Amy J. Bregar

Adherence patterns to National Comprehensive Cancer Network (NCCN) guidelines for referral to cancer genetic professionals

OBJECTIVE Genetic predisposition is responsible for 5-10% of breast cancer, 10% of ovarian cancer and 2-5% of uterine cancer. The study objective was to compare genetic counseling and testing referral rates among women with breast cancer that met NCCN referral guidelines to the referral rates among women with gynecologic cancers and determine predictors of referral. METHODS Utilizing an institutional tumor registry database, patients from an academic womens oncology program were identified who met a subset of NCCN guidelines for genetic referral between 2004 and 2010. Patients diagnosed with ovarian cancer, breast cancer ≤50years of age, or uterine cancer <50years of age were included. A retrospective electronic chart review was conducted to evaluate for a genetic referral and uptake of genetic testing. RESULTS 820 women were included (216 uterine, 314 breast, and 290 ovarian cancer). The overall genetic referral rate was 21.7%. 34% of eligible breast cancer patients were referred compared to 13.4% of uterine cancer and 14.5% of ovarian cancer patients (p<0.0001). Younger age, breast cancer diagnosis, family history and earlier stage were all significant referral predictors. The odds of being referred increased with the number of affected family members. 70.8% of referred patients, consulted with genetics. Among those who consulted with genetics, 95.2% underwent testing. CONCLUSIONS Although increasing, genetic counseling remains underutilized across cancer diagnosis. Women with breast cancer are more likely to be referred than women with gynecologic cancers. Younger age, earlier stage and positive family history appear to be predictive of referral for genetic evaluation.

Trends in the use of neoadjuvant chemotherapy for advanced ovarian cancer in the United States.

OBJECTIVE Neoadjuvant chemotherapy and interval debulking surgery for the treatment of advanced ovarian cancer has remained controversial, despite the publication of two randomized trials comparing this modality with primary cytoreductive surgery. This study describes temporal trends in the utilization of neoadjuvant chemotherapy and interval debulking surgery in clinical practice in the United States. METHODS We completed a time trend analysis of the National Cancer Data Base. We identified women with stage IIIC and IV epithelial ovarian cancer diagnosed between 2004 and 2013. We categorized subjects as having undergone one of four treatment modalities: primary cytoreductive surgery followed by adjuvant chemotherapy, neoadjuvant chemotherapy followed by interval debulking surgery, surgery only, and chemotherapy only. Temporal trends in the frequency of treatment modalities were evaluated using Joinpoint regression, and χ2 tests. RESULTS We identified 40,694 women meeting inclusion criteria, of whom 27,032 (66.4%) underwent primary cytoreductive surgery and adjuvant chemotherapy, 5429 (13.3%) received neoadjuvant chemotherapy and interval surgery, 5844 (15.4%) had surgery only, and 2389 (5.9%) received chemotherapy only. The proportion of women receiving neoadjuvant chemotherapy and surgery increased from 8.6% to 22.6% between 2004 and 2013 (p<0.001), and adoption of this treatment modality occurred primarily after 2007 (95%CI 2006-2009; p=0.001). During this period, the proportion of women who received primary cytoreductive surgery and chemotherapy declined from 68.1% to 60.8% (p<0.001), and the proportion who underwent surgery only declined from 17.8% to 9.9% (p<0.001). CONCLUSION Between 2004 and 2013 the frequency of neoadjuvant chemotherapy and interval surgery increased significantly in the United States.

Outcomes of Women With High-grade and Low-grade Advanced-stage Serous Epithelial Ovarian Cancer

