Faculty Bibliography

Objective: To systematically review and summarize the literaure on nongenetic risk factors that may contribute to the racial disparity in uterine fibroids (UF) that disproportionality impacts Black individuals at 2-3 times the rate of White individuals and how the racial disparity has been studied to date. Evidence Review: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol checklist guided the systematic review process. From January 1 to June 1, 2021, relevant articles were retrieved from PubMed, EMBASE, Web of Science, and Cochrane Library. Multiple investigators screened, assessed, extracted, and critically appraised the data. Results: A total of 44 articles examined the relationship among UFs, race/ethnicity, and nongenetic risk factors, including cardiometabolic features, comorbidities, diet, chemical exposures, vitamin D levels, reproductive characteristics and socioeconomic factors, and life experiences. Most studies reported on the same 3 cohort study populations, and there was inconsistent statistical reporting of the race/ethnicity, risk factors, and UF relationship. Conclusion: Many potential risk factors related to the racial disparity in UF have been studied thus far. There is still little conclusive evidence regarding which risk factors are the greatest contributors to racial disparities in UF. Promising areas of research deserve greater attention and a greater diversity of study populations and analytical methods.

BACKGROUND:Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. PATIENTS AND METHODS/METHODS:In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. RESULTS:Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). CONCLUSIONS:Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

Objectives: The efficacy of treatments for advanced, recurrent metastatic endometrial cancers (EC) remains limited. In-depth, high-dimensional immune profiling of recurrent EC subtypes is much needed in order to describe the immune composition within the tumor microenvironment.
Method(s): A 2:1 randomized phase 2 trial was conducted comparing the combination of cabozantinib and nivolumab (Arm A) versus nivolumab (Arm B) in women with recurrent measurable EC (NCT03367741). A third exploratory cohort (Arm C) included EC patients with the carcinosarcoma subtype, and patients who had prior immunotherapy (IO). Fresh baseline core biopsies were collected and processed into single-cell suspensions for high-dimensional CyTOF analysis with a 36-marker immune profiling panel. Immune composition was determined by unsupervised single-cell clustering using PhenoGraph and visualized by uniform manifold approximation and projection (UMAP). The differential abundance (DA) of unique immune cell subsets present in the baseline biopsies was determined using the diffcyt-DA-EdgeR method.
Result(s): Cabozantinib plus nivolumab demonstrates improved PFS and ORR compared to nivolumab in heavily pre-treated women with recurrent EC. Unsupervised clustering of CD45+ cells from baseline biopsies (n=40) using PhenoGraph resulted in 35 unique immune cell subsets defined their expression of lineage and activation/checkpoint markers (e.g. PD-1, PD-L1, TIGIT, 4-1BB, CD39, CD69 and others). Broadly, these PhenoGraph-defined subsets constitute the major immune populations including CD4 and CD8 T cells, regulatory T cells, gammaδ T cells, B cells, innate lymphoid/natural killer (NK) cells, and monocyte/macrophages and dendritic cells. In-depth CyTOF analysis of the tumor microenvironment identified a higher proportion of activated tissue-resident gammaδ T cells in patients who had prior IO and who benefit from the combination therapy (non-progressors, n=4; progressors, n=5; 6 log fold-change, adjusted P=0.001). We did not observe any statistically significant differences in the baseline immune composition between IO-naïve (Arm A and B) endometrioid (n=13), serous (n=7) and carcinosarcoma tumors (n=4). However, in comparison to endometrioid and serous tumors, carcinosarcoma tumors may trend towards a lower abundance (not significant) of CD45RA+CD27+CD28+ CD4 and CD8 T cells, and CD45RA+CD69- NK cells. All three histological subtypes had a similar abundance of activated, tissue-resident PD-1+TIGIT+CD69+CD103+ CD8 T cells. Microsatellite instability high (MSI-H; n=2; both endometrioid) tumors were excluded from our analysis.
Conclusion(s): In comparison to nivolumab monotherapy, combination cabozantinib and nivolumab treatment improved PFS and ORR in recurrent EC patients. To our knowledge, this is the first study reporting in-depth immune profiling analysis of core biopsies from EC patients. The tumor immune microenvironment of EC is comprised of several immune populations with unique phenotypes related to their expression of activation and checkpoint markers.
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BACKGROUND: Metastatic and recurrent cervical cancer is rarely a curable disease. Systemic chemotherapy is typically recommended for treatment based on clinical trials in the first-line or second-line setting. Rare patients who progress through 2 salvage regimens will have the performance status, medical ability, and desire to continue cytotoxic therapy. For these patients, there are no data to provide effective counseling regarding expected response rates (RRs) and toxicities. We sought to review our experience with this patient population. METHODS: A single institution review was performed of all patients treated for cervical cancer between January 1, 2000 and June 30, 2013. Eligible patients were those who received at least 3 unique salvage chemotherapy regimens following primary surgery or radiation. RRs, survival statistics and toxicities were evaluated. RESULTS: Twenty-three of 710 (3.2%) patients treated for cervical cancer met eligibility criteria. Nineteen received 2 or more cycles of a third-line regimen and were assessed for response and progression-free survival. The remainder were included in analysis of overall survival and toxicity. The RR to third-line chemotherapy was 10% (1 complete, 1 partial). An additional 27% achieved stable disease. In total, 57% suffered a grade 3 or 4 toxicity. The progression-free survival from the beginning of third-line therapy was 3.8 months, and the overall survival was 7.4 months. CONCLUSIONS: Patients eligible to receive third-line chemotherapy for metastatic and recurrent cervical cancer can expect minimal benefit at the cost of significant toxicity. Quality of life considerations should be of paramount importance when counseling regarding the risks and benefits of further cytotoxic therapy.

