Gunjal Garg

Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer

OBJECTIVE In light of the recent changes in the International Federation of Gynecology and Obstetrics (FIGO) staging system, the objective of this study was to determine the prognostic significance of positive peritoneal cytology (PPC) among patients with early stage endometrial cancer. METHODS Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Only those patients with stage I/II endometrial cancer who had undergone a complete staging procedure (lymph-node removal) were included. Statistical analyses used Chi-square test, Kaplan-Meier log rank, and Cox proportional hazards models. RESULTS A total of 14,704 patients were identified: 14,219 with negative peritoneal cytology (NPC) and 485 with positive peritoneal cytology. More patients with PPC compared to those with NPC were diagnosed with high-risk factors such grade III disease (40.2% vs. 23.8%, p<0.0001), and unfavorable histologic types such as clear cell/serous carcinoma (17.5% vs. 7.5%, p=<0.0001) and carcinosarcoma (9.3% vs. 5.6%, p<0.0001). When compared to patients with negative peritoneal cytology, survival was significantly worse among patients with positive peritoneal cytology (p<0.0001): 5-year disease specific survival 95.1% vs. 80.8% in endometrioid adenocarcinoma; 78.0% vs. 50.4% in clear cell/serous cancer; and 64.7% vs. 32.3% in carcinosarcoma. After adjusting for other contributing factors in the multivariable model, PPC remained an independent predictor of poor survival (p<0.0001) in all histologic types examined. CONCLUSION PPC is an independent risk factor in patients with early stage endometrial cancer. Although, no longer a part of the current FIGO staging criteria, peritoneal cytology status should still be considered for accurate risk-stratification of these patients.

Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134

Pancreatic adenocarcinoma is highly resistant to conventional therapeutics and has been shown to evade apoptosis by deregulation of the X‐linked and cellular inhibitors of apoptosis proteins (XIAP and cIAP). Second mitochondria‐derived activator of caspases (Smac) induces and amplifies cell death by reversing the anti‐apoptotic activity of IAPs. Thus, Smac‐derived peptide analogues (peptidomimetics) have been developed and shown to represent promising cancer therapeutics. Sigma‐2 receptors are overexpressed in many proliferating tumor cells including pancreatic cancer. Selected ligands to this receptor are rapidly internalized by cancer cells. These characteristics have made the sigma‐2 receptor an attractive target for drug delivery because selective delivery to cancer cells has the potential to increase therapeutic efficacy while minimizing toxicity to normal tissues.

Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer

BackgroundDrug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms. Inhibition of apoptosis by the inhibitor of apoptosis proteins (IAPs) represents one such mechanism, and can be overcome by a mitochondrial protein called second mitochondria-derived activator of caspases (SMAC). We have previously shown that the ligands of sigma-2 receptors effectively induce tumor cell death. Additionally, because sigma-2 receptors are preferentially expressed in tumor cells, their ligands provide an effective mechanism for selective anti-cancer therapy.MethodsIn the current work, we have improved upon the previously described sigma-2 ligand SW43 by conjugating it to a pro-apoptotic small molecule SMAC mimetic SW IV-52, thus generating the novel cancer therapeutic SW IV-134. The new cancer drug was tested for receptor selectivity and tumor cell killing activity in vitro and in vivo.ResultsWe have shown that SW IV-134 retained adequate sigma-2 receptor binding affinity in the context of the conjugate and potently induced cell death in ovarian cancer cells. The cell death induced by SW IV-134 was significantly greater than that observed with either SW43 or SW IV-52 alone and in combination. Furthermore, the intraperitoneal administration of SW IV-134 significantly reduced tumor burden and improved overall survival in a mouse xenograft model of ovarian cancer without causing significant adverse effects to normal tissues. Mechanistically, SW IV-134 induced degradation of cIAP-1 and cIAP-2 leading to NF-қB activation and TNFα-dependent cell death.ConclusionsOur findings suggest that coupling sigma-2 ligands to SMAC peptidomimetics enhances their effectiveness while maintaining the cancer selectivity. This encouraging proof-of-principle preclinical study supports further development of tumor-targeted small peptide mimetics via ligands to the sigma-2 receptor for future clinical applications.

Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein Meso-TR3.