OBJECTIVE To compare outcomes of women with advanced-stage low-grade serous ovarian cancer and high-grade serous ovarian cancer and identify factors associated with survival among patients with advanced-stage low-grade serous ovarian cancer. METHODS A retrospective study of patients diagnosed with grade 1 or 3, advanced-stage (stage IIIC and IV) serous ovarian cancer between 2003 and 2011 was undertaken using the National Cancer Database, a large administrative database. The effect of grade on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. Among women with low-grade serous ovarian cancer, propensity score matching was used to compare all-cause mortality among similar women who underwent chemotherapy and lymph node dissection and those who did not. RESULTS A total of 16,854 (95.7%) patients with high-grade serous ovarian cancer and 755 (4.3%) patients with low-grade serous ovarian cancer were identified. Median overall survival was 40.7 months among high-grade patients and 90.8 months among women with low-grade tumors (P<.001). Among patients with low-grade serous ovarian cancer in the propensity score-matched cohort, the median overall survival was 88.2 months among the 140 patients who received chemotherapy and 95.9 months among the 140 who did not receive chemotherapy (P=.7). Conversely, in the lymph node dissection propensity-matched cohort, median overall survival was 106.5 months among the 202 patients who underwent lymph node dissection and 58 months among the 202 who did not (P<.001). CONCLUSION When compared with high-grade serous ovarian cancer, low-grade serous ovarian cancer is associated with improved survival. In patients with advanced-stage low-grade serous ovarian cancer, lymphadenectomy but not adjuvant chemotherapy was associated with improved survival.

Evaluation of anal cytology and dysplasia in women with a history of lower genital tract dysplasia and malignancy.

OBJECTIVE To compare the prevalence of abnormal anal cytology, high-risk anal HPV and biopsy proven anal dysplasia among women with a history of lower genital tract malignancy compared to those with dysplasia. METHODS A prospective cohort study was performed from December 2012 to February 2014 at outpatient clinics at an academic medical center. Women with a history of high-grade cervical, vulvar, or vaginal dysplasia, or malignancy were recruited. Anal cytology and HPV genotyping were performed. All women with abnormal anal cytology were referred for high-resolution anoscopy and biopsy. RESULTS Sixty-seven women had a lower genital tract malignancy and 123 had a history of genital dysplasia. Average age in the malignancy group was 52.6years (range 27-86) versus 43.5years (range 21-81) in the dysplasia group (p<0.0002). Similar rates of anal dysplasia were seen in both groups, 12.99% (10 cases) in the malignancy group, versus 12.20% (15) in the dysplasia group (p=1.0). Six women in the malignancy group had anal intraepithelial neoplasia (AIN2+) compared to 2 in the dysplasia group (p=0.03). CONCLUSIONS We found high rates of abnormal anal cytology and HPV in women with lower genital tract dysplasia and malignancy. We also found high rates of anal dysplasia in both groups with a trend towards increased rate in those women with history of genital malignancy. Since precancerous anal lesions are detectable and treatable, anal cancer screening may be potentially useful in both of these higher risk groups.

Anal Cytology and Human Papillomavirus Genotyping in Women With a History of Lower Genital Tract Neoplasia Compared With Low-Risk Women.

OBJECTIVE: To compare the prevalence of abnormal anal cytology and high-risk human papillomavirus (HPV) among women with a history of HPV-related genital neoplasia with women without a history of HPV-related genital neoplasia. METHODS: A cross-sectional cohort study was performed from December 2012 to February 2014. Women were recruited from outpatient clinics at an academic medical center. Women with a history of high-grade cervical, vulvar, or vaginal cytology, dysplasia, or cancer were considered the high-risk group. Women with no history of high-grade anogenital dysplasia or cancer were considered the low-risk group. Human immunodeficiency virus–positive women were excluded. Anal cytology and HPV genotyping were performed. Women with abnormal anal cytology were referred for high-resolution anoscopy. RESULTS: There were 190 women in the high-risk group and 83 in the low-risk group. The high-risk group was slightly older: 57 years compared with 47 years (P=.045); 21.7% of low-risk women had abnormal anal cytology compared with 41.2% of high-risk women (P=.006). High-risk HPV was detected in the anal canal of 1.2% of the low-risk group compared with 20.8% of the high-risk group (P<.001). Among women who underwent anoscopy, no anal dysplasia was detected in the low-risk group, whereas 13.4% in the high-risk group had anal dysplasia with 4.2% having anal intraepithelial neoplasia 2 or greater (P<.001). CONCLUSION: Human immunodeficiency virus–negative women with a history of lower genital tract neoplasia are more likely to have positive anal cytology, anal high-risk HPV, and anal intraepithelial neoplasia. Anal cancer screening should be considered for these high-risk women. LEVEL OF EVIDENCE: II

