Samadder, N. Jewel

Abstract Background There are an estimated 1.4 million colorectal cancer (CRC) survivors in the United States. Research on endocrine and metabolic diseases over the long term in CRC survivors is limited. Obesity is a risk factor for CRC; thus it is of interest to investigate diseases that may share this risk factor, such as diabetes, for long-term health outcomes among CRC survivors. Methods A total of 7114 CRC patients were identified from the Utah Population Database and matched to a general population cohort of 25 979 individuals on birth year, sex, and birth state. Disease diagnoses (assessed over three time periods of 1–5 years, 5–10 years, and >10 years) were identified using electronic medical records and statewide ambulatory and inpatient discharge data. Cox proportional hazard models were used to estimate the risk of endocrine and metabolic disease. Results Across all three time periods, risks for endocrine and metabolic diseases were statistically significantly greater for CRC survivors compared with the general population cohort. At 1–5 years postdiagnosis, CRC survivors’ risk for diabetes mellitus with complications was statistically significantly elevated (hazard ratio [HR] = 1.36, 99% confidence interval [CI] = 1.09 to 1.70). CRC survivors also experienced a 40% increased risk of obesity at 1–5 years postcancer diagnosis (HR= 1.40, 99% CI= 1.66 to 2.18) and a 50% increased risk at 5–10 years postdiagnosis (HR = 1.50, 99% CI= 1.16 to 1.95). Conclusions Endocrine and metabolic diseases were statistically significantly higher in CRC survivors throughout the follow-up periods of 1–5 years, 5–10 years, and more than 10 years postdiagnosis. As the number of CRC survivors increases, understanding the long-term trajectory is critical for improved survivorship care.

Objectives: To determine the risk and risk factors for mental illness among colorectal cancer (CRC) survivors across short-term and long-term follow-up periods. Methods: We used the Utah Cancer Registry to identify CRC survivors diagnosed between 1997 and 2013. Mental health diagnoses were available in electronic medical records and statewide facilities data that were linked by the Utah Population Database. CRC survivors were matched to individuals from a general population cohort. The risk of developing a mental illness was compared between cohorts. The association between mental illness and mortality was also analyzed. Results: In total, 8961 CRC survivors and 35,897 individuals in a general population cohort were identified. CRC survivors were at increased risk for any mental health diagnosis at 0 to 2 years (hazard ratio [HR], 3.70; 95% confidence interval [CI], 3.47-3.95), >2 to 5 years (HR, 1.23; 95% CI, 1.09-1.38), and >5 years (HR, 1.20; 95% CI, 1.07-1.36) after cancer diagnosis. CRC survivors were also at increased risk of depressive disorders specifically during the same time periods. At >5 years, CRC survivors still had an increased risk of developing many mental health diagnoses. Factors associated with increased risk of any mental health disorder among CRC survivors included colostomy and Charlson Comorbidity Index of 1+. There was an increased risk of death for CRC survivors diagnosed with any mental health disorder (HR, 2.18; 95% CI, 2.02-2.35) and depression (HR, 2.10; 95% CI, 1.92-2.28). Conclusions: CRC survivors are at increased risk for mental health disorders in the short-term and long-term. Survivors who develop mental health disorders also experience decreased survival.

Abstract Background: Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor β (ESR2) has been associated with colorectal cancer stage and survival. Methods: In this prospective cohort study, we examined smoking, MHT, and folate-associated colorectal cancer risks by ESR2 protein expression level among participants in the Iowa Women's Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded colorectal cancer tissue specimens were collected and evaluated for ESR2 protein expression by IHC. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between smoking, MHT, or folate and ESR2-defined colorectal cancer subtypes. Results: Informative environmental exposure and protein expression data were available for 491 incident colorectal cancer cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR, 4.24; 95% CI, 1.81–9.91 for ESR2-low and RR, 2.15; 95% CI, 1.05–4.41 for ESR2-high for ≥40 cigarettes compared with nonsmokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR, 0.54; 95% CI, 0.26–1.13 for >5 years compared with never use). No associations were found for folate. Conclusions: In this study, smoking and MHT were associated with ESR2 expression patterns. Impact: These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women. Cancer Epidemiol Biomarkers Prev; 24(4); 713–9. ©2015 AACR.

