Background: This thesis is composed of three studies. In the first paper, we tested the association of metformin use with prostate cancer incidence. In the second paper, we examined the association of metformin use with all-cause and prostate cancer specific mortality. The final paper explored the benefit of detailed pathology review to predict mortality among diabetic men with prostate cancer. Methods: A total of 5306 incident diabetic men older than 66 who subsequently developed prostate cancer were identified using the Ontario Diabetes Database and the Ontario Cancer Registry between 1994-2008. The association of metformin use and risk of prostate cancer and its grade was tested with a nested case-control design using a conditional logistic regression model. We used a cohort design with a time dependent Cox-proportional hazard model to examine the association of metformin use and mortality. Finally, we employed a c-statistic and Net Reclassification Improvement analysis to study the impact of pathology abstraction on predicting mortality. Results: The data suggest metformin use was not associated with the risk of prostate cancer or its grade at presentation. However, each additional 6 month of metformin use was associated with a 24% decrease in prostate-cancer-specific and 8% decrease in all-cause mortality. Pathology abstraction improved the accuracy in predicting all-cause and prostate-cancer specific mortality. Conclusions: In our study metformin use was not associated with a decreased risk of prostate cancer, but had a significant impact on all-cause and prostate cancer specific mortality. These results may serve as proof of concept in designing an interventional study of metformin to delay progression in prostate cancer.

Background: This thesis is composed of three studies. In the first paper, we tested the association of metformin use with prostate cancer incidence. In the second paper, we examined the association of metformin use with all-cause and prostate cancer specific mortality. The final paper explored the benefit of detailed pathology review to predict mortality among diabetic men with prostate cancer. Methods: A total of 5306 incident diabetic men older than 66 who subsequently developed prostate cancer were identified using the Ontario Diabetes Database and the Ontario Cancer Registry between 1994-2008. The association of metformin use and risk of prostate cancer and its grade was tested with a nested case-control design using a conditional logistic regression model. We used a cohort design with a time dependent Cox-proportional hazard model to examine the association of metformin use and mortality. Finally, we employed a c-statistic and Net Reclassification Improvement analysis to study the impact of pathology abstraction on predicting mortality. Results: The data suggest metformin use was not associated with the risk of prostate cancer or its grade at presentation. However, each additional 6 month of metformin use was associated with a 24% decrease in prostate-cancer-specific and 8% decrease in all-cause mortality. Pathology abstraction improved the accuracy in predicting all-cause and prostate-cancer specific mortality. Conclusions: In our study metformin use was not associated with a decreased risk of prostate cancer, but had a significant impact on all-cause and prostate cancer specific mortality. These results may serve as proof of concept in designing an interventional study of metformin to delay progression in prostate cancer.

Background Reported outcomes for colorectal cancer associated with Inflammatory Bowel Disease are inconsistent. We compared survival outcomes in colorectal cancer patients with and without Inflammatory Bowel Disease using a population-based cohort and elicited prognostic factors associated with survival Methods Adult patients with a diagnosis of colorectal cancer in 2007-2015 were identified from the Ontario Cancer Registry. Those with Inflammatory Bowel Disease were detected via the validated Ontario Crohn’s and Colitis Cohort. Primary outcome measure was overall survival from time of colorectal cancer diagnosis until the date of death. Secondary outcome measures included treatments received and publicly-provided health care costs. Results Colorectal cancer was diagnosed in 67,137 with Inflammatory Bowel Disease present in 783 (1.2%). The Inflammatory Bowel Disease-associated colorectal cancer patients were younger at diagnosis (median range 55-59 vs 70-74, p<0.001). Five-year survival in Inflammatory Bowel Disease-associated patients was 56.4% (95% CI 52.6-59.9) and 57.0% (95% CI 56.6-57.4) in sporadic colorectal cancer (p=0.8). Inflammatory Bowel Disease was a significant predictor of death (Hazard Ratio=1.45, 95% CI 1.29-1.63, p<0.001) after adjusting for other variables. In patients under 50, 5-year survival was significantly (p<0.001) reduced in the Inflammatory Bowel Disease population (56.8%, 95% CI 49.4-63.5) compared with the sporadic colorectal cancer population (71.4%, 95% CI 70.0-72.7). Similar results were observed in those 50-64 years old. Conclusion Young patients (<65) with Inflammatory Bowel Disease-associated colorectal cancer have worse survival outcomes than young (<65) patients with sporadic colorectal cancer. These findings inform prognostication and may direct future research for this high-risk population. / Thesis / Master of Science (MSc) / Background Reported outcomes for colorectal cancer associated with Inflammatory Bowel Disease are inconsistent. We compared survival outcomes in colorectal cancer patients with and without Inflammatory Bowel Disease using a population-based cohort and elicited prognostic factors associated with survival Methods Adult patients with a diagnosis of colorectal cancer in 2007-2015 were identified from the Ontario Cancer Registry. Those with Inflammatory Bowel Disease were detected via the validated Ontario Crohn’s and Colitis Cohort. Primary outcome measure was overall survival from time of colorectal cancer diagnosis until the date of death. Secondary outcome measures included treatments received and publicly-provided health care costs. Results Colorectal cancer was diagnosed in 67,137 with Inflammatory Bowel Disease present in 783 (1.2%). The Inflammatory Bowel Disease-associated colorectal cancer patients were younger at diagnosis (median range 55-59 vs 70-74, p<0.001). Five-year survival in Inflammatory Bowel Disease-associated patients was 56.4% (95% CI 52.6-59.9) and 57.0% (95% CI 56.6-57.4) in sporadic colorectal cancer (p=0.8). Inflammatory Bowel Disease was a significant predictor of death (Hazard Ratio=1.45, 95% CI 1.29-1.63, p<0.001) after adjusting for other variables. In patients under 50, 5-year survival was significantly (p<0.001) reduced in the Inflammatory Bowel Disease population (56.8%, 95% CI 49.4-63.5) compared with the sporadic colorectal cancer population (71.4%, 95% CI 70.0-72.7). Similar results were observed in those 50-64 years old. Conclusion Young patients (<65) with Inflammatory Bowel Disease-associated colorectal cancer have worse survival outcomes than young (<65) patients with sporadic colorectal cancer. These findings inform prognostication and may direct future research for this high-risk population.