Laparoscopic staging for apparent stage I epithelial ovarian cancer

BACKGROUND: Whereas advances in minimally invasive surgery have made laparoscopic staging technically feasible in stage I epithelial ovarian cancer, the practice remains controversial because of an absence of randomized trials and lack of high‐quality observational studies demonstrating equivalent outcomes. OBJECTIVE: This study seeks to evaluate the association of laparoscopic staging with survival among women with clinical stage I epithelial ovarian cancer. STUDY DESIGN: We used the National Cancer Data Base to identify all women who underwent surgical staging for clinical stage I epithelial ovarian cancer diagnosed from 2010 through 2012. The exposure of interest was planned surgical approach (laparoscopy vs laparotomy), and the primary outcome was overall survival. The primary analysis was based on an intention to treat: all women whose procedures were initiated laparoscopically were categorized as having had a planned laparoscopic procedure, regardless of subsequent conversion to laparotomy. We used propensity methods to match patients who underwent planned laparoscopic staging with similar patients who underwent planned laparotomy based on observed characteristics. We compared survival among the matched cohorts using the Kaplan‐Meier method and Cox regression. We compared the extent of lymphadenectomy using the Wilcoxon rank‐sum test. RESULTS: Among 4798 eligible patients, 1112 (23.2%) underwent procedures that were initiated laparoscopically, of which 190 (17%) were converted to laparotomy. Women who underwent planned laparoscopy were more frequently white, privately insured, from wealthier ZIP codes, received care in community cancer centers, and had smaller tumors that were more frequently of serous and less often of mucinous histology than those who underwent staging via planned laparotomy. After propensity score matching, time to death did not differ between patients undergoing planned laparoscopic vs open staging (hazard ratio, 0.77, 95% confidence interval, 0.54–1.09; P = .13). Planned laparoscopic staging was associated with a slightly higher median lymph node count (14 vs 12, P = .005). Planned laparoscopic staging was not associated with time to death after adjustment for receipt of adjuvant chemotherapy, histological type and grade, and pathological stage (hazard ratio, 0.82, 95% confidence interval, 0.57–1.16). CONCLUSION: Surgical staging via planned laparoscopy vs laparotomy was not associated with worse survival in women with apparent stage I epithelial ovarian cancer.

Emerging strategies for targeting PI3K in gynecologic cancer.

Ovarian, endometrial and cervical cancers are the most prevalent gynecologic cancers in the United States and account for significant mortality. Translational research into these cancers has highlighted the distinctive molecular and genomic profiles of these cancers finding that, even within a disease site, the landscapes and drivers of neoplasia are distinctive. Despite this molecular diversity, activation of the phosphatidylinositol-3-kinase (PI3K) pathway appears to be conserved in subsets of these tumors, suggesting that strategies that antagonize mediators in this signaling cascade could offer anti-tumor efficacy. Extensive pre-clinical and clinical data have demonstrated that single agent targeted therapies lead to modest single agent activity of generally limited duration, even in the setting of innate PI3K pathway activation via mutation or amplification. These findings in the laboratory and clinic have prompted investigations into resistance pathways following PI3K pathway inhibition in order to understand escape pathways and restore tumor cell sensitivity. A next generation of clinical trial investigations will focus on novel combinations in order to define how these important therapeutics can be used in the clinic. This review will present preclinical data that supports the role of the PI3K pathway in ovarian, endometrial and cervical cancers, in addition to discussing the reported clinical trial experience with PI3K pathway inhibition. A specific focus will be on the rationale behind ongoing clinical trials utilizing novel agents in concert with PI3K pathway inhibitors to reverse resistance in populations with and without gain of function alterations in this oncogenic signaling cascade.

Disparities in receipt of care for high-grade endometrial cancer: A National Cancer Data Base analysis

