Rapid improvements in cancer survival led to the realization that many modalities used to treat or control cancer may cause accelerated aging in cancer survivors. Clinically, “accelerated aging” phenotypes in cancer survivors include secondary cancers, frailty, chronic organ dysfunction, and cognitive impairment, all of which can impact long-term health and quality of life in cancer survivors. The treatment-induced accelerated aging in cancer survivors could be explained by telomere attrition, cellular senescence, stem cell exhaustion, DNA damage, and epigenetic alterations. Several aging clocks and biomarkers of aging have been proposed to be potentially useful in estimating biological age, which can provide specific information about how old an individual is biologically independent of chronological age. Measuring biological age in cancer survivors may be important for two reasons. First, it can better predict the risk of cancer treatment-related comorbidities than chronological age. Second, biological age may provide additional value in evaluating the effects of treatments and personalizing cancer therapies to maximize efficacy of treatment. A deeper understanding of treatment-induced accelerated aging in individuals with cancer may lead to novel strategies that reduce the accelerated aging and improve the quality of life in cancer survivors.

The role of the innate immune response in colorectal cancer is understudied. We examined the survival of colorectal cancer patients in relation to eosinophils, innate immune cells, infiltrating the tumor. Tissue microarrays were constructed from paraffin-embedded tumor tissues collected between 1986 and 2002 from 441 post-menopausal women diagnosed with colorectal cancer in the Iowa Women’s Health Study. Tissue microarrays were stained with an eosinophil peroxidase antibody. Eosinophils in epithelial and stromal tissues within the tumor (called epithelial and stromal eosinophils, hereafter) were counted and scored into three and four categories, respectively. In addition, the degree of eosinophil degranulation (across epithelial and stromal tissues combined) was quantified and similarly categorized. We used Cox regression to estimate the hazard ratios and 95% confidence interval for all-cause and colorectal cancer death during 5-year follow-up after diagnosis and during follow-up through 2011 (‘total follow-up’). The hazard ratios associated with eosinophil scores were adjusted for age of diagnosis, SEER (Surveillance, Epidemiology, and End Results) stage, tumor grade, body mass, and smoking history. High tumor stromal eosinophil score was inversely correlated with age and stage, and was associated with a decreased risk for all-cause and colorectal cancer death: hazard ratios (95% confidence intervals) were 0.61 (0.36–1.02; P-trend=0.02) and 0.48 (0.24–0.93; P-trend=0.01), respectively, during the 5-year follow-up for the highest vs lowest category. The inverse associations also existed for total follow-up for all-cause and colorectal cancer death for the highest vs lowest stromal eosinophil score: hazard ratios (95% confidence intervals) were 0.72 (0.48–1.08; P-trend=0.04) and 0.61 (0.34–1.12; P-trend=0.04), respectively. Further adjustment for treatment, comorbidities, additional lifestyle factors, tumor location, or molecular markers did not markedly change the associations, while adjustment for cytotoxic T cells slightly attenuated all associations. The infiltration of tumors with eosinophils, especially in stromal tissue, may be an important prognostic factor in colorectal cancer.

Summary: Background: Aspirin is associated with decreased risk of colorectal cancer (CRC), potentially by modulating the gut microbiome.Aims: To evaluate the effect of aspirin on the gut microbiome in a double‐blinded, randomised placebo‐controlled pilot trial.Methods: Healthy volunteers aged 50‐75 received a standard dose of aspirin (325 mg, N = 30) or placebo (N = 20) once daily for 6 weeks and provided stool samples every 3 weeks for 12 weeks. Serial measurements of gut microbial community composition and bacterial abundance were derived from 16S rRNA sequences. Linear discriminant analysis of effect size (LEfSe) was tested for between‐arm differences in bacterial abundance. Mixed‐effect regression with binomial distribution estimated the effect of aspirin use on changes in the relative abundance of individual bacterial taxa via an interaction term (treatment × time).Results: Over the study period, there were differences in microbial composition in the aspirin vs placebo arm. After treatment, four taxa were differentially abundant across arms: Prevotella, Veillonella, Clostridium XlVa and Clostridium XVIII clusters. Of pre‐specified bacteria associated with CRC (n = 8) or aspirin intake (n = 4) in published studies, interactions were significant for four taxa, suggesting relative increases in Akkermansia, Prevotella and Ruminococcaceae and relative decreases in Parabacteroides, Bacteroides and Dorea in the aspirin vs placebo arm.Conclusion: Compared to placebo, aspirin intake influenced several microbial taxa (Ruminococcaceae, Clostridium XlVa, Parabacteroides and Dorea) in a direction consistent with a priori hypothesis based on their association with CRC. This suggests that aspirin may influence CRC development through an effect on the gut microbiome. The findings need replication in a larger trial.