Abstract Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. The TP53 (p53) protein, encoded by the TP53 tumor-suppressor gene that is commonly mutated in colorectal cancer, can be readily assessed to differentiate biologically distinct colorectal cancer subtypes. In this prospective cohort study, we examined CS-, HT-, and FI-associated colorectal cancer risks by TP53 protein expression level among Iowa Women's Health Study (IWHS) participants. The IWHS recruited 41,836 randomly selected Iowa women, ages 55 to 69 years, with a valid driver's license at study entry in 1986. Self-reported exposure variables were assessed at baseline. Incident colorectal cancer cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected and evaluated for TP53 protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between CS, HT, or FI and TP53-defined colorectal cancer subtypes. Informative environmental exposure and protein expression data were available for 492 incident colorectal cancer cases: 222 (45.1%) TP53 negative, 72 (14.6%) TP53 low, and 198 (40.2%) TP53 high. Longer duration (>5 years) of HT was inversely associated with TP53 high colorectal cancers (RR, 0.50; 95% CI, 0.27–0.94). No other statistically significant associations were observed. These data support possible heterogeneous effects from HT on TP53-related pathways of colorectal carcinogenesis in older women. Cancer Epidemiol Biomarkers Prev; 23(2); 350–5. ©2013 AACR.

Abstract Background: Cigarette smoking (CS) is an established colorectal cancer (CRC) risk factor. The p53 protein, encoded by the TP53 tumor suppressor gene that is commonly mutated in CRC, is important in cell cycle arrest needed to repair DNA damage or induce apoptosis to prevent tumor propagation. In this prospective cohort study, we examined CS-associated CRC risks by p53 protein expression level in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). CS and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 CRC cases diagnosed through 12/31/2002. CS was categorized by smoking status (never, current, former), average number of cigarettes per day (1-19, 20-39, > 40) and cumulative pack-years (1-19, 20-39, > 40). P53 protein expression was determined by immunohistochemistry on tissue microarrays. Tumor cores were scored by combining both staining intensity and percent of cells stained to determine negative, low or high p53 protein expression levels. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Of the 732 available CRC cases, 486 (66%) had complete CS and p53 data. Associations between CS and CRC subtypes defined by p53 expression level are shown in the Table. Conclusions: These data demonstrate no clear heterogeneity of CS with CRC subtypes defined by p53 expression levels among older women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1677. doi:1538-7445.AM2012-1677

Abstract Background: Despite recent advances in prevention and therapy, colorectal cancer (CRC) continues to account for nearly 50,000 deaths per year in the US. TNM stage is the current CRC prognostic standard, yet within-stage prognostic heterogeneity is well documented. Microsatellite instability (MSI), CpG island methylation phenotype (CIMP), and BRAF- and KRAS-mutation status represent candidate prognostic markers. However, associations between these markers and CRC survival have not been described in a population-based setting. Methods: Data and tissue resources were obtained from the Iowa Women's Health Study (IWHS), which recruited 41,836 women, ages 55-69 years, at study entry (1986). Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 representative CRC cases diagnosed through 12/31/2002. Established laboratory methods were used to characterize CRC cases: MSI-H or MSS/MSI-L (by instability in β3 vs. <3 out of 10 markers, respectively); CIMP+ or CIMP− (by promoter hypermethylation in β3 vs. 0-2 out of 5 genes, respectively); BRAFwt or BRAFmut (by fluorescent allele specific PCR to detect the V600E point mutation in exon 15); and KRASwt or KRASmut (by direct sequence analysis of codons 12 and 13 in exon 2). Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for time to death of any cause adjusted for age, stage, grade, and treatment status. Results: CRC cases with informative molecular marker data ranged from 515/732 (70%) for KRAS to 548/732 (75%) for MSI status. Mean follow-up was 4.4 years for deceased individuals and 11.2 years for women alive at last contact. After multivariable adjustment, both MSS/MSI-L (p=0.004) and KRASmut (p=0.048) tumors were associated with poorer survival. Survival did not significantly differ across levels of CIMP and BRAF status. Conclusions: MSI and KRAS status may influence CRC survival among older women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4492. doi:1538-7445.AM2012-4492