Inflammation‐ and angiogenesis‐related biomarkers are correlated with cancer‐related fatigue in colorectal cancer patients: Results from the ColoCare Study

Cancer‐related fatigue is one of the most common side effects of colorectal cancer treatment and is affected by biomedical factors. We investigated the association of inflammation‐ and angiogenesis‐related biomarkers with cancer‐related fatigue. Pre‐surgery (baseline) serum samples were obtained from n = 236 newly diagnosed colorectal cancer patients. Meso Scale Discovery assays were performed to measure levels of biomarkers for inflammation and angiogenesis (CRP, SAA, IL‐6, IL‐8, MCP‐1, sICAM‐1, sVCAM‐1, TNFα, VEGFA and VEGFD). Cancer‐related fatigue was assessed with the EORTC QLQ‐30 questionnaire at baseline and 6 and 12 months post‐surgery. We tested associations using Spearman's partial correlations and logistic regression analyses, adjusting for age, sex and body mass index. sICAM‐1 and VEGFD showed a significant positive correlation with cancer‐related fatigue at baseline and 6‐, and 12‐month follow‐up (sICAM‐1: r = 0.19, p = 0.010; r = 0.24, p = 0.004; r = 0.25, p = 0.006; VEGFD: r = 0.20, p = 0.006; r = 0.15, p = 0.06; r = 0.23, p = 0.01 respectively). Biomarkers of inflammation and angiogenesis measured prior to surgery are associated with cancer‐related fatigue in colorectal cancer patients throughout various time points. Our results suggest the involvement of overexpressed sICAM‐1 and VEGFD in the development of fatigue.     

Detection of colorectal neoplasia: Combination of eight blood‐based,cancer‐associated protein biomarkers

Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed eight cancer‐associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19‐9, CEA, hs‐CRP, CyFra21‐1, Ferritin, Galectin‐3 and TIMP‐1 were determined in EDTA‐plasma using the Abbott ARCHITECT® automated immunoassay platform. Primary endpoints were detection of (i) CRC and high‐risk adenoma and (ii) CRC. Logistic regression was performed. Final reduced models were constructed selecting the four biomarkers with the highest likelihood scores. Subjects (N = 4,698) were consecutively included during 2010–2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer and 193 rectal cancer. Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high‐risk, 1,342 had nonneoplastic bowell disease and 1,978 subjects had ‘clean’ colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood‐based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in the selection of CEA, hs‐CRP, CyFra21‐1 and Ferritin for the two endpoints; AUCs were 0.76 and 0.84, respectively. The postive predictive value at 90% sensitivity was 25% for endpoint 1 and the negative predictive value was 93%. For endpoint 2, the postive predictive value was 18% and the negative predictive value was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high risk of the presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC.     

Pre‐operative serum albumin level substantially predicts post‐operative morbidity and mortality among patients with colorectal cancer who undergo elective colectomy

The quantitative relationship between serum albumin level and surgical outcomes has not been clearly established. This study included 3732 patients with colon cancer who underwent a potentially curative colectomy. Post‐operative mortality and morbidity were analysed according to the patients' demographic data, pre‐operative comorbidities, and tumour‐related factors. Age, asthma, renal impairment, and albumin level were significantly associated with post‐operative morbidity and mortality in the multivariate analyses. Logistic regression analysis revealed linear relationships of post‐operative morbidity and mortality with albumin level. The morbidity and mortality rates decreased by 7.3% and 15.6%, respectively, for each 0.1 g/dL increase in albumin level. This finding remained significant in the hypoalbuminaemia subgroup but not in the normoalbuminaemia subgroup. That is, the morbidity and mortality rates significantly decreased by 8.7% and 17.7%, respectively (both P < 0.001), in the former group and decreased by 2.7% (P = 0.112) and 11.6% (P = 0.092), respectively, in the latter group. This study demonstrated that serum albumin level linearly predicted the post‐operative morbidity and mortality among the colorectal cancer patients. Pre‐operative serum albumin level may therefore be used as a continuous rather than a categorical marker of disease severity, especially among patients with hypoalbuminaemia.     