PURPOSE To examine patterns of care and survival for Hispanic women compared to white and African American women with high-grade endometrial cancer. METHODS We utilized the National Cancer Data Base (NCDB) to identify women diagnosed with uterine grade 3 endometrioid adenocarcinoma, carcinosarcoma, clear cell carcinoma and papillary serous carcinoma between 2003 and 2011. The effect of treatment on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS 43,950 women were eligible. African American and Hispanic women had higher rates of stage III and IV disease compared to white women (36.5% vs. 36% vs. 33.5%, p<0.001). African American women were less likely to undergo surgical treatment for their cancer (85.2% vs. 89.8% vs. 87.5%, p<0.001) and were more likely to receive chemotherapy (36.8% vs. 32.4% vs. 32%, p<0.001) compared to white and Hispanic women. Over the entire study period, after adjusting for age, time period of diagnosis, region of the country, urban or rural setting, treating facility type, socioeconomic status, education, insurance, comorbidity index, pathologic stage, histology, lymphadenectomy and adjuvant treatment, African American women had lower overall survival compared to white women (Hazard Ratio 1.21, 95% CI 1.16-1.26). Conversely, Hispanic women had improved overall survival compared to white women after controlling for the aforementioned factors (HR 0.87, 95% CI 0.80-0.93). CONCLUSIONS Among women with high-grade endometrial cancer, African American women have lower all-cause survival while Hispanic women have higher all-cause survival compared to white women after controlling for treatment, sociodemographic, comorbidity and histopathologic variables.

Associations between residual disease and survival in epithelial ovarian cancer by histologic type

OBJECTIVE Surgical cytoreduction has been postulated to affect survival by increasing the efficacy of chemotherapy in ovarian cancer. We hypothesized that women with high-grade serous ovarian cancer, which usually responds to chemotherapy, would derive greater benefit from complete cytoreduction than those with histologic subtypes that are less responsive to chemotherapy, such as mucinous and clear cell carcinoma. METHODS We conducted a retrospective cohort study of patients who underwent primary cytoreductive surgery and adjuvant chemotherapy for stage IIIC or IV epithelial ovarian cancer from 2011 to 2013 using data from the National Cancer Database. We constructed multivariable models to quantify the magnitude of associations between residual disease status (no residual disease, ≤1cm, or >1cm) and all-cause mortality by histologic type among women with clear cell, mucinous, and high-grade serous ovarian cancer. Because 26% of the sample had unknown residual disease status, we used multiple imputations in the primary analysis. RESULTS We identified 6,013 women with stage IIIC and IV high-grade serous, 307 with clear cell, and 140 with mucinous histology. The association between residual disease status and mortality hazard did not differ significantly among histologic subtypes of ovarian cancer (p for interaction=0.32). In covariate adjusted models, compared to suboptimal cytoreduction, cytoreduction to no gross disease was associated with a hazard reduction of 42% in high-grade serous carcinoma (hazard ratio [HR]=0.58, 95% confidence interval [CI]=0.49-0.68), 61% in clear cell carcinoma (HR=0.39, 95% CI=0.22-0.69), and 54% in mucinous carcinoma (HR=0.46, 95% CI=0.22-0.99). CONCLUSIONS We found no evidence that surgical cytoreduction was of greater prognostic importance in high-grade serous carcinomas than in histologies that are less responsive to chemotherapy.

Intensive care admissions among ovarian cancer patients treated with primary debulking surgery and neoadjuvant chemotherapy-interval debulking surgery

OBJECTIVE Admissions to intensive care units (ICU) are costly, but are necessary for some patients undergoing radical cancer surgery. When compared to primary debulking surgery (PDS), neoadjuvant chemotherapy (NACT) with interval debulking surgery, is associated with less peri-operative morbidity. In this study, we compare rates, indications and lengths of ICU stays among ovarian cancer patients admitted to the ICU within 30days of cytoreduction, either primary or interval. METHODS A retrospective chart review was performed of patients with stage III-IV ovarian cancer who underwent surgical cytoreduction at two large academic medical centers between 2010 and 2014. Chi square tests, Student t-tests, and Mann-U Whitney tests were used. RESULTS A total of 635 patients were included in the study. There were 43 ICU admissions, 7% of patients. Compared to NACT, a higher percentage of PDS patients required ICU admission, 9.4% vs 3.9% of patients (P=0.004). ICU admission indications did not vary between PDS and NACT patients. NACT patients admitted to the ICU had comparable mean surgical complexity scores to those PDS patients admitted to the ICU, 6.2 (95%CI 5.3-7.1) vs 4.5 (95%CI 3.1-6.0) (P=0.006). Length of ICU admission did not vary between groups, PDS 2.7days (95%CI 2.3-3.2) vs 3.5days (95%CI 1.5-5.6) for NACT (P=0.936). CONCLUSIONS The rate of ICU admissions among patients undergoing PDS is higher than for NACT. Among patients admitted to the ICU, indications for admission, length of stay and surgical complexity were similar between patients treated with NACT and PDS.