The association between progesterone receptor expression and survival in women with adult granulosa cell tumors.

BACKGROUND: Granulosa cell tumors (GCT) variably express estrogen receptors (ER) and progesterone receptors (PR). The goal of this study is to evaluate the relationship between ER and PR expression patterns and clinical outcomes in women with GCT. METHODS: A multicenter, retrospective analysis was performed of all cases of GCT diagnosed between 1989 and 2012. Immunohistochemical staining for ER and PR was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue and interpreted using a semiquantitative scoring system that incorporated tumor cell staining proportion and intensity. Demographics, disease status, and survival information were collected. Associations between ER and PR staining scores and recurrence-free and overall survival were assessed using univariate Cox proportional hazards models. RESULTS: FFPE tumor blocks were available for 149/186 GCT patients. The majority of the women had clinical stage I disease (76%). ER and PR expression was present in 52% and 98% of subjects, respectively. The median composite scores of ER and PR staining were 1 (range 0-8) and 9 (range 0-15), respectively. In univariate analysis, PR composite score >9 was strongly associated with decreased recurrence-free survival (HR = 2.9, 95% CI = 1.5-5.5) and decreased overall survival (HR = 3.7, CI 1.3-10.2). ER composite score was not a significant predictor of recurrence-free survival or overall survival (p = 0.7, HR = 1.1, 95% CI 0.6-2.0 and p = 0.06, HR = 1.1, 95% CI 0.4-2.9, respectively). CONCLUSIONS: Our results reveal that high PR composite score (≥9) was associated with both decreased recurrence-free and overall survival in patients with GCT while ER expression was not associated with survival outcomes.

Emerging biomarkers in ovarian granulosa cell tumors.

OBJECTIVE: Although the majority of ovarian granulosa cell tumors can be successfully managed with surgery, a subset require chemotherapy for residual and recurrent disease. The benefit of chemotherapy in this population, however, remains controversial. There is therefore interest in the development of more tolerable and effective treatment options for advanced ovarian granulosa cell tumors. We report the use of immunohistochemistry to investigate how biomarkers could inform clinical trials in granulosa cell tumors with an emphasis on emerging androgen antagonistic, immunotherapeutic, and anti-angiogenic approaches. METHODS: Immunohistochemistry for androgen receptor, the immune markers programmed cell death ligand 1, indoleamine-2,3 dioxygenase, and cluster of differentiation 8, and the vascular marker cluster of differentiation 31 were evaluated on formalin-fixed paraffin-embedded whole tissue sections from 29 cases of adult-type granulosa cell tumors. Results were evaluated with clinicopathologic variables including recurrence. RESULTS: 59% of granulosa cell tumors were androgen receptor-positive, suggesting a potential role for anti-androgen therapy in this tumor type. In contrast, the targetable immune modulatory molecules programmed cell death ligand 1 and indoleamine-2,3 dioxygenase were scarcely expressed, with no cases showing tumorous programmed cell death ligand 1 and a single case demonstrating very focal tumorous indoleamine-2,3 dioxygenase staining. A minority of cases expressed programmed cell death ligand 1 in occasional tumor-associated macrophages and indoleamine-2,3 dioxygenase in peritumoral vessels. Tumor-infiltrating cytotoxic T cells were also scarce in granulosa cell tumors, arguing against a significant role for immunotherapy in the absence of additional immunostimulation. Cluster of differentiation 31 immunostaining revealed a range of vascular densities across granulosa cell tumors, and future studies evaluating the role of vascular density as a predictor of response to angiogenesis inhibition are warranted. None of the biomarkers investigated were significantly correlated with recurrence, and the only clinicopathologic feature significantly correlated with outcome was stage at presentation. CONCLUSIONS: Biomarker data suggest that many ovarian granulosa cell tumors could be candidates for anti-androgen therapy, while the potential role for immunotherapy appears more limited. Vascular density could be useful for identifying optimal candidates for angiogenesis inhibition. Incorporation of these biomarkers into clinical trials could help optimize patient selection.