Vascular cell adhesion molecule‐1 (VCAM‐1)—An increasing insight into its role in tumorigenicity and metastasis

Vascular cell adhesion molecule‐1 (VCAM‐1) first attracted attention more than two decades ago as endothelial adhesion receptor with key function for leukocyte recruitment in term of cellular immune response. The early finding of VCAM‐1 binding to melanoma cells, and thus a suggested mechanistic contribution to metastatic spread, was the first and for a long time the only link of VCAM‐1 to cancer sciences. In the last few years, hallmarked by a growing insight into the molecular understanding of tumorigenicity and metastasis, an impressive variety of VCAM‐1 functionalities in cancer have been elucidated. The present review aims to provide a current overview of VCAM‐1 relevance for tumor growth, metastasis, angiogenesis, and related processes. By illustrating the intriguing role of VCAM‐1 in cancer disease, VCAM‐1 is suggested as a new and up to now underestimated target in cancer treatment and in clinical diagnosis of malignancies.     

A seven‐gene signature can predict distant recurrence in patients with triple‐negative breast cancers who receive adjuvant chemotherapy following surgery

The aim of this study was to investigate candidate genes that might function as biomarkers to differentiate triple negative breast cancers (TNBCs) among patients, who received adjuvant chemotherapy after curative surgery. We tested whether the results of a NanoString expression assay that targeted 250 prospectively selected genes and used mRNA extracted from formalin‐fixed, paraffin‐embedded would predict distant recurrence in patients with TNBC. The levels of expression of seven genes were used in a prospectively defined algorithm to allocate each patient to a risk group (low or high). NanoString expression profiles were obtained for 203 tumor tissue blocks. Increased expressions of the five genes (SMAD2, HRAS, KRT6A, TP63 and ETV6) and decreased expression of the two genes (NFKB1 and MDM4) were associated favorable prognosis and were validated with cross‐validation. The Kaplan–Meier estimates of the rates of distant recurrence at 10 years in the low‐ and high‐risk groups according to gene expression signature were 62% [95% confidence interval (CI), 48.6–78.9%] and 85% (95% CI, 79.2–90.7%), respectively. When adjusting for TNM stage, the distant recurrence‐free survival (DRFS)s in the low‐risk group was significantly longer than that in the high‐risk group (p <0.001) for early stage (I and II) and advanced stage (III) tumors. In a multivariate Cox regression model, the gene expression signature provided significant predictive power jointly with the TNM staging system. A seven‐gene signature could be used as a prognostic model to predict DRFS in patients with TNBC who received curative surgery followed by adjuvant chemotherapy.     

Association of PAI‐1 gene polymorphism with survival and chemotherapy‐related vascular toxicity in testicular cancer

BACKGROUND:

High Plasminogen‐Activator Inhibitor 1 (PAI‐1) expression by tumors has been associated with poor prognosis in several cancer types, and high systemic PAI‐1 levels with increased thrombosis risk. The authors investigated whether the germline 4G/5G deletion/insertion polymorphism in the PAI‐1 promoter (rs1799889), which may influence PAI‐1 expression, is associated with survival and chemotherapy‐related vascular toxicity in testicular cancer (TC).

METHODS:

Data were collected on PAI‐1 4G/5G polymorphism, survival, venous thromboembolism (VTE), and coronary heart disease (CHD) for 324 non‐seminomatous TC patients treated with platinum‐based chemotherapy. Genotypes were compared regarding survival and disease outcome. VTE and CHD incidence were compared with adjustment for cardiovascular risk factors and prothrombotic gene polymorphisms of coagulation factors II/prothrombin (G20210A) and V (G1691A).

RESULTS:

The 4G/4G variant of PAI‐1 4G/5G polymorphism shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared with 4G/5G and 5G/5G (24% vs 8% and 15%; chi‐square P = .003). In addition, the 4G/4G variant shows reduced TC‐related survival with a hazard ratio of 2.69 (95% CI, 1.26‐5.73; P = .010) for TC‐related death (adjusted for IGCCC). This is related to an increased risk for refractory disease and early relapses (odds ratio, 3.35; 95% CI, 1.48‐7.59; P = .004). PAI‐1 4G/5G polymorphism is not associated with VTE and CHD risk.