OBJECTIVE: Adherence to treatment regimen and schedule is recommended to improve control of disease and overall survival (OS) in locally advanced cervical cancer. However, treatment-related toxicities and patient and physician factors all impact timely completion of treatment. We sought to correlate adherence to treatment plan with survival and toxicities of patients treated for locally advanced cervical cancer. MATERIALS AND METHODS: A retrospective review of patients treated for advanced cervical cancer at our institution between 2003 and 2011 was performed. Demographics, clinicopathologic variables, treatment, and disease outcomes were collected. Endpoints of disease outcome were disease-free survival and OS. Statistical analyses were performed using the Kaplan-Meier method, log-rank test, and Cox regression analysis. RESULTS: A total of 162 patients met the inclusion criteria and were included in study analysis. A total of 95% of patients were treated with both radiation and concurrent chemotherapy. Mean radiation dose to point A was 72 Gy. In total, 77% had complete response to primary therapy. Severe (grade 3/4) late radiation toxicities were seen in 10.5% of patients. Stage and total radiation dose to point A were significant predictors of survival for the entire cohort. Among patients receiving at least 72 Gy and brachytherapy, duration of treatment was significantly associated with both disease-free survival and OS. CONCLUSIONS: Adherence to both optimal treatment time and radiation dose is significantly associated with improved survival. Total radiation dose is an independent predictor of survival among patients with locally advanced cervical cancer.

OBJECTIVES: Cervical cancer and its treatments impair women's sexual function. These complications may or may not be regarded when clinicians develop treatment plans. We aim to investigate the considerations of providers toward the sex life of cervical cancer patients. METHODS: All members of the Society of Gynecologic Oncology received a questionnaire assessing their opinions and practices toward specific questions regarding the sexual functioning of their patients. RESULTS: Of the 124 providers who completed the survey, the majority were Board Certified Gynecologic Oncologists (56%) with an average of 15years in training. Approximately 23% received training about sexual dysfunction. Providers without formal training were more likely to agree that: "Information regarding sexual function in patients undergoing treatment for cervical cancer is lacking" (p=0.02). Providers with over 10years of experience were more likely to agree that "sex is private and discussing it with patients will interfere with our provider-patient relationship" (p=0.03). International clinicians were more likely to agree that: "I feel uncomfortable initiating discussions regarding sexual function with patients" (p=0.03), "Sex is private and discussing it with patients will interfere in our provider-patient relationship" (p=0.02), and "If a patient has a sexual problem, they will raise the subject" (p=0.009). CONCLUSIONS: Years of clinical experience, provider age, a history of training on regarding sexual dysfunction and an international setting of practice affect providers' opinions and practices toward sexual issues of cervical cancer patients. More formal, relevant training regarding sexual dysfunction is warranted for clinicians who treat cervical cancer patients.

OBJECTIVES: Advanced vulvar cancers involving midline structures pose a therapeutic challenge. Our objectives were to review the management and outcomes, and identify factors influencing primary treatment modality. METHODS: Patients with midline vulvar cancers diagnosed from 1985 to 2012 were included in the analysis. Medical records were abstracted for demographics, clinico-pathological findings, treatment, and outcomes. Groin node status was defined by clinical findings or pathology. Survival was analyzed by Kaplan-Meier method and differences by log-rank test and Cox proportional hazards model. Factors influencing treatment modality were evaluated using stepwise logistic regression. RESULTS: Forty-two patients were identified. Twenty-one underwent primary radical vulvectomy and 21 underwent primary radiation. Median tumor diameter was 3.4cm (range 2-9cm) for primary radical vulvectomy and 5cm (range 2.3-15cm) for primary radiation. Primary radiation was significantly associated with a tumor diameter >/=5cm (p=0.02), or when 2 or more midline (p=0.008) or 1 or more mucosal structures (p=0.03) were involved. On multivariate analysis, age and tumor diameter were predictors of progression-free survival (PFS) (p=0.02 and p=0.0004, respectively) and overall survival (OS) (p=0.03 and p=0.0005, respectively). Thirty-month OS for primary surgery and primary radiation was 74% and 71% (p=0.78), respectively. There were no differences in PFS or recurrence rates between the two treatment groups. CONCLUSIONS: Clinical tumor diameter and the number of midline or mucosal structures involved influence selection of primary treatment modality. Survival outcomes and recurrence rates did not differ between treatment groups. Age and tumor diameter are important prognostic factors for survival.