Cervical cancer care in rural Virginia: The impact of distance from an academic medical center on outcomes & the role of non-specialized radiation centers.

OBJECTIVE: To determine whether distance to a tertiary care facility affects outcomes for locally advanced cervical cancer and to evaluate the impact of receiving care at non-specialized centers in rural communities. METHODS: Retrospective, single institution study of patients with locally advanced cervical cancer managed with chemo-radiation from January 1, 2000 to June 1, 2014. Kaplan-Meier survival curves and Cox proportional hazard models were used to compare progression free and overall survival for patients by median distance to the tertiary care facility (<72 miles or >72 miles) and facility where treatment was received. RESULTS: 180 patients met inclusion criteria. There was no difference in PFS or OS between the travel distance cohorts. When compared by location of external beam radiation, patients treated at outside facilities were older (p = 0.02) and significantly more likely to be insured (95.6% versus 71.7%, p < 0.0002). There were more recurrences among patients treated at outside facilities (31.1% versus 15.8%) but this was non-significant (p = 0.24). On multivariable analysis, FIGO stage and insurance status were associated with overall survival. Uninsured patients had a significantly increased hazard risk of death as compared to privately insured patients (HR 3.85 95% CI 3.07-4.64, p = 0.0008). CONCLUSIONS: Median distance to a tertiary care facility had no significant impact on PFS or OS, however treating facility for radiation may influence recurrence rates. Having non-private insurance or being uninsured is significantly associated with increased risk of death and speaks to the many barriers these patients face.

Mesothelium expression of vascular cell adhesion molecule-1 (VCAM-1) is associated with an unfavorable prognosis in epithelial ovarian cancer (EOC).

BACKGROUND: Mesothelium vascular cell adhesion molecule-1 (VCAM-1) expression in the metastatic epithelial ovarian cancer (EOC) microenvironment is induced by tumor and mediates tumor cell invasion. VCAM-1 imaging suggests expression during treatment is an indicator of platinum resistance. Here, we assess the potential prognostic significance of mesothelium VCAM-1 expression and prospectively evaluate whether soluble VCAM-1 (sVCAM-1) is a surrogate for mesothelium expression. METHODS: A retrospective review of EOC patients was performed to evaluate outcomes with mesothelium VCAM-1 expression determined by immunohistochemistry of peritoneum or omentum specimens. A prospective cohort of EOC patients was identified and followed through primary treatment. Serum for sVCAM-1 evaluation, which was performed via enzyme-linked immunosorbent assay, was collected before surgery or neoadjuvant chemotherapy and at each treatment cycle. Peritoneal specimens were obtained during debulking to assess mesothelial VCAM-1 expression. RESULTS: A retrospective review identified 54 advanced-stage EOC patients. Patients expressing mesothelium VCAM-1 had shortened overall survival (44 vs 79 months, P = 0.035) and progression-free survival (18 vs 67 months, P = 0.010); the median time to platinum resistance was 36 months for VCAM-1-expressing patients and not yet determined for the VCAM-1-negative group. In our prospective observational cohort, 18 EOC patients completed primary treatment; 3 were negative for mesothelium VCAM-1 expression, and sVCAM-1 did not vary between groups. CONCLUSIONS: Mesothelium VCAM-1 expression is negatively associated with progression-free and overall survival in EOC. This is especially compelling in light of previous data suggesting that persistent VCAM-1 expression during treatment is an indicator of platinum resistance. Our pilot study had insufficient cases to determine whether sVCAM-1 would substitute for mesothelium expression. Cancer 2017;123:977-84. © 2016 American Cancer Society.

Cutting costs and standardizing care: Once-per-cycle complete blood count monitoring may be safe for patients undergoing platinum-based chemotherapy.