CONCLUSIONS:

The 4G/4G variant of PAI‐1 4G/5G polymorphism may be an unfavorable prognostic as well as predictive factor for response to chemotherapy in TC patients. If confirmed, it may contribute to the identification of patients with increased risk for refractory disease. Cancer 2010. © 2010 American Cancer Society.     

Effects of supplemental calcium and vitamin D on tight‐junction proteins and mucin‐12 expression in the normal rectal mucosa of colorectal adenoma patients

The physical gut barrier, comprised of a thick mucus layer and the epithelium, plays an important role in defense against microbes and foreign antigens. Calcium and vitamin D may be involved in maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which may lead to endotoxemia and inflammation, and contribute to colorectal carcinogenesis. We investigated supplemental calcium (1200 mg, daily) and/or vitamin D₃ (1000 IU daily) effects on intestinal barrier function‐related biomarkers in a subset of 105 participants from a large colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of the tight junction proteins claudin‐1 (CLDN1), occludin (OCLD), and mucin‐12 (MUC12) in the normal‐appearing colorectal mucosa using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, in the calcium relative to the no calcium group, the CLDN1, OCLD, and MUC12 expression increased by 14% (P = 0.17), 23% (P = 0.11), and 22% (P = 0.07), respectively. In secondary analyses, the estimated calcium treatment effects were greater among participants with baseline serum 25‐OH‐vitamin D concentrations below the median value of 22.69 ng/mL (CLDN1: 29%, P = 0.04; OCLD: 36%, P = 0.06; MUC12: 35%, P = 0.05). There were no biomarker expression changes in the vitamin D₃ alone group; however, modest increases were found in the combined calcium/vitamin D₃ group. At baseline, obesity, history of a sessile‐serrated adenoma, colorectal MIB‐1/Ki‐67 expression, and a family history of colorectal cancer were associated with CLDN1, OCLD, and MUC12 expression. Our study supports continued investigation of factors that could affect intestinal mucosal barrier integrity relevant to colorectal carcinogenesis.     

Locoregional recurrence of pT3N0M0 breast cancer after mastectomy is not higher than that of pT1‐2N0M0: An analysis for radiotherapy

The purpose of this study was to investigate the value of post‐operative radiotherapy in the treatment of pT3N0M0 breast cancer after mastectomy. We analyzed the clinical data of 1390 patients with pT1‐3N0M0 breast cancer who were admitted and treated from 1998 to 2007 at the Sun Yat‐sen University Cancer Center. All patients underwent mastectomy and did not receive radiotherapy. The locoregional recurrence‐free survival, distant metastasis‐free survival and overall survival of different T stages of breast cancer were compared. The median follow‐up duration was 72 months. The 10‐year locoregional recurrence‐free survival patients with pT1N0, pT2N0 and pT3N0 breast cancers were 95.3, 91.9 and 93.6%, respectively (χ² = 2.550, P = 0.279). The 10‐year distant metastasis‐free survival rates of patients with pT1N0, pT2N0 and pT3N0 breast cancers were 88.1%, 81.0% and 78.4%, respectively (χ² = 8.254, P = 0.016). The 10‐year overall survival rates of patients with pT1N0, pT2N0 and pT3N0 breast cancers were 91.9%, 83.5% and 73.0%, respectively (χ² = 12.403, P = 0.002). Univariate analyses failed to identify any prognostic factors for locoregional recurrence in pT3N0 patients. Multivariate analysis showed that the T stage had no effect on locoregional recurrence. The locoregional recurrence rate in patients with pT3N0M0 breast cancer who underwent mastectomy and did not receive postoperative radiotherapy was not higher than that in patients with pT1‐2N0M0 breast cancer who received the same treatment, suggesting that routine adjuvant post‐operative radiotherapy should not be recommended in this patient population.     

