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Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected DNA from primary tumor specimens (P), hepatic metastasis specimens after treatment (M), and liquid biopsies (L) taken prior to (pre), during (intra), and after (post) treatment to next generation sequencing. We performed Nanostring expression analysis in P and M specimens. Comparative bioinformatics and statistical analysis revealed typical mutational patterns with frequent alterations in TP53, APC, and KRAS in P specimens (n = 48). P and pre-L (n = 42), as well as matched P and M (n = 30), displayed a similar mutation spectrum. In contrast, gene expression profiles classified P (n = 31) and M (n = 23), distinguishable by up-regulation of immune/cytokine receptor and autophagy programs. Switching of consensus molecular subtypes from P to M occurred in 58.3% of cases. M signature genes SFRP2 and SPP1 associated with inferior survival, as validated in an independent cohort. Molecular changes during first-line treatment were detectable by expression profiling rather than by mutational tumor and liquid biopsy analyses. SFRP2 and SPP1 may serve as biomarkers and/or actionable targets.

In this study, we investigated the in vivo metastasis suppression effects of the platelet-derived growth factor receptor inhibitor dasatinib, which targets cancer-associated fibroblasts (CAFs), in combination with an anti-programmed cell death-1 (PD-1) antibody. We classified clinical CRC cases as inflamed, excluded, or desert using immunohistochemical analysis and evaluated the tumor stroma. The excluded type was the most common, and cases with high-volume stroma in the primary lesions also had a high stromal volume in the liver metastatic lesions. Liver-metastasis mouse models with different stromal volumes were established and treatment-induced changes in the tumor immune microenvironment were evaluated. The anti-PD-1 antibody alone exhibited a therapeutic effect for the liver metastases with low stromal volumes but not for the liver metastases with high stromal volumes. In contrast, antitumor effects were observed with anti-PD-1 antibody/dasatinib combination therapy even in the liver metastases with high stromal volumes. Combination therapy reduced the stromal volume, promoted immune cell infiltration, induced antitumor cytotoxic T-cell responses, activated antitumor immunity, and promoted tumor regression. These results suggest that CAFs play an important role in the immune evasion of CRC and that anti-PD-1 antibody/dasatinib combination therapy has potential as a treatment option for patients with metastatic CRC for whom immunotherapy alone is ineffective.

Background and aim Co‐morbidities and computerized tomography‐measured muscle abnormalities are both common in cancer patients and independently adversely influence clinical outcomes. Muscle abnormalities are also evident in other diseases, such as diabetes and obesity. This study examined for the first time the association between co‐morbidities and muscle abnormalities in patients diagnosed with colorectal cancer (CRC). Methods This cross‐sectional study included 3051 non‐metastatic patients with Stages I–III CRC. Muscle abnormalities, measured at diagnosis, were defined as low skeletal muscle mass index (SMI) or low skeletal muscle radiodensity (SMD) quantified using computerized tomography images using optimal stratification. Co‐morbidities included in the Charlson index were ascertained. χ2 tests were used to compare the prevalence of co‐morbidities by the presence or absence of each muscle abnormality. Logistic regressions were performed to evaluate which co‐morbidities predicted muscle abnormalities adjusting for age, sex, body mass index, weight change, cancer stage, cancer site, race/ethnicity, and smoking. Results Mean age was 63 years; 50% of patients were male. The prevalence of low SMI and low SMD were 43.1% and 30.2%, respectively. Co‐morbidities examined were more prevalent in patients with low SMD than in those with normal SMD, and most remained independent predictors of low SMD after adjustment for covariates. Co‐morbidities associated with higher odds of low SMD included myocardial infarction [odds ratio (OR) = 1.77, P = 0.023], congestive heart failure (OR = 3.27, P < 0.001), peripheral vascular disease (OR = 2.15, P = 0.002), diabetes with or without complications (OR = 1.61, P = 0.008; OR = 1.46, P = 0.003, respectively), and renal disease (OR = 2.21, P < 0.001). By contrast, only diabetes with complications was associated with lower odds of low SMI (OR = 0.64, P = 0.007). Conclusions Prevalence of muscle abnormalities was high in patients with non‐metastatic CRC. Pre‐existing co‐morbidities were associated with low SMD, suggestive of a potential shared mechanism between fat infiltration into muscle and each of these co‐morbidities.

The present study was undertaken to analyze prognostic and genetic interactions between type 2 diabetes and metastatic colorectal cancer. Patients’ survival was depicted through the Kaplan–Meier product limit method. Prognostic factors were examined through the Cox proportional‐hazards regression model, and associations between diabetes and clinical‐pathologic variables were evaluated by the χ2 test. In total, 203 metastatic colorectal cancer patients were enrolled. Lymph nodes (P = 0.0004) and distant organs (> 2 distant sites, P = 0.0451) were more frequently involved in diabetic patients compared with those without diabetes. Diabetes had an independent statistically significant negative prognostic value for survival. Highly selected patients with cancer and/or diabetes as their only illness(es) were divided into three groups: (a) seven oligo‐metastatic patients without diabetes, (b) 10 poly‐metastatic patients without diabetes, and (c) 12 poly‐metastatic diabetic patients. These groups of patients were genetically characterized through the Illumina NovaSeq 6000 (San Diego, CA, USA) platform and TruSigt™Oncology 500 kit, focusing on genes involved in diabetes and colorectal cancer. Gene variants associated with diabetes and cancer were more frequent in patients in group 3. We found that type 2 diabetes is a negative prognostic factor for survival in colorectal cancer. Diabetes‐associated gene variants could concur with malignancy, providing a rational basis for innovative models of tumor progression and therapy. Type 2 diabetes (T2D) is a frequent comorbidity among metastatic colorectal cancer patients. Here we show that T2D is a negative prognostic factor and hypothesize that genetic polymorphisms involved in diabetes could concur with malignancy providing new insights for innovative models of tumor progression and therapy in this subset of patients.

