Racial Disparities in Patients with Stage IIIC Endometrial Cancer

Purpose/Objective(s): To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma (EC). Materials/Methods: A retrospective multi-institutional cohort study was conducted across 13 Northern American academic centers and included patients with stage IIIC endometrial carcinoma (EC) who received both chemotherapy and radiation in an adjuvant setting. Overall survival (OS) and recurrence-free survival (RFS) were calculated by Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. Propensity score matching was used to estimate the effect of race on survival outcomes. Statistical analyses were conducted using statistical software. Results: A total of 90 Black and 568 non-Black patients (83%) were identified with a median age at diagnosis of 62 (Interquartile Range (IQR) 55-70). Median follow-up was 45.3 months (IQR 24-71 months). Black patients were significantly older (p\u3c0.0001), had significantly more non-endometrioid histology (p\u3c0.0001), grade 3 tumors (p\u3c0.0001) and were more likely to have \u3e1 positive paraaortic lymph nodes (PALN) compared to non-black patients. The presence of lymphovascular space invasion (LVSI), depth of myometrial involvement, number of total nodes involved, adnexal and cervical involvement and stage were not correlated with race (all p\u3e0.1). As for treatment type, chemoradiotherapy sequencing approach was not correlated with race and no difference in number of chemotherapy cycles between Black and non-Black patients (p=0.32) was observed. Black patients were more often treated with external beam radiation therapy (EBRT) (43.3% and 24%, respectively) while a higher proportion of non-black patients received both EBRT and vaginal cuff brachytherapy (VBT) (65% vs. 38 %) (P\u3c0.0001) despite similar cervical involvement. The 5-year estimated OS and RFS rates were 45% and 47% compared to 77% and 68% for Black patients vs. non-black patients, respectively (p\u3c0.001). After propensity score matching, the 2 groups were well balanced for most of the covariates (age, histology, stage, grade, number of positive PALN, adnexal and cervical involvement) except for depth of myometrial invasion and radiation type. The estimated hazard ratios (HRs) of Black vs. non-Black patients were 1.613 (95% CI = (1.01, 2.575), p-value = 0.045) for OS and 1.487 (95% CI = (0.906, 2.440), p-value = 0.116) for RFS, indicating that Black patients have significantly worse OS. RFS differences did not reach statistical significance. Conclusion: Compared to non-Black patients, Black patients have higher rates of non-endometrioid histology, grade 3 tumors and number of PALNs. After propensity score matching, Black patients had worse OS but no statistically significant difference in RFS. Racial disparities could be mitigated by better access to care, equitable inclusion on randomized trials, and identification of genomic/molecular differences to better tailor adjuvant treatment

T cell adhesion and cytolysis of pancreatic cancer cells: a role for E-cadherin in immunotherapy?

Pancreatic cancer is an aggressive and potent disease, which is largely resistant to conventional forms of treatment. However, the discovery of antigens associated with pancreatic cancer cells has recently suggested the possibility that immunotherapy might become a specific and effective therapeutic option. T cells within many epithelia, including those of the pancreas, are known to express the αEβ7-integrin adhesion molecule, CD103. The only characterised ligand for CD103 is E-cadherin, an epithelial adhesion molecule which exhibits reduced expression in pancreatic cancer. In our study, CD103 was found to be expressed only by activated T cells following exposure to tumour necrosis factor beta 1, a factor produced by many cancer cells. Significantly, the expression of this integrin was restricted mainly to class I major histocompatibility complex-restricted CD8+ T cells. The human pancreatic cancer cell line Panc-1 was transfected with human E-cadherin in order to generate E-cadherin negative (wild type) and positive (transfected) sub-lines. Using a sensitive flow cytometric adhesion assay it was found that the expression of both CD103 (on T cells) and E-cadherin (on cancer cells) was essential for efficient adhesion of activated T cells to pancreatic cancer cells. This adhesion process was inhibited by the addition of antibodies specific for CD103, thereby demonstrating the importance of the CD103→E-cadherin interaction for T-cell adhesion. Using a 51Cr-release cytotoxicity assay it was found that CD103 expressing T cells lysed E-cadherin expressing Panc-1 target cells following T cell receptor stimulation; addition of antibodies specific for CD103 significantly reduced this lysis. Furthermore, absence of either CD103 from the T cells or E-cadherin expression from the cancer cells resulted in a significant reduction in cancer cell lysis. Therefore, potentially antigenic pancreatic cancer cells could evade a local anti-cancer immune response in vivo as a consequence of their loss of E-cadherin expression; this phenotypic change may also favour metastasis by reducing homotypic adhesion between adjacent cancer cells. We conclude that effective immunotherapy is likely to require upregulation of E-cadherin expression by pancreatic cancer cells or the development of cytotoxic immune cells that are less dependent on this adhesion molecule for efficient effecter function