Assessing individual risk for high‐risk colorectal adenoma at first‐time screening colonoscopy

Assessing risk of colorectal adenoma at first‐time colonoscopy that are of higher likelihood of developing advanced neoplasia during surveillance could help tailor first‐line colorectal cancer screening. We developed prediction models for high‐risk colorectal adenoma (at least one adenoma ≥1 cm, or with advanced histology, or ≥3 adenomas) among 4,881 asymptomatic white men and 17,970 women who underwent colonoscopy as their first‐time screening for colorectal cancer in two prospective US studies using logistic regressions. C‐statistics and Hosmer–Lemeshow tests were used to evaluate discrimination and calibration. Ten‐fold cross‐validation was used for internal validation. A total of 330 (6.7%) men and 678 (3.8%) women were diagnosed with high‐risk adenoma at first‐time screening colonoscopy. The model for men included age, family history of colorectal cancer, BMI, smoking, sitting watching TV/VCR, regular aspirin/NSAID use, physical activity, and a joint term of multivitamin and alcohol. For women, the model included age, family history of colorectal cancer, BMI, smoking, alcohol, beef/pork/lamb as main dish, regular aspirin/NSAID, calcium, and oral contraceptive use. The C‐statistic of the model for men was 0.67 and 0.60 for women (0.64 and 0.57 in cross‐validation). Both models calibrated well. The predicted risk of high‐risk adenoma for men in the top decile was 15.4% vs. 1.8% for men in the bottom decile (Odds Ratio [OR] = 9.41), and 6.6% vs. 2.1% for women (OR = 3.48). In summary, we developed and internally validated an absolute risk assessment tool for high‐risk colorectal adenoma among the US population that may provide guidance for first‐time colorectal cancer screening.     

Gene‐expression signature of tumor recurrence in patients with stage II and III colon cancer treated with 5′fluoruracil‐based adjuvant chemotherapy

Although receiving adjuvant chemotherapy after radical surgery, a disappointing proportion of patients with colorectal cancer will develop tumor recurrence. Probability of relapse is currently predicted from pathological staging, there being a need for additional markers to further select high‐risk patients. This study was aimed to identify a gene‐expression signature to predict tumor recurrence in patients with Stages II and III colon cancer treated with 5′fluoruracil (5FU)‐based adjuvant chemotherapy. Two‐hundred and twenty‐eight patients diagnosed with Stages II–III colon cancer and treated with surgical resection and 5FU‐based adjuvant chemotherapy were included. RNA was extracted from formalin‐fixed, paraffin‐embedded tissue samples and expression of 27 selected candidate genes was analyzed by RT‐qPCR. A tumor recurrence predicting model, including clinico‐pathological variables and gene‐expression profiling, was developed by Cox regression analysis and validated by bootstrapping. The regression analysis identified tumor stage and S100A2 and S100A10 gene expression as independently associated with tumor recurrence. The risk score derived from this model was able to discriminate two groups with a highly significant different probability of tumor recurrence (HR, 2.75; 95%CI, 1.71–4.39; p = 0.0001), which it was maintained when patients were stratified according to tumor stage. The algorithm was also able to distinguish two groups with different overall survival (HR, 2.68; 95%CI, 1.12–6.42; p = 0.03). Identification of a new gene‐expression signature associated with a high probability of tumor recurrence in patients with Stages II and III colon cancer receiving adjuvant 5FU‐based chemotherapy, and its combination in a robust, easy‐to‐use and reliable algorithm may contribute to tailor treatment and surveillance strategies.     

Effect of miR‐122 and its target gene cationic amino acid transporter 1 on colorectal liver metastasis

Control of liver metastasis is an important issue in the treatment of colorectal cancer (CRC). MicroRNAs have been shown to be involved in the development of many cancers, but little is known about their role in the process of colorectal liver metastasis. We compared miRNA expression between primary colorectal tumors and liver metastasis to identify those involved in the process of metastasis. Cancer cells were isolated from formalin‐fixed paraffin‐embedded primary CRC samples and their corresponding metastatic liver tumors in six patients using laser capture microdissection, and miRNA expression was analyzed using TaqMan miRNA arrays. The most abundant miRNA in liver metastasis compared with primary tumors was miR‐122. Immunohistochemical analysis revealed that the expression levels of cationic amino acid transporter 1 (CAT1), a negative target gene of miR‐122, were lower in liver metastases than primary tumors (P < 0.001). Expression levels of CAT1 in 132 primary tumors were negatively correlated with the existence of synchronous liver metastasis (P = 0.0333) and tumor stage (P < 0.0001). In an analysis of 121 colon cancer patients without synchronous liver metastasis, patients with CAT1‐low colon cancer had significantly shorter liver metastasis‐free survival (P = 0.0258) but not overall survival or disease‐free survival. Overexpression of miR‐122 and concomitant suppression of CAT1 in the primary tumor appears to play important roles in the development of colorectal liver metastasis. Expression of CAT1 in the primary CRC has the potential to be a novel biomarker to predict the risk of postoperative liver metastasis of CRC patients.     