The comparison of the genetic profiles between primary and metastatic colorectal cancer (CRC) is needed to enable the discovery of useful therapeutic targets against metastatic CRCs. We performed the targeted next generation sequencing assay of 170 cancer-associated genes for 142 metastatic CRCs, including 95 pairs of primary and metastatic CRCs, to reveal their genomic characteristics and to assess the genetic heterogeneity. The most frequently mutated gene in primary and metastatic CRCs was APC (71% vs. 65%), TP53 (54% vs. 57%), KRAS (45% vs. 44%), PIK3CA (16% vs. 19%), SMAD4 (15% vs. 14%) and FBXW7 (11% vs. 11%). The concordance in the top six frequently mutated genes was 85%, on average. The overall mutation frequencies were consistent with two sets of public data (TCGA and MSKCC). To the author’s knowledge, this is the first study to compare the genetic profiles of our cohort with that of the metastatic CRCs from MSKCC. Comparative sequencing analysis between primary and metastatic CRCs revealed a high degree of genetic concordance in the current clinically actionable genes. Therefore, the genetic investigation of archived primary tumor samples with the challenges of obtaining an adequate sample from metastatic sites appears to be sufficient for the application of cancer precision medicine in the metastatic setting.

For patients with isolated liver metastases from colorectal cancer who are not candidates for potentially curative resections, non-surgical local treatments may be useful. Non-surgical local treatments are classified according to how the treatment is administered. Local treatments are applied directly on hepatic parenchyma, such as radiofrequency, microwave hyperthermia and cryotherapy. Locoregional therapies are delivered through the hepatic artery, such as chemoinfusion, chemoembolization or selective internal radiation with Yttrium 90 radioembolization. The purpose of this review is to describe the different interventional therapies that are available for these patients in routine clinical practice, the most important clinical trials that have tried to demonstrate the effectiveness of each therapy and recommendations from principal medical oncologic societies.

Purpose Various chemotherapy administration methods have been used to prevent liver metastasis (LM) in patients with colorectal cancer (CRC). This network meta‐analysis evaluated the efficacy of these different methods in preventing LM in CRC patients who underwent curative surgery. Method A systematic search of randomized controlled trials reporting the efficacy of various adjuvant chemotherapy methods in patients with colorectal cancer who underwent curative surgery was conducted. The primary outcome was the LM rate. Results This network meta‐analysis included 19 studies reporting on 12,588 participants, comparing portal vein infusion chemotherapy (PVIC) versus hepatic arterial infusion chemotherapy (HAIC) versus systematic chemotherapy (SC) versus surgery alone. The HAIC group had the lowest LM rate when compared to the other three groups (odds ratio [OR] of PVIC vs. HAIC: 1.86; OR of SC vs. HAIC: 1.98; and HAIC vs. surgery alone: 0.43). The LM rate did not differ significantly between PVIC, SC, and surgery alone. The recurrence rates were lower for PVIC and HAIC than for surgery alone (the ORs for PVIC and HAIC were 0.73 [95% CI: 0.58–0.92] and 0.45 [95% CI: 0.26–0.77]). The mortality rates of patients undergoing PVIC and HAIC were lower than that of patients undergoing surgery alone (the ORs for PVIC and HAIC were 0.77 [95% CI: 0.64–0.93] and 0.49 [95% CI: 0.24–0.98]). Anastomotic leakage, cardiopulmonary leakage, diarrhea, nausea and vomiting, oral ulceration, wound infection, or ileus did not differ significantly between the four groups. PVIC showed the highest hepatic toxicity rate compared to those for SC, HAIC, and surgery alone. Conclusion HAIC might be a satisfactory method for preventing LM in patients with CRC undergoing curative surgery. We compared four different methods (portal vein infusion chemotherapy, hepatic arterial infusion chemotherapy, systematic chemotherapy, and surgery alone) for preventing liver metastasis in patients with colorectal cancer undergoing curative surgery by means of a network meta‐analysis and concluded that hepatic arterial infusion chemotherapy might be a satisfactory method.

Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making.

Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major ef-forts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the im-provements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complex-ity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the compre-hensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the applica-tion of the resulting dynamic changes to a precision medicine- based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC.

Background The aim of this study was to evaluate the rate of complications from the primary tumour (CPT) requiring surgical or endoscopic intervention during chemotherapy treatment in patients with incurable synchronous stage IV colorectal cancer, the possibility of predicting such complications and their influence on survival. Methods One hundred and twenty-five patients were initially treated with chemotherapy. Patients were grouped on the basis of appearance or not of CPT. We assessed the relation between age, gender, carcinoembryonic antigen (CEA) level, primary tumour location, alkaline phosphatase level, unilobar or bilobar liver involvement, presence of peritoneal carcinomatosis, the number of sites of metastatic disease, the addition of target therapies to chemotherapy, the ability to traverse the tumour with an endoscope and the appearance of complications due to the primary tumour and overall survival. Results Mean age was 64.9 years, and 89 patients were men. Over a mean of 234 days, 25 patients (20 %) developed a CPT. Eighteen patients required surgery, and seven were treated exclusively by an endoscopic procedure. Mean survival was 15.8 months. We found a statistically relevant correlation between the inability to traverse the tumour with an endoscope and the occurrence of a CPT. There was no statistical differences in survival between both groups, but patients receiving target therapies had better survival. Conclusion Twenty percent of patients will suffer a CPT during chemotherapy treatment. The inability to pass the tumour with an endoscope can predict the CPT. Survival was only related to the addition of target therapies to chemotherapy.