Chromosomal instability drives metastasis through a cytosolic DNA response

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs

The relationship of study and authorship characteristics on trial sponsorship and self-reported conflicts of interest among neuro-oncology clinical trials

Propose: To examine the association between trial sponsorship sources, self-reported conflicts of interest (COI), and study and author characteristics in central nervous system (CNS) oncology clinical trials (CT). Methods: MEDLINE search was performed for original CT on “Central Nervous System Neoplasms“[Mesh]. The investigators assessed for relationships between funding source (industry, academic or cooperative, none, not described), COI (presented, none, or not reported), CT, and author characteristics. Results: From 2010 to 2015, 319 CT were considered eligible. The majority of the studies involved primary gliomas (55.2%) and were Phase II CT (59.2%). Drug therapy was investigated in 83.0% of the CT. The remaining studies investigated surgery or radiotherapy. A minority of papers were published in journals with impact factor (IF) higher than > 10 (16%) or in regions other than North America and Europe (20.4%). Overall, 83.1% of studies disclosed funding sources: 32.6% from industry alone, 33.9% from an academic or cooperative group, and 10.7% from a mixed funding model. COI data was reported by 85.9% of trials, of which 56.2% reported no COI and 43.8% reported a related COI. Significant predictors for sponsorship (industry and/or academia) on univariate analysis were study design, type of intervention, journal impact factor, study conclusion, transparency of COI and presence of COI. On multivariate analysis, type of intervention, (P < 0.001), journal impact factor (IF) (P = 0.003), presence of COI (P < 0.001) and study conclusion (P = 0.003) remained significant predictors of sponsorship. For predicting COI, significant variables on univariate analysis were disease type, type of intervention, journal IF, funding source, and intervention arm being related to sponsor. On multivariate analysis, disease type (P = 0.003), journal IF (P < 0.001), type of intervention (P = 0.001), and funding source (P = 0.008) remained significant. Conclusions: The majority of CNS CT reported some external funding sources and non-related COI. We identified that drug trials, higher IF, presence of COI, and a neutral or negative study conclusion are associated with external funding. Likewise drug trials, higher IF, and glioma trials are associated with presence of COI

Funding source, conflict of interest and positive conclusions in neuro-oncology clinical trials

We aimed to test any association between authors’ conclusions and self-reported COI or funding sources in central nervous system (CNS) studies. A review was performed for CNS malignancy clinical trials published in the last 5 years. Two investigators independently classified study conclusions according to authors’ endorsement of the experimental therapy. Statistical models were used to test for associations between positive conclusions and trials characteristics. From February 2010 to February 2015, 1256 articles were retrieved; 319 were considered eligible trials. Positive conclusions were reported in 56.8% of trials with industry-only, 55.6% with academia-only, 44.1% with academia and industry, 77.8% with none, and 76.4% with not described funding source (p = 0.011). Positive conclusions were reported in 60.4% of trials with unrelated COI, 60% with related COI, and 60% with no COI reported (p = 0.997). Factors that were significantly associated with the presence of positive conclusion included trials design (phase 1) [OR 11.64 (95 CI 4.66–29.09), p < 0.001], geographic location (outside North America or Europe) [OR 1.96 (95 CI 1.05–3.79), P = 0.025], primary outcomes (non-overall or progression free survival) [OR 3.74 (95 CI 2.27–6.18), p < 0.001], and failure to disclose funding source [OR 2.45 (95 CI 1.22–5.22), p = 0.011]. In a multivariable regression model, all these factors remained significantly associated with trial’s positive conclusion. Funding source and self-reported COI did not appear to influence the CNS trials conclusion. Funding source information and COI disclosure were under-reported in 14.1 and 17.2% of the CNS trials. Continued efforts are needed to increase rates of both COI and funding source reporting