Prognostic value of programmed death‐ligand 1 expression in patients with stage III colorectal cancer

The programmed death‐1/programmed death‐ligand 1 (PD‐L1) pathway is a negative feedback pathway that suppresses the activity of T cells. Previous studies reported that high PD‐L1 expression on tumor cells (TC) was associated with poor survival in patients with colorectal cancer; however, the prognostic evaluation of these studies was limited because they included patients at various disease stages. The purpose of the present study was to evaluate the relationship between PD‐L1 status in the immune microenvironment and the clinicopathological features of stage III colorectal cancer. Two hundred and thirty‐five patients were included in the analysis. PD‐L1 expression on TC and tumor‐infiltrating mononuclear cells (TIMC) was evaluated by immunohistochemistry. The median follow‐up of thisi study was 52.9 months. A total of 8.1% of stage III colorectal cancer showed high PD‐L1 expression on TC and 15.3% showed high PD‐L1 expression on TIMC. Patients with high PD‐L1 expression on TC had significantly shorter disease‐free survival (DFS) than patients with low expression (hazard ratio [HR] 2.36; 95% confidence interval [CI], 1.21–4.62; P = 0.012). In addition, patients with high PD‐L1 expression on TIMC were associated with longer DFS than patients with low expression (HR 0.40; 95% CI, 0.16–0.98; P = 0.046). These findings suggest that PD‐L1 expression status may be a new predictor of recurrence for stage III colorectal cancer patients and highlight the necessity of evaluating PD‐L1 expression on TC and TIMC separately in the tumor microenvironment.     

PAI‐1 induces Src inhibitor resistance via CCL5 in HER2‐positive breast cancer cells

Tyrosine kinase Src is overexpressed and activated in various tumors, including breast cancer, and is supposed to promote cancer formation and development. Src inhibitors have been developed recently and have shown efficacy in breast cancer as a single agent or in combination with anti‐HER2 antibodies or chemotherapy. Unfortunately, the potency of Src inhibitor is limited by the development of drug resistance. In our study, we established an Src inhibitor saracatinib‐resistant breast cancer cell line (SKBR‐3/SI) for the first time and by evaluating mRNA expression profile, we found that plasminogen activator inhibitor‐1 (PAI‐1) was upregulated in saracatinib‐resistant cells compared to the parent cells. Further study demonstrated that PAI‐1 might induce saracatinib resistance in breast cancer cells by increasing the secretion of chemokine (C‐C motif) ligand 5 (CCL5). Functional assays showed that PAI‐1 and CCL5 overexpression promoted cell proliferation and migration in breast cancer cells, while inhibition of PAI‐1 and CCL5 decreased cell proliferation and migration in saracatinib‐resistant cells. We also showed that targeting PAI‐1 or CCL5 could reverse saracatinib resistance, which deserves more attention in clinical settings.     

Programmed cell death ligand‐1 protein expression and CD274/PD‐L1 gene amplification in colorectal cancer: Implications for prognosis

Programmed cell death ligand‐1 (PD‐L1) detection assays have not been standardized for patients with colorectal cancer, and the prognostic value of PD‐L1 expression is unclear. We compared the PD‐L1 expression patterns in colorectal cancer samples using various immunohistochemical assays using 3 primary PD‐L1 antibodies (assay 1, MIH1; assay 2, E1L3; and assay 3, 22C3) and investigated the prognostic implication of PD‐L1 expression using each. Additionally, PD‐L1 gene amplification was evaluated using FISH. The percentage scorings and positivity rates of the 3 assays differed; the degrees of correlation and concordance between assays 2 and 3 were relatively high, whereas assay 1 was an outlier. Multivariate analyses indicated that PD‐L1 positivity in tumor cells and its negativity in tumor‐infiltrating lymphocytes were independent predictors of poorer overall and disease‐free survival in patients with colorectal cancer. PD‐L1 gene amplification was found in 2 patients (PD‐L1/CEP ratio, 5.60 and 5.84, respectively); both had strong PD‐L1 expression according to immunohistochemistry. Overall, our study showed that PD‐L1 expression status in tumor and immune cells is an independent prognostic factor in patients with colorectal cancer. Standardizations of both PD‐L1 detection using immunohistochemistry and the cut‐off for positivity are necessary. Finally, PD‐L1 gene amplification was found in a small fraction of samples, suggesting the possibility of an ancillary test for PD‐L1 evaluation.     