AIM: The aim of this study was to evaluate whether frequency of complete blood count (CBC) testing during chemotherapy for gynecologic cancer impacts hospital admissions or rates of neutropenic fever. METHODS: A retrospective cohort study was performed at a single academic institution. Patients undergoing platinum-based chemotherapy for endometrial or ovarian cancer from January 2010 to December 2014 were identified from a clinical database. Patients receiving dose-dense chemotherapy or on a clinical trial were excluded. Electronic chart review collected demographic and clinical characteristics. The primary outcome was the rate of febrile neutropenia or hospital admission. RESULTS: A total of 174 patients were identified, 63 (36%) with endometrial and 111 (64%) with ovarian cancer. Fifty-four percent of patients received multiple CBC per cycle compared with 46% who only had one CBC per cycle. The majority of patients were treated with a platinum-based doublet (85%). Dose reductions, addition of granulocyte colony stimulating factor, and rates of grade 3 or 4 anemia and neutropenia were significantly associated with more frequent testing. There was no difference in rates of neutropenic fever (5.3 vs 3.8%, P = 0.45) or hospital admission (22.3 vs 21.3%, P = 0.86) for multiple versus single CBC monitoring. CONCLUSION: More frequent laboratory testing detected more cases of grade 3 or 4 hematopoietic toxicities and was associated with more interventions. There were no differences in number of hospitalizations or cases of neutropenic fever by frequency of laboratory testing, suggesting that it may be appropriate to decrease routine laboratory tests for select patients.

Impact of obesity on outcomes of hysterectomy.

STUDY OBJECTIVES: To evaluate the impact of obesity on complications of hysterectomy. STUDY DESIGN: Retrospective cohort study (Canadian Task Force II-2). SETTING: The Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI. PATIENTS: Patients who had a hysterectomy at WIH between July 2006 and January 2009. INTERVENTIONS: Hysterectomy by any mode. MEASUREMENTS AND MAIN RESULTS: We collected data from medical records of all laparoscopic hysterectomies during the time period and collected data from a random subset of abdominal and vaginal hysterectomies. The independent variable, body mass index, was grouped according to World Health Organization guidelines. A composite of surgical complications was generated. Multivariable logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). We collected data from 907 hysterectomies, and 29.9% (n = 267) of the population was obese. Eighteen percent of patients (n = 154) had at least 1 complication. Compared to non-obese women, obese women were at increased odds of having any complication (OR 1.62, 95% CI 1.12-2-34). Performing subgroup analyses by mode of hysterectomy and controlling for confounding factors, we were unable to detect differences odds of complications between obese and non-obese women who underwent either an abdominal, vaginal, or laparoscopic hysterectomy. CONCLUSION: In our study, we found that among women who had a hysterectomy, obese women had a higher rate of complications than nonobese women.

Endometrial Cancer Characteristics and Risk of Recurrence.

OBJECTIVES: To describe clinicopathologic characteristics and survival outcomes of endometrial adenocarcinomas stratified by mismatch repair (MMR) status. METHODS: Single-institution, retrospective study of all women with endometrioid adenocarcinomas treated from January 2012 through December 2017. Patients were categorized into one of three groups based on MMR testing: intact MMR expression (MMR+), probable MMR mutation (MMR-), or MLH1 hypermethylation (hMLH1+). Demographics, pathologic characteristics, recurrence rates, and survival differences were analyzed. RESULTS: In total, 316 women were included in the analysis: 235 (74.4%) patients in the MMR+ group, 10 (3.1%) in the MMR- group, and 71 (22.5%) in the hMLH1+ group. Patients with hMLH1+ were significantly older, exhibited higher-grade histology and presence of lymphovascular space invasion, and were more likely to have received adjuvant treatment. The early stage hMLH1+ patients were more likely to recur (15.3% hMLH1+ vs 2.3% MMR+ vs 12.5% MMR-, P < .001). Hypermethylation remained a significant predictor of recurrence in multivariable analysis (odds ratio, 5.09; 95% confidence interval [CI], 1.54-16.86; P = .008). Recurrence-free survival was significantly reduced in early stage hMLH1+ (hazard ratio, 7.40; 95% CI, 2.80-21.62; P < .001). CONCLUSIONS: Women with hMLH1+ endometrial cancer have worse prognostic features and recur more frequently, even in patients traditionally considered low risk for recurrence.