Nina R. Shah

Cardiovascular disease is the leading cause of death among endometrial cancer patients

OBJECTIVE To evaluate the causes of death among women with endometrial cancer. METHODS SEER registries from 1973-1988 were queried to perform a retrospective cohort study of women with invasive epithelial endometrial cancer. Causes of death were compared according to grade and stage. RESULTS 33,232 women with incident cases of endometrial cancer had died at the time of last follow up. Overall, women were most likely to die from cardiovascular disease (35.9%, 95% CI 35.3-36.3%), followed by other causes, other malignancies, and endometrial cancer. Women with low grade localized cancer were most likely to die of cardiovascular disease, while women with high grade advanced cancer were least likely to die of cardiovascular disease and most likely to die of endometrial cancer. For the entire population, risk of death from cardiovascular causes surpasses the risk of death from endometrial cancer 5 years after diagnosis. CONCLUSIONS Higher risk of cardiac death among endometrial cancer patients likely reflects the high probability of curative cancer treatment and the prevalence of cardiac disease and risk factors. As the probability of dying of endometrial cancer decreases with time, the probability of dying of cardiovascular disease increases. Interventions and investigations aimed at addressing risk factors for cardiovascular disease may have the greatest potential to improve survival for women diagnosed with endometrial cancer and should feature prominently in treatment and survivorship plans.

Bariatric surgery decreases the risk of uterine malignancy.

OBJECTIVE To describe the risk of uterine malignancy among women who have had weight loss surgery. METHODS We performed a retrospective cohort study among inpatient admissions of women 18years, or older, registered in the University HealthSystem Consortium (UHC) dataset. The rate of uterine malignancy per hospital admission was calculated. Rates were compared according to whether diagnoses at the time of discharge included history of bariatric surgery, and further, according to whether there was a diagnosis of obesity. RESULTS In admissions of patients who did not have a history of prior bariatric surgery, the rate of uterine malignancy was 599/100,000 (95% CI 590 to 610). Among obese women who had not previously undergone bariatric operations, the rate was 1409/100,000 (95% CI 1380 to 1440). Of women admitted who had a history of bariatric surgery, the rate of uterine malignancy was 408/100,000 (95% CI 370 to 450). The relative risk of uterine malignancy in all admissions for women who had prior bariatric surgery, compared to obese women who had not had bariatric surgery, was 0.29 (95% CI 0.26-0.32). Among women who had bariatric surgery and were not currently obese, the relative risk of uterine malignancy was 0.19 (95% CI 0.17-0.22) compared to obese women who had not undergone bariatric surgery. CONCLUSION A history of bariatric surgery is associated with a 71% reduced risk for uterine malignancy overall, and an 81% reduced risk if normal weight is maintained after surgery. This finding suggests that obesity may be a modifiable risk factor related to development of endometrial cancer.

Changing demographics of cervical cancer in the United States (1973-2008).

OBJECTIVE To describe changes in the cervical cancer population. METHODS The SEER database 9 registries from 1973 to 2008 were queried to perform a retrospective cohort study of women with invasive cervical cancer. Estimated annual percent change (EAPC) in incidence rates and 95% confidence intervals (CI) over the entire study period were compared according to age, stage, race, and cell type (squamous [SCC] and adenocarcinoma [ACA]). Proportions and odds ratios (OR) were calculated for patients diagnosed during the second half (1990-2008) compared to first half (1973-89) of the study period. RESULTS 40,363 women with cervical cancer were entered into SEER. The EAPC are falling fastest among those with localized disease (-2.5%; 95% CI -2.8 to -2.1), age≥50 (-3.0%; 95% CI=-3.2 to -2.8), and black women (-3.8%; 95% CI=-4.1 to -3.6). The odds of a newly diagnosed cervical cancer patient having advanced disease are 10% higher, being less than age 50 are 37% higher, and being Asian or Pacific Islander are 68% higher in the second time period as compared to the first. CONCLUSIONS In the US, the population with cervical cancer is changing. Patients are presently significantly more likely to be pre-menopausal, Asian or Pacific Islander, and more frequently have non-squamous histology than previously. These progressive and cumulative changes could be due to the disparate impact of current population based screening and prevention strategies. Understanding the implications of these evolving population characteristics may facilitate planning targeted studies and interventions for cervical cancer prevention, screening and treatment in the future.

