Matthew A. Powell

Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers

To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan–Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III–IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I–II (74, 82, and 86%; P<0.0001) and stage III–IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients.

Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes

Endometrial carcinoma is the most common gynecological malignancy in the United States. Although most women present with early disease confined to the uterus, the majority of persistent or recurrent tumors are refractory to current chemotherapies. We have identified a total of 11 different FGFR2 mutations in 3/10 (30%) of endometrial cell lines and 19/187 (10%) of primary uterine tumors. Mutations were seen primarily in tumors of the endometrioid histologic subtype (18/115 cases investigated, 16%). The majority of the somatic mutations identified were identical to germline activating mutations in FGFR2 and FGFR3 that cause Apert Syndrome, Beare–Stevenson Syndrome, hypochondroplasia, achondroplasia and SADDAN syndrome. The two most common somatic mutations identified were S252W (in eight tumors) and N550K (in five samples). Four novel mutations were identified, three of which are also likely to result in receptor gain-of-function. Extensive functional analyses have already been performed on many of these mutations, demonstrating they result in receptor activation through a variety of mechanisms. The discovery of activating FGFR2 mutations in endometrial carcinoma raises the possibility of employing anti-FGFR molecularly targeted therapies in patients with advanced or recurrent endometrial carcinoma.

Lymph Node Staging by Positron Emission Tomography in Cervical Cancer: Relationship to Prognosis

PURPOSE A previous retrospective study demonstrated that positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) was more sensitive than computed tomography for lymph node staging in patients with cervical cancer; the findings on FDG-PET were strongly associated with progression-free survival. Therefore, a prospective cohort study was initiated to evaluate FDG-PET lymph node staging in a larger patient population. PATIENTS AND METHODS The study was conducted between July 2000 and March 2009. All 560 patients with cervical cancer underwent pretreatment FDG-PET lymph node staging. Treatment included surgery alone, surgery and postoperative radiation therapy, and definitive radiation or combination radiation and chemotherapy. PET findings were correlated with the risk of disease progression and with survival. Results Overall, 47% of patients had lymph node involvement by FDG-PET at diagnosis. The frequency of lymph node metastasis increased with clinical stage and was similar to that in historical surgical series. Within a stage, patients with PET-positive lymph nodes had significantly worse disease-specific survival than those with PET-negative lymph nodes (P < .001). Disease-specific survival was stratified into distinct groups based on the most distant level of PET-detected nodal disease (none, pelvic, para-aortic, or supraclavicular; P < .001). The hazard ratios for disease recurrence increased incrementally based on the most distant level of nodal disease: pelvic 2.40 (95% CI, 1.63 to 3.52), para-aortic 5.88 (95% CI, 3.80 to 9.09), and supraclavicular 30.27 (95% CI 16.56 to 55.34). CONCLUSION Nodal involvement detected by FDG-PET in cervical cancer relates to clinical stage, is comparable to historical data, and stratifies patient recurrence and survival outcomes.

Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis.

The study was undertaken to determine the safety and efficacy of the monoclonal, antivascular endothelial growth factor antibody bevacizumab in combination with cytotoxic chemotherapy for women with platinum‐refractory ovarian cancer.

Clinical Outcomes of Definitive Intensity-Modulated Radiation Therapy With Fluorodeoxyglucose-Positron Emission Tomography Simulation in Patients With Locally Advanced Cervical Cancer

PURPOSE This study aimed to evaluate the toxicity and clinical outcomes for cervical cancer patients treated definitively with intensity-modulated radiation therapy (IMRT) compared with non-IMRT treatment. METHODS AND MATERIALS This prospective cohort study included 452 patients with newly diagnosed cervical cancer treated with curative intent (135 IMRT and 317 non-IMRT). Treatment involved external irradiation and brachytherapy, and 85% of patients received concurrent chemotherapy. All IMRT patients underwent an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET/CT) simulation. A 3-month post-therapy PET was obtained to evaluate treatment response. Toxicity was scored by the Common Terminology Criteria for Adverse Events Version 3.0. RESULTS The IMRT and non-IMRT groups had similar stage distribution and histology. For all patients, the post-therapy FDG-PET response correlated with overall recurrence risk (p < 0.0001) and cause-specific survival (p < 0.0001). Post-treatment FDG-PET findings were not significantly different between the IMRT and non-IMRT patients (p = 0.9774). The mean follow-up for all patients alive at the time of last follow-up was 52 months (72 months non-IMRT, 22 months IMRT). At last follow-up, 178 patients (39 IMRT, 139 non-IMRT) had developed a recurrence. The difference in recurrence-free survival between the two groups did not reach statistical significance (p = 0.0738), although the IMRT group showed better overall and cause-specific survivals (p < 0.0001). Of the patients, 62 patients (8 IMRT and 54 non-IMRT) developed Grade 3 or greater bowel or bladder complications, and by cumulative hazard function analysis the risk was significantly less for patients treated with IMRT (p = 0.0351). CONCLUSION Cervical cancer patients treated with FDG-PET/CT-guided IMRT have improved survival and less treatment-related toxicity compared with patients treated with non-IMRT radiotherapy.