BackgroundThe targeted delivery of cancer therapeutics represents an ongoing challenge in the field of drug development. TRAIL is a promising cancer drug but its activity profile could benefit from a cancer-selective delivery mechanism, which would reduce potential side effects and increase treatment efficiencies. We recently developed the novel TRAIL-based drug platform TR3, a genetically fused trimer with the capacity for further molecular modifications such as the addition of tumor-directed targeting moieties. MUC16 (CA125) is a well characterized biomarker in several human malignancies including ovarian, pancreatic and breast cancer. Mesothelin is known to interact with MUC16 with high affinity. In order to deliver TR3 selectively to MUC16-expressing cancers, we investigated the possibility of targeted TR3 delivery employing the high affinity mesothelin/MUC16 ligand/receptor interaction.MethodsUsing genetic engineering, we designed the novel cancer drug Meso-TR3, a fusion protein between native mesothelin and TR3. The recombinant proteins were produced with mammalian HEK293T cells. Meso-TR3 was characterized for binding selectivity and killing efficacy against MUC16-positive cancer cells and controls that lack MUC16 expression. Drug efficacy experiments were performed in vitro and in vivo employing an intraperitoneal xenograft mouse model of ovarian cancer.ResultsSimilar to soluble mesothelin itself, the strong MUC16 binding property was retained in the Meso-TR3 fusion protein. The high affinity ligand/receptor interaction was associated with a selective accumulation of the cancer drug on MUC16-expressing cancer targets and directly correlated with increased killing activity in vitro and in a xenograft mouse model of ovarian cancer. The relevance of the mesothelin/MUC16 interaction for attaching Meso-TR3 to the cancer cells was verified by competitive blocking experiments using soluble mesothelin. Mechanistic studies using soluble DR5-Fc and caspase blocking assays confirmed engagement of the extrinsic death receptor pathway. Compared to non-targeted TR3, Meso-TR3 displayed a much reduced killing potency on cells that lack MUC16.ConclusionsSoluble Meso-TR3 targets the cancer biomarker MUC16 in vitro and in vivo. Following attachment to the tumor via surface bound MUC16, Meso-TR3 acquires full activation with superior killing profiles compared to non-targeted TR3, while its bioactivity is substantially reduced on cells that lack the tumor marker. This prodrug phenomenon represents a highly desirable property because it has the potential to enhance cancer killing with fewer side-effects than non-targeted TRAIL-based therapeutics. Thus, further exploration of this novel fusion protein is warranted as a possible therapeutic for patients with MUC16-positive malignancies.

Patterns of care, predictors, and outcomes of chemotherapy in elderly women with early-stage uterine carcinosarcoma: A population-based analysis

OBJECTIVE To examine the patterns of care, predictors, and impact of chemotherapy on survival in elderly women diagnosed with early-stage uterine carcinosarcoma. METHODS The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify women 65 years or older diagnosed with stage I-II uterine carcinosarcomas from 1991 through 2007. Multivariable logistic regression and Cox-proportional hazards models were used for statistical analysis. RESULTS A total of 462 women met the eligibility criteria; 374 had stage I, and 88 had stage II uterine carcinosarcomas. There were no appreciable differences over time in the percentages of women administered chemotherapy for early stage uterine carcinosarcoma (14.7% in 1991-1995, 14.9% in 1996-2000, and 17.9% in 2001-2007, P=0.67). On multivariable analysis, the factors positively associated with receipt of chemotherapy were younger age at diagnosis, higher disease stage, residence in the eastern part of the United States, and lack of administration of external beam radiation (P<0.05). In the adjusted Cox-proportional hazards regression models, administration of three or more cycles of chemotherapy did not reduce the risk of death in stage I patients (HR: 1.45, 95% CI: 0.83-2.39) but was associated with non-significant decreased mortality in stage II patients (HR: 0.83, 95% CI: 0.32-1.95). CONCLUSIONS Approximately 15-18% of elderly patients diagnosed with early-stage uterine carcinosarcoma were treated with chemotherapy. This trend remained stable over time, and chemotherapy was not associated with any significant survival benefit in this patient population.

Intestinal perforation in gynecologic oncology: Do all patients benefit from surgical management?

OBJECTIVE To identify those patients with gynecologic cancers and intestinal perforation in whom conservative management may be appropriate. METHODS A retrospective review was performed of all gynecologic oncology patients with intestinal perforation at our institution between 1995 and 2011. The Kaplan-Meier method and Cox proportional hazards models were used to analyze factors influencing survival. RESULTS Forty-three patients met the study criteria. The mean age was 59 years (range: 38-82 years). A large number of patients had peritoneal carcinomatosis and history of bowel obstruction. Surgery was performed in 28 patients, and 15 were managed conservatively. Overall mortality at 1, 3, 6, and 12 months was 26%, 40%, 47%, and 59%, respectively. Only cancer burden at the time of perforation was independently predictive of mortality. Patients with peritoneal carcinomatosis, distant metastasis, or both were at 42 times higher risk of death than those with no evidence of disease (95% CI: 3.28-639.83), and at 7 times higher risk of death than those with microscopic/localized disease (95% CI: 1.77-29.94). When adjusted for the extent of disease spread, management approach (conservative vs. surgical) was not a significant predictor of survival (p≥0.05). The length of hospital stay (19 days vs. 7 days) and the complication rate (75% vs. 26.7%) were significantly higher in the surgical group than in the non-surgical group (p<0.05). CONCLUSIONS Patients who develop intestinal perforation in the setting of widely metastatic disease have a particularly poor prognosis. Aggressive surgical management is unlikely to benefit such patients and further impairs their quality of life.