The risk of uterine malignancy is linearly associated with body mass index in a cohort of US women

OBJECTIVE We sought to quantify the relationship of uterine malignancy with body mass index (BMI). STUDY DESIGN The University HealthSystem Consortium database was queried to identify all women undergoing total hysterectomy with a recorded BMI in the overweight and obese categories. Least squares regression was applied to evaluate the association between increasing BMI and the proportion of women with a diagnosis of uterine malignancy. Multivariate binary logistic regression was performed to adjust for other known risk factors including age, race, and other comorbidities. RESULTS There were 6905 women who met inclusion criteria; 1891 (27.4%) of these had uterine malignancy. There is a linear relationship (y = 0.015x - 0.23, R(2) = 0.92) of the probability of uterine malignancy vs BMI. After adjusting for other risk factors, we found that each 1-U increase in BMI was significantly, independently associated with an 11% increase in the proportion of patients diagnosed with uterine malignancy (odds ratio, 1.11; 95% confidence interval, 1.09-1.13; P < .001). CONCLUSION In a population of women undergoing hysterectomy, we observed a linear increase in the frequency of uterine cancer associated with increasing BMI. This finding suggests that even relatively modest weight gain may significantly raise cancer risk. In the United States, the mean BMI for women is 26.5 kg/m(2) and it is estimated that more than half of US women have a BMI within the studys range. Our results could, therefore, be relevant to a majority of the population. The findings could increase popular acceptance of weight management as a key component of general health maintenance and, possibly, as an additional approach to cancer risk reduction.

FAK Inhibition Disrupts a β5 Integrin Signaling Axis Controlling Anchorage-Independent Ovarian Carcinoma Growth

Ovarian cancer ascites fluid contains matrix proteins that can impact tumor growth via integrin receptor binding. In human ovarian tumor tissue arrays, we find that activation of the cytoplasmic focal adhesion (FAK) tyrosine kinase parallels increased tumor stage, β5 integrin, and osteopontin matrix staining. Elevated osteopontin, β5 integrin, and FAK mRNA levels are associated with decreased serous ovarian cancer patient survival. FAK remains active within ovarian cancer cells grown as spheroids, and anchorage-independent growth analyses of seven ovarian carcinoma cell lines identified sensitive (HEY, OVCAR8) and resistant (SKOV3-IP, OVCAR10) cells to 0.1 μmol/L FAK inhibitor (VS-4718, formerly PND-1186) treatment. VS-4718 promoted HEY and OVCAR8 G0–G1 cell-cycle arrest followed by cell death, whereas growth of SKOV3-IP and OVCAR10 cells was resistant to 1.0 μmol/L VS-4718. In HEY cells, genetic or pharmacological FAK inhibition prevented tumor growth in mice with corresponding reductions in β5 integrin and osteopontin expression. β5 knockdown reduced HEY cell growth in soft agar, tumor growth in mice, and both FAK Y397 phosphorylation and osteopontin expression in spheroids. FAK inhibitor–resistant (SKOV3-IP, OVCAR10) cells exhibited anchorage-independent Akt S473 phosphorylation, and expression of membrane-targeted and active Akt in sensitive cells (HEY, OVCAR8) increased growth but did not create a FAK inhibitor–resistant phenotype. These results link osteopontin, β5 integrin, and FAK in promoting ovarian tumor progression. β5 integrin expression may serve as a biomarker for serous ovarian carcinoma cells that possess active FAK signaling. Mol Cancer Ther; 13(8); 2050–61. ©2014 AACR.

Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer.

