.

OBJECTIVE: To determine the cost-effectiveness of the addition of pembrolizumab in various combinations in patients with recurrent/metastatic cervical cancer. METHODS: A decision-analysis model evaluated the cost-effectiveness of chemotherapy plus pembrolizumab and bevacizumab (CPB) relative to chemotherapy plus pembrolizumab (CP) and chemotherapy plus bevacizumab (CB) in cervical cancer patients. Data from KEYNOTE-826 was used to estimate quality-adjusted life-years (QALYs). Drug cost estimates were obtained using average wholesale prices. Incremental cost-effectiveness ratios (ICERs) were calculated to determine cost/QALY. The willingness-to-pay threshold (WTP) was set a $100,000/QALY. Sensitivity analyses were performed on cost and effectiveness for pembrolizumab-containing regimens. RESULTS: Cost of treatment with CB, CP, and CPB were $416 million (M), $713 M, and $1.51 billion, respectively. Relative to CB, the ICER for CP was $92,678. CPB was dominated. Sensitivity analyses were performed varying the cost and efficacy of CP and CPB. If overall survival (OS) with CP decreased from 24.4 months to 23.4 months, the ICER would exceed the WTP. If the OS from CP is assumed to be 20.4 months, the ICER increases to $187,746. The ICER for CP improves to $63,670 when the model is restricted to PD-L1 positive cancers. With CP eliminated, CPB becomes cost-effective relative to CB if the cost of pembrolizumab per cycle decreases from $12,080 to $2913 for the baseline model and to $4644 for the PD-L1 model. CONCLUSIONS: CP is cost-effective relative to CB for recurrent or metastatic cervical cancer. The efficacy of CPB would need to far exceed both CB and CP to be cost-effective. Restricting the model to patients with PD-L1 positive tumors dramatically improves the ICER for CP relative to CB by $30,000/QALY.

Cervical carcinoma with histologic components of sarcomatoid carcinoma and multiple basaloid variants: A case report and review of the literature.

Cervical cancer with co-existing pathologic components of squamous cell carcinoma, basaloid morphology and sarcomatoid carcinoma is rare, with limited reports in the literature. Here we present a patient who underwent a modified radical hysterectomy for cervical cancer, with final pathology specimen demonstrating multiple histologic variants including basal carcinoma, adenoid cystic-like areas, basaloid squamous cell carcinoma and areas of high-grade transformation to sarcomatoid carcinoma.

Lenvatinib plus pembrolizumab in advanced recurrent endometrial cancer: A cost-effectiveness analysis.

OBJECTIVE: To determine the cost-effectiveness of lenvatinib plus pembrolizumab (LP) in patients with microsatellite stable (MSS), recurrent, pretreated endometrial cancer (EC). METHODS: A decision analysis model was created to evaluate the cost-effectiveness of LP relative to doxorubicin, pegylated liposomal doxorubicin (PLD), and bevacizumab in patients with recurrent pretreated MSS EC. Published data was used to estimate quality adjusted life years (QALYs) and drug cost estimates were obtained using average wholesale prices. A health state utility (HSU) penalty of -0.10 was applied to the LP group to account for treatment toxicity. Incremental cost-effectiveness ratios (ICERs) were calculated to determine cost/QALY. The willingness to pay threshold (WTP) was set at $100,000 per QALY saved. Sensitivity analyses were performed on cost, effectiveness, and HSU penalty for LP. RESULTS: Costs of treatment with doxorubicin, PLD, and bevacizumab are $23.7 million (M), $56.9 M, and $250.8 M respectively. Cost of treatment with LP is $1.8 billion. Relative to doxorubicin, the ICERs for PLD, bevacizumab, and LP are $56,808, $345,824, and $1.6 M respectively. A sensitivity analysis varying the cost of LP shows that if the combined drug cost decreases from over $58,000 to less than $11,000 per cycle, this strategy would be cost-effective. Eliminating the HSU penalty for LP decreased the ICER $1.0 M while increasing the penalty to -0.20 increased the ICER to $3.7 M. CONCLUSIONS: LP is not cost-effective in patients with recurrent pretreated, MSS EC. A dramatic reduction in cost of LP is required for this novel strategy to be cost-effective.

Lateral thoracotomy for epicardial pacemaker placement in patients with congenital heart disease.

OBJECTIVES: Our institution adopted a lateral thoracotomy approach to epicaridal pacemaker implantation with the objective of avoiding epicardial scar tissue and to achieve adequate lead pacing and sensing. We sought to assess the short-term outcomes of this approach. METHODS: A single-centre review was conducted in paediatric patients and adults with congenital heart disease or inherited arrhythmia syndromes who underwent a lateral thoracotomy for epicardial pacemaker placement from August 2010 to January 2016. Patient histories were recorded along with outcomes including complications, lead and generator performance. RESULTS: Twenty-one operations were performed in 20 patients (median age 17 years, range 3 months-49 years), including 19 pacemakers and 2 implantable-cardioverter defibrillators (ICDs). Prior epicardial pacemakers had been placed in 11 (55%) patients, including 3 with multiple pacemakers. Most patients had undergone at least 1 prior cardiac operation, with a mean of 3.2 (range 0-7) prior cardiac operations. Through our lateral thoracotomy approach, 17 of the 19 attempted atrial leads (89%) and 20 of the 20 attempted ventricular leads (100%) were successfully implanted with acceptable pacing thresholds. Complications included 1 (5%) bleeding, 2 (10%) pacemaker pocket revisions and 1 late death at 6 months unrelated to the pacemaker. There were no lead failures at a mean follow-up period of 27.5 months (range of 0.7-56.1 months). CONCLUSIONS: The lateral thoracotomy is a useful approach for epicardial pacemaker implantation in patients with congenital heart disease or inherited arrhythmia syndromes including those with multiple prior operations.