Post‐diagnosis alcohol intake and prostate cancer survival: A population‐based cohort study

Alcohol consumption has been declared a Group 1 carcinogen by the International Agency for Research on Cancer (IARC) and is a potential risk factor for several types of cancer mortality. However, evidence for an association with prostate cancer survival remains inconsistent. We examined how alcohol consumption post‐diagnosis was associated with survival after prostate cancer diagnosis. Men diagnosed with prostate cancer (n = 829) in Alberta, Canada between the years 1997 and 2000 were recruited into a population‐based case–control study and then followed for up to 19 years for survival outcomes. Pre‐ and post‐diagnosis alcohol consumption, clinical characteristics and lifestyle factors were collected through in‐person interviews shortly after diagnosis and again 2–3 years post‐diagnosis. Cox proportional hazards were used to examine how post‐diagnosis alcohol consumption was associated with all‐cause and prostate cancer‐specific mortality (competing risk analysis too), in addition to first recurrence/progression or new primary cancer. Most participants reported drinking alcohol (≥once a month for 6 months) post‐diagnosis (n = 589, 71.0%). Exceeding Canadian Cancer Society (CCS) alcohol consumption recommendations (≥2 drinks/day) post‐diagnosis was associated with prostate cancer‐specific mortality relative to non‐drinkers (aHR: 1.82, 95% CI: 1.07–3.10) with borderline evidence of a linear trend. Interestingly, those in the highest quartile of drinks/week pre‐ and post‐diagnosis also had a twofold increase for prostate‐specific mortality (aHR: 2.67, 95% CI: 1.28–5.56) while controlling for competing risks. Our results support post‐diagnosis alcohol consumption was associated with increased mortality after prostate cancer diagnosis, specifically for prostate cancer‐related death. Future studies focused on confirming this burden of disease are warranted.     

Tumor expression of calcium sensing receptor and colorectal cancer survival: Results from the nurses’ health study and health professionals follow‐up study

Although experimental evidence suggests calcium‐sensing receptor (CASR) as a tumor‐suppressor, the prognostic role of tumor CASR expression in colorectal carcinoma remains unclear. We hypothesized that higher tumor CASR expression might be associated with improved survival among colorectal cancer patients. We evaluated tumor expression levels of CASR by immunohistochemistry in 809 incident colorectal cancer patients within the Nurses' Health Study and the Health Professionals Follow‐up Study. We used Cox proportional hazards regression models to estimate multivariable hazard ratio (HR) for the association of tumor CASR expression with colorectal cancer‐specific and all‐cause mortality. We adjusted for potential confounders including tumor biomarkers such as microsatellite instability, CpG island methylator phenotype, LINE‐1 methylation level, expressions of PTGS2, VDR and CTNNB1 and mutations of KRAS, BRAF and PIK3CA. There were 240 colorectal cancer‐specific deaths and 427 all‐cause deaths. The median follow‐up of censored patients was 10.8 years (interquartile range: 7.2, 15.1). Compared with patients with no or weak expression of CASR, the multivariable HRs for colorectal cancer‐specific mortality were 0.80 [95% confidence interval (CI): 0.55–1.16] in patients with moderate CASR expression and 0.50 (95% CI: 0.32–0.79) in patients with intense CASR expression (p‐trend = 0.003). The corresponding HRs for overall mortality were 0.85 (0.64–1.13) and 0.81 (0.58–1.12), respectively. Higher tumor CASR expression was associated with a lower risk of colorectal cancer‐specific mortality. This finding needs further confirmation and if confirmed, may lead to better understanding of the role of CASR in colorectal cancer progression.