Background: Host immune response may predict the course of colorectal cancer. We examined the survival of 468 colorectal cancer patients associated with two tumor-infiltrating immune biomarkers, the number of cytotoxic T lymphocytes (CTLs), and the activated CTLs, as reflected by the number of cells expressing granzyme B (GZMB) in the prospective Iowa Women's Health Study.Methods: Using paraffin-embedded tissue samples, we constructed and immunostained tumor microarrays with CD8 (for CTL) and GZMB antibodies. We scored CTL and GZMB densities in tumor epithelial and stromal tissues and also created a composite score for each biomarker (sum of the scores across tissue compartments). Cox regression estimated the HR and 95% confidence intervals (CI) for all-cause and colorectal cancer–specific death associated with each composite score.Results: CTL and GZMB composite scores were positively correlated (r = 0.65) and each biomarker was inversely correlated with stage at diagnosis. Both composite scores were higher in proximal colon tumors and tumors characterized by MSI-high, CIMP-high, or BRAF mutation status. HRs (95% CI) were 0.53 (0.38–0.75; Ptrend = 0.0004) and 0.66 (0.51–0.86; Ptrend = 0.002) for all-cause death, respectively, and 0.30 (0.18–0.51; Ptrend < 0.0001) and 0.41 (0.27–0.63; Ptrend < 0.0001) for colorectal cancer–related death, respectively. Including CTL and GZMB scores simultaneously in the model significantly improved the predictive performance of the models for all-cause and colorectal cancer–related death.Conclusions: Higher tumor infiltration with CTL and GZMB cells is associated with improved all-cause and cancer-specific survival of colorectal cancer patients.Impact: Both the number of CTLs and GZMB appear to be useful prognostic factors in colorectal cancer, irrespective of stage. Cancer Epidemiol Biomarkers Prev; 26(4); 622–31. ©2016 AACR.

Background: Chronic inflammation has been implicated in the etiology of colorectal cancer (CRC), but epidemiologic findings on the association between circulating inflammatory markers and CRC risk are inconsistent. We hypothesized that increased concentrations of systemic inflammatory markers–white blood cell count (WBC), fibrinogen, von Willebrand factor (VWF), factor VIII (FVIII), and C-reactive protein (CRP)–and decreased albumin concentration would be associated with increased CRC risk in the Atherosclerosis Risk in Communities prospective cohort. Methods: WBC, fibrinogen, VWF, FVIII, and albumin, measured in 1987–1989 in 13,414 men and women, were transformed to z-scores and summed up to construct a blood “inflammation z-score.” Albumin was included with a negative sign, because its concentration decreases with greater inflammation. A total of 308 incident CRC cases were identified through 2006 in initially cancer-free participants. CRP was measured in 1996–1998 in 9,836 cancer-free people who developed 166 CRCs through 2006. Proportional hazard models were used to estimate the HR and 95% CI of CRC in relation to each individual marker and the inflammation z-score. Results: After multivariate adjustment, for the highest versus lowest quartile, there was a statistically significant positive association of CRC risk with fibrinogen: HR = 1.50 (95% CI, 1.05–2.15), P = 0.03; inflammation z-score: HR = 1.65 (95% CI, 1.15–2.35), P = 0.01; and CRP: HR = 1.97 (95% CI, 1.13–3.43, P = 0.02. Conclusions: These findings indicate that greater levels of fibrinogen, CRP, and blood inflammation z-score are associated with increased CRC risk. Impact: The study provides further evidence that precancer inflammation may contribute to CRC etiology. Cancer Epidemiol Biomarkers Prev; 20(2); 297–307. ©2011 AACR.

Background: Serum β-2 microglobulin (B2M), a major histocompatibility complex class I molecule that is a biomarker of kidney filtration and increased cell turnover, is elevated at the time of diagnosis in hematological and some solid cancers. However, serum B2M was not examined prospectively as a marker for cancer risk. We hypothesized that in a population without a prior cancer diagnosis, serum B2M is associated with risk of cancer (n = 2,436), including colorectal (n = 255), lung (n = 298), breast (n = 424), and prostate (n = 524) cancers, and hematological (n = 176) malignancies.Methods: The analytical cohort (n = 12,300) was followed for incident cancers from 1990 through 2006. B2M (range, 0.9–57.8 mg/L) was measured in stored serum collected in 1990–1992. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals for cancer incidence and mortality in relation to quartiles of B2M.Results: Adjusting for age, sex, race, center, education, body mass index, smoking, aspirin, and hormone therapy (in women) and comparing highest to lowest B2M quartiles, HRs were 1.25 (1.06–1.47; Ptrend = 0.002) for total cancer risk and 2.21 (1.32–3.70; Ptrend=0.001) for colorectal cancer risk, with similar HRs for colon and rectal cancers. These associations remained after adjustment for an inflammatory biomarker, C-reactive protein, and after excluding the first three years of follow-up. Significant associations were also observed for mortality from total, lung, and hematological cancers.Conclusions: These findings provide the first evidence that higher serum B2M is associated with increased colorectal cancer risk.Impact: This study supports B2M as a potential biomarker for colorectal cancer risk. Cancer Epidemiol Biomarkers Prev; 25(4); 657–64. ©2016 AACR.