OBJECTIVE Focal adhesion kinase (FAK) is overexpressed in serous ovarian cancer. Loss of merlin, a product of the neurofibromatosis 2 tumor suppressor gene, is being evaluated as a biomarker for FAK inhibitor sensitivity in mesothelioma. Connections between merlin and FAK in ovarian cancer remain undefined. METHODS Nine human and two murine ovarian cancer cell lines were analyzed for growth in the presence of a small molecule FAK inhibitor (PF-271, also termed VS-6062) from 0.1 to 1 μM for 72 h. Merlin was evaluated by immunoblotting and immunostaining of a human ovarian tumor tissue array. Growth of cells was analyzed in an orthotopic tumor model and evaluated in vitro after stable shRNA-mediated merlin knockdown. RESULTS Greater than 50% inhibition of OVCAR8, HEY, and ID8-IP ovarian carcinoma cell growth occurred with 0.1 μM PF-271 in anchorage-independent (p<0.001) but not in adherent culture conditions. PF-271-mediated reduction in FAK Y397 phosphorylation occurred independently of growth inhibition. Suspended growth of OVCAR3, OVCAR10, IGROV1, IGROV1-IP, SKOV3, SKOV3-IP, A2780, and 5009-MOVCAR was not affected by 0.1 μM PF-271. Merlin expression did not correlate with serous ovarian tumor grade or stage. PF-271 (30 mg/kg, BID) did not inhibit 5009-MOVCAR tumor growth and merlin knockdown in SKOV3-IP and OVCAR10 cells did not alter suspended cell growth upon PF-271 addition. CONCLUSIONS Differential responsiveness to FAK inhibitor treatment was observed. Intrinsic low merlin protein level correlated with PF-271-mediated anchorage-independent growth inhibition, but reduction in merlin expression did not induce sensitivity to FAK inhibition. Merlin levels may be useful for patient stratification in FAK inhibitor trials.

Abstract 752: Genetic and pharmacological FAK inhibition disrupt a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Ovarian cancer spreads via cell shedding and growth within malignant ascites. Effective targeted therapies have not been developed for ovarian cancer. Ascites contains an abundance of matrix proteins, and spheroids maintain integrin receptor expression. Through databases analyses we find that elevated osteopontin (OPN), β5 integrin, and focal adhesion kinase (FAK) mRNA levels are associated with decreased overall survival of serous ovarian cancer patients treated with platinum and taxol. In ovarian tumor tissue arrays, increased FAK activation (FAK Y397 phosphorylation) correlated with elevated tumor grade in parallel with increased in β5 integin and OPN levels. FAK is a cytoplasmic tyrosine kinase that remains active in spheroids, and treatment of seven ovarian carcinoma cell lines with sub-micromolar levels of FAK inhibitor (PND-1186) identified sensitive (HEY and OVCAR8), intermediate (OVCAR3, ID8-IP, and IGROV1-IP), and resistant (SKOV3-IP and OVCAR10) cells to blockage of growth under anchorage-independent conditions. Genetic or pharmacological FAK inhibition within ID8-IP or HEY cells selectively prevents anchorage-independent growth in culture and tumor growth in mice with corresponding reductions in β5 integrin and OPN expression. β5 knockdown reduced HEY growth in soft agar, tumor growth in mice, FAK Y397 phosphorylation, and OPN expression in spheroids. Although FAK inhibitor resistant ovarian carcinoma cells (SKOV3-IP and OVCAR10) were associated with anchorage-independent Akt S473 phosphorylation, membrane-targeted and activated Akt expression in sensitive cells (HEY and OVCAR8) resulted in only a partial rescue of FAK inhibitor-associated growth block. These results support the hypothesis that OPN, αvβ5 integrins, and FAK may function as a signaling axis promoting ovarian tumor progression. Although Akt signaling pathway activation is a common event in serous ovarian cancer, our results suggest that this may not impart complete resistance to FAK inhibitor treatment. Supported by NIH CA102310 Citation Format: Isabelle Tancioni, Sean Uryu, Florian Sulzmaier, Nina Shah, Christine Lawson, Nichol L.G. Miller, Christine Jean, Xiao Lei Chen, Kristy K. Ward, David D. Schlaepfer. Genetic and pharmacological FAK inhibition disrupt a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 752. doi:10.1158/1538-7445.AM2014-752

