Yaling Yin

Prognostic Factors for Locoregional Recurrence in Neuroendocrine Tumors of the Rectum

BACKGROUND: Optimal management of rectal neuroendocrine tumors is not yet well defined. Various pathologic factors, particularly tumor size, have been proposed as prognostic markers. OBJECTIVE: We characterized sequential patients diagnosed with rectal neuroendocrine tumors in a population-based setting to determine whether tumor size and other pathologic markers could be useful in guiding locoregional management. DESIGN: This study is a retrospective analysis of data from the British Columbia provincial cancer registry. SETTINGS: The study was conducted at a tertiary care center. PATIENTS: Sequential patients diagnosed with rectal neuroendocrine tumors between 1999 and 2011 were identified. Neuroendocrine tumors were classified as G1 and G2 tumors with a Ki-67 ⩽20% and/or mitotic count ⩽20 per high-power field. MAIN OUTCOME MEASURES: Baseline clinicopathologic data including TNM staging, depth of invasion, tumor size, treatment modalities, and outcomes including survival data were measured. RESULTS: Of 91 rectal neuroendocrine tumors, the median patient age was 58 years, and 35 were men. Median tumor size was 6 mm. Median length of follow-up was 58.1 months, with 3 patients presenting with stage IV disease. Treatment included local ablation (n = 5), local excision (n = 79), surgical resection (n = 4), and pelvic radiation (n = 1; T3N1 tumor). Final margin status was positive in 17 cases. Local relapse occurred in 8 cases and 1 relapse to bone 13 months after T3N1 tumor resection. Univariate analysis demonstrated an association between local relapse and Ki-67, mitotic count, grade, and lymphovascular invasion (p < 0.01). Larger tumor size was associated with decreased disease-free survival. LIMITATIONS: Sample size was 91 patients in the whole provincial population over a 13-year time period because of the low incidence of rectal neuroendocrine tumors. CONCLUSIONS: In this population-based cohort, rectal neuroendocrine tumors generally presented with small, early tumors and were treated with local excision or surgical resection without pelvic radiation. Pathologic markers play a role in risk stratification and prognostication. See Video Abstract at http://links.lww.com/DCR/A514.

Sex Disparities in Outcomes of Early Stage Colorectal Cancer: A Population-Based Study

Micro‐Abstract In an evaluation of the prognostic role of sex on colorectal cancer (CRC)‐specific outcomes, we reviewed all patients with resected stage I to III colorectal cancer referred to cancer centers in a large, representative Canadian province. Men had worse overall and recurrence‐free survival compared to women; however, CRC‐specific survival and time to recurrence did not differ significantly between men and women. This suggests that the trajectory of CRC is similar irrespective of sex when noncancer causes of death are excluded. Background Women have been shown to experience longer overall survival after colorectal cancer (CRC) diagnosis than men even after adjusting for disease stage and management. However, the etiology of this observation is not well understood, and the impact of non‐CRC health conditions on survival has not been described. We aimed to evaluate the prognostic role of sex on CRC‐specific outcomes. Patients and Methods All patients who underwent primary resection of stage I to III CRC from 2001 to 2005, and who were referred to cancer centers in a large, representative Canadian province were reviewed. Baseline patient characteristics, including common comorbidities, were compared between men and women. Multivariable analysis was used to evaluate the associations between sex and survival outcomes. Results We identified 1837 patients. Median age was 69 (interquartile range 60‐76) years, and there were 867 women (47%) and 970 men (53%). Men were more likely to report ischemic heart disease, diabetes, dyslipidemia, and obesity (all P < .001). On multivariable analysis, men had worse overall and recurrence‐free survival compared to women (hazard ratio [HR] = 1.38, 95% confidence interval [CI] 1.15‐1.64; and HR = 1.40, 95% CI, 1.18‐1.67, respectively). However, CRC‐specific outcomes, including CRC‐specific survival and time to recurrence, did not differ significantly between men and women (HR = 1.15, 95% CI, 0.91‐1.45; and HR = 1.12, 95% CI, 0.90‐1.40, respectively). Conclusion Women diagnosed with early stage CRC lived longer and had better general health than men. When noncancer causes of death were excluded, however, the trajectory of CRC appeared similar irrespective of sex. Early identification and better management of comorbidities may narrow the survival gap between men and women.

Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2

Cyclin-dependent kinase 10 (CDK10), a CDC2-related kinase, is highly expressed in colorectal cancer. Its role in the pathogenesis of colorectal cancer is unknown. This study examines the function of CDK10 in colorectal cancer, and demonstrates its role in suppressing apoptosis and in promoting tumor growth in vitro and in vivo. Modulation of CDK10 expression in colorectal cancer cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant colorectal cancer cell lines have an exaggerated apoptotic response and reduced proliferative capacity. In vivo, inhibiting CDK10 in colorectal cancer following intratumoral injections of lentivirus-mediated CDK10 siRNA in a patient-derived xenograft mouse model demonstrated its efficacy in suppressing tumor growth. Furthermore, using a tissue microarray of human colorectal cancer tissues, the potential for CDK10 to be a prognostic biomarker in colorectal cancer was explored. In tumors of individuals with colorectal cancer, high expression of CDK10 correlates with earlier relapse and shorter overall survival. The findings of this study indicate that CDK10 plays a role in the pathogenesis in colorectal cancer and may be a potential therapeutic target for treatment. Mol Cancer Ther; 16(10); 2292–303. ©2017 AACR.

593PEFFECT OF RESECTION OF METASTASIS (ROM) AND ALL 3, 4 AND 5 ACTIVE AGENTS IN METASTATIC COLORECTAL CANCER (MCRC) BETWEEN 1995-2010

ABSTRACT Aim: Significant changes in surgical and systemic management of mCRC have occurred since 1995. The impact of exposure to All 3 Agents (5-Fluorouracil, Irinotecan, Oxaliplatin), All 4 (plus Bevacizumab) or All 5 (plus EGFR inhibitors [i]) and ROM is not well described. The objective of this study is to characterize the 15-year changes in surgical and systemic therapy and to measure associations between these treatments advances and outcomes. Methods: All patients with relapsed or mCRC referred to the BC Cancer Agency diagnosed in 1995-96, 2000, 2003-04, 2006 and 2009-10 were included. Outcomes and systemic therapy data were prospectively collected. Information on ROM of liver, lung, ovarian, peritoneal and other sites was retrospectively abstracted. Cox regression analysis was conducted to examine associations between treatment variables and Overall Survival (OS), while accounting for era of diagnosis. Results: Variable p-value 1Year Hazard Ratio 95% CI ROM vs no ROM 0.32 0.25 0.36 All 3 Agents vs. None 0.33 0.25 0.39 All 4 or 5 Agents vs.None 0.21 0.18 0.25 Only 1-2 Agents vs. None 0.68 0.62 0.74 A total of 3731 eligible patients were included with a median age of 68 years which did not differ between eras (p = .13). In 2009-10, 24% of treated patients underwent ROM, 42% received All 3 Agents, 54% received Bevacizumab and 18% received anti-EGFR agents. Patients who were only able to receive 1-2 agents had a median OS of 1.18 years (95% CI 1.09-1.25), those treated with All 3 Agents survived 1.93 years (95% CI 1.77-2.11) and those with All 4 or 5 Agents survived 2.49 years (95% CI 2.30-2.66). Median OS of ROM patients was 3.65 years (95% CI 3.25-3.95). Regression analysis demonstrated the independent prognostic effect of systemic therapy and ROM. Conclusions: The introduction of 4 and 5 active agents in mCRC is associated with a measurable improvement OS with an incremental effect related to an increasing number of agents received. ROM is associated with prolonged survival, independent of systemic therapy. Effects are independent of era of diagnosis. Disclosure: All authors have declared no conflicts of interest.