Inhibition of Activated Fibroblast Growth Factor Receptor 2 in Endometrial Cancer Cells Induces Cell Death Despite PTEN Abrogation

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.

Utility of parametrectomy for early stage cervical cancer treated with radical hysterectomy

Removal of the parametrial soft tissue is recommended for patients with cervical cancer undergoing radical hysterectomy. Parametrectomy results in significant morbidity. The objective of the study was to determine factors predictive of parametrial tumor spread and to define a subset of patients at low risk for parametrial disease.

Microsatellite Instability and Epigenetic Inactivation of MLH1 and Outcome of Patients With Endometrial Carcinomas of the Endometrioid Type

PURPOSE Most studies of microsatellite instability (MSI) and outcomes in endometrial cancer patients have included varied histologic subtypes. Nonetheless, MSI occurs almost exclusively in endometrioid tumors. The impact of MSI on outcomes in patients with endometrial cancer is controversial. We sought to determine whether MSI and MLH1 methylation are associated with clinicopathologic variables and survival outcomes in a large series of patients with endometrial carcinomas of the endometrioid type. PATIENTS AND METHODS Tumor samples, blood, and clinicopathologic data were prospectively collected and analyzed for 446 patients with endometrioid carcinomas. MSI was determined using five National Cancer Institute (NCI) consensus panel markers, and the methylation status of the MLH1 promoter was determined by combined bisulfite restriction analysis (COBRA). Associations with clinicopathologic variables and survival outcomes were evaluated. RESULTS MSI was identified in 147 cases (33%). MSI was associated with higher International Federation of Gynecology and Obstetrics (FIGO) grade (P < .0001). MSI+ tumors without MLH1 methylation were associated with younger age (P < .001). MSI was not associated with overall survival (OS; hazard ratio [HR], 1.011; 95% CI, 0.688 to 1.484; P = .96) or disease-free survival (DFS; HR 0.951; 95% CI, 0.554 to 1.635; P = .86). The combined MSI/MLH1 methylation status (treating MSI- as the reference) did not predict OS (MSI+/MLH1-U: HR, 0.62; 95% CI, 0.27 to 1.44; P = .26; MSI+/MLH1-M: HR, 0.95; 95% CI, 0.62 to 1.46; P = .82) or DFS (MSI+/MLH1-U: HR, 0.51; 95% CI, 0.22 to 1.19; P = .12; MSI+/MLH1-M: HR, 0.93; 95% CI, 0.62 to 1.40; P = .72). CONCLUSION MSI is not associated with survival in patients with endometrioid endometrial cancer.

Disparities in Ovarian Cancer Care Quality and Survival According to Race and Socioeconomic Status

BACKGROUND The relationship between racial and socioeconomic status (SES) disparities and the quality of epithelial ovarian cancer care and survival outcome are unclear. METHODS A population-based analysis of National Cancer Data Base (NCDB) records for invasive primary epithelial ovarian cancer diagnosed in the period from 1998 to 2002 was done using data from patients classified as white or black. Adherence to National Comprehensive Cancer Network (NCCN) guideline care was defined by stage-appropriate surgical procedures and recommended chemotherapy. The main outcome measures were differences in adherence to NCCN guidelines and overall survival according to race and SES and were analyzed using binomial logistic regression and multilevel survival analysis. RESULTS A total of 47 160 patients (white = 43 995; black = 3165) were identified. Non-NCCN-guideline-adherent care was an independent predictor of inferior overall survival (hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.38 to 1.47). Demographic characteristics independently associated with a higher likelihood of not receiving NCCN guideline-adherent care were black race (odds ratio [OR] = 1.36, 95% CI = 1.25 to 1.48), Medicare payer status (OR = 1.20, 95% CI = 1.12 to 1.28), and not insured payer status (OR = 1.33, 95% CI = 1.19 to 1.49). After controlling for disease and treatment-related variables, independent racial and SES predictors of survival were black race (HR = 1.29, 95% CI = 1.22 to 1.36), Medicaid payer status (HR = 1.29, 95% CI = 1.20 to 1.38), not insured payer status (HR = 1.32, 95% CI = 1.20 to 1.44), and median household income less than

Phase II Evaluation of Paclitaxel and Carboplatin in the Treatment of Carcinosarcoma of the Uterus: A Gynecologic Oncology Group Study

35 000 (HR = 1.06, 95% CI = 1.02 to 1.11). CONCLUSIONS These data highlight statistically and clinically significant disparities in the quality of ovarian cancer care and overall survival, independent of NCCN guidelines, along racial and SES parameters. Increased efforts are needed to more precisely define the patient, provider, health-care system, and societal factors leading to these observed disparities and guide targeted interventions.