Abstract 2823: Low merlin level as a biomarker for sensitivity of ovarian cancer cell lines to FAK inhibition

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that undergoes gene amplification in >20% of serous ovarian cancers. In addition to increased tumor growth and spread, ovarian cancer patients with FAK amplification have a poorer prognosis with decreased overall survival. Merlin, a product of the NF2 tumor suppressor gene, is being evaluated as a biomarker for sensitivity to FAK inhibition in human clinical trials for malignant mesothelioma. As it remains undetermined whether linkages exist between merlin and FAK in other tumor types, we evaluated nine human and two murine ovarian cancer cell lines with sub-micromolar levels of FAK inhibitor (PF-271) for effects on anchorage-independent cell growth. Cells were identified as sensitive (OVCAR3, OVCAR8, HEY, ID8-IP), intermediate (A2780, IGROV1), or resistant (OVCAR10, IGROV1-IP, SKOV3, SKOV3-IP, 5009) to FAK inhibition. Notably, merlin protein levels were high in all resistant cell lines, moderate in intermediate cell lines, and low or undetectable in sensitive cell lines. Oral FAK inhibitor administration reduced orthotopic tumor growth of sensitive (ID8-IP, low merlin) but not resistant (5009, high merlin) murine ovarian carcinoma cells. However, stable knockdown of merlin expression in resistant SKOV3-IP and OVCAR10 human ovarian carcinoma cells did not induce sensitivity to FAK inhibition in vitro. These results support the notion that high merlin expression is correlated with a FAK-inhibitor resistant phenotype, likely through an indirect mechanistic linkage. Nevertheless, merlin protein levels may serve as a biomarker to predict ovarian cancer sensitivity or resistance to FAK inhibitor treatment. Supported by NIH CA102310 Citation Format: Nina R. Shah, Isabelle Tancioni, Kristy K. Ward, Christine Lawson, Xiao Lei Chen, Nichol L.G. Miller, Florian J. Sulzmaier, Sean Uryu, David D. Schlaepfer. Low merlin level as a biomarker for sensitivity of ovarian cancer cell lines to FAK inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2823. doi:10.1158/1538-7445.AM2014-2823

Urinary diversions: A time to enrich surgical training?

OBJECTIVE To assess the potential exposure to complex urologic procedures, specifically urinary diversion, during a gynecologic oncology fellowship. METHODS We queried the University HealthSystem Consortium (UHC) database to determine the total number of urinary diversions performed from October 2008 to August 2012. This data was used to estimate the mean number of urinary diversions performed each year. Gender, primary diagnosis, type of diversion, gynecologic oncologist involvement, and medical center were explored. RESULTS Of the nearly 21,000 urinary diversions performed in UHC participating hospitals during the study period, 6180 (29.5%) were performed in women. On average, 1648 urinary diversions are performed in women each year, with gynecologic malignancies accounting for 6.8% of cases. We estimate that a gynecologic oncologist was involved with 87 cases per year at nonprofit academic medical centers in the US. With approximately 112 clinically active fellows per year during the study period, this equates to less than one diversion per clinical fellow per year if cases are equally distributed among centers. However, the majority of urinary diversions with gynecologic oncologist involvement were performed at just a fraction of centers. Thus, only a small contingent of fellows may be getting the greatest exposure to urinary diversions. CONCLUSIONS The majority of urinary diversions in women in the US are performed for bladder carcinoma by urologists. The estimated number of cases per clinical gynecologic oncology fellow per year is less than one. Strategies to improve fellow exposure to urinary diversion and consideration of alternative surgical training modalities should be explored.