Abstract 1378: Factors influencing survival in gynecologic oncology patients diagnosed with intestinal perforation and pneumatosis intestinalis.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Objective: To investigate the potential factors associated with survival in gynecologic oncology patients diagnosed with intestinal perforation and pneumatosis intestinalis. Methods: A retrospective chart review was performed of all gynecologic oncology patients with intestinal perforation and/or pneumatosis intestinalis at our institutionbetween 1995 and 2011. Factors influencing survival from time of diagnosis were analyzed using Kaplan-Meier method and Cox proportional hazard models. Results: Forty-five patients met the study criteria. The median age was 59 years (range: 38-82 years). Surgery was performed in 28 patients (62%). Among the 17 patients (38%) managed conservatively, 9 (53%) were under hospice care and 8 had a contained perforation (47%). Overall mortality at 1, 3, 6, and 12 months was 27%, 40%, 49%, and 60%, respectively. The corresponding numbers in the surgery group were 14%, 29%, 32%, and 50%, and in the non-surgery group 47%, 59%, 76%, and 76%, respectively. Importantly, all 18 patients who died within the first 3 months had active cancer at time of diagnosis and CA125 levels were 100 were reported in only 2 patients of the 17 who lived longer than 12 months. Seven patients developed perforation after using bevacizumab. Of these, 3 were treated with surgery and 4 were managed conservatively. The three patients treated surgically died at 26 days, 56 days, and 58 days post-surgery. Of the 4 patients treated conservatively, one was still alive at last follow-up (2.7 years), the other three died at 3 days, 34 days, and 126 days after diagnosis. On univariate analysis, advanced stage disease, no cancer- directed surgery, receipt of >3 chemotherapy regimens, active cancer at the time of perforation, conservative management of perforation, and CA125 >100 were negatively associated with survival (p<0.05). On multivariate analysis, only active cancer at diagnosis was independently predictive of mortality (HR: 7.31, 95%CI: 1.20-69.68). Conclusions: Bowel perforation and pneumatosis intestinalis carry grave prognosis in patients with gynecologic cancers. Although surgical management is performed in patients with free intestinal leak, overall prognosis is poor and conservative management should be considered. The ultimate prognosis is most closely associated with the amount of cancer present at time of diagnosis and should be given due consideration to avoid aggressive surgical treatment in those unlikely to derive significant benefit. Citation Format: Gunjal Garg, Shabnam Pourbolghasem, Gongfu Zhou, Matthew A. Powell, Premal H. Thaker, Andrea R. Hagemann, Ivy Wilkinson-Ryan, L. Stewart Massad, David G. Mutch. Factors influencing survival in gynecologic oncology patients diagnosed with intestinal perforation and pneumatosis intestinalis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1378. doi:10.1158/1538-7445.AM2013-1378

Abstract 169: Temporal trends, predictors, and outcome of chemotherapy in elderly women with advanced stage endometrial cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Objective. Randomized clinical trials have suggested that adjuvant chemotherapy improves survival for women with advanced stage (III-IV) endometrial cancer. Despite the fact the endometrial cancer is common in the elderly, a minority of women >65 years of age were represented in these trials. We performed a population-based analysis to determine the use and impact on survival of adjuvant chemotherapy in elderly women with advanced stage endometrial cancer. Methods. The Surveillance Epidemiology, and End Results (SEER)-Medicare database was utilized to identify women diagnosed with stage III-IV endometrial cancer diagnosed from 1998-2007. Only those patients who had undergone a hysterectomy were included. The use of chemotherapy within 6 months of diagnosis and its impact on survival was examined using multivariable logistic regression and Cox proportional hazards models. Results. A total of 1819 women including 1193 with stage III and 626 with stage IV tumors were identified. Adjuvant chemotherapy was given to 46% of women. Use of chemotherapy increased with time from 42% in 1998 to 63% in 2007 (P 65 years of age receive chemotherapy. In addition to year of diagnosis, stage and histology are the strongest predictors of receipt of chemotherapy. Among elderly women with endometrial cancer, chemotherapy is associated with a reduction in mortality. Citation Format: Gunjal Garg, Zainab Siddiq, Gongfu Zhou, Matthew A. Powell, Thomas Herzog, David G. Mutch, Jason D. Wright. Temporal trends, predictors, and outcome of chemotherapy in elderly women with advanced stage endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 169. doi:10.1158/1538-7445.AM2013-169