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Background: No biomarkers are currently available to predict the efficacy of trifluridine/tipiracil (FTD/TPI) in chemorefractory metastatic colorectal cancer. The multicohort REGOLAND study aims at exploring and validating circulating markers potentially able to predict benefit from regorafenib in this setting., Material and Methods: In the retrospective 'regorafenib exploratory cohort', including 105 patients treated with regorafenib, baseline (d1) plasma levels of angiogenesis-related biomarkers and their early modulation after 15 days (d15) of treatment were investigated for correlation with clinical outcome. Based on a pre-specified statistical hypothesis, main retrospective findings were prospectively challenged in the 'regorafenib validation cohort', including 100 patients treated with regorafenib. Prospectively validated putative biomarkers were then assessed in the control 'FTD/TPI cohort', including 93 patients treated with FTD/TPI., Results: In the 'regorafenib exploratory cohort', the early (d15) increase of Angiopoietin-2 (Ang-2) was associated with longer progression-free survival (HR:0.57 [95%CI:0.38-0.88], P = 0.004) and a trend towards longer OS (HR:0.74 [95%CI:0.48-1.14], P = 0.165), than the early decrease. Similar results were prospectively confirmed in the 'regorafenib validation cohort' (HR for progression-free survival:0.72 [95%CI:0.48-1.08], P = 0.095; HR for OS:0.77 [95%CI:0.51-1.16], P = 0.204). No predictive impact was shown for the early modulation of Ang-2 in the 'FTD/TPI cohort'. High baseline Ang-2 levels predict poor prognosis in all the investigated cohorts, independently of other clinical prognostic variables., Conclusions: The early modulation of circulating Ang-2 predicts the efficacy of regorafenib. Baseline Ang-2 plasma levels are an independent prognostic biomarker in chemorefractory metastatic colorectal cancer., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.C. reports personal fees from Roche, Amgen, Bayer, and Servier; research funding from Merck Serono; and a consulting or advisory role with Roche, Bayer, Amgen. All other authors report no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Regorafenib is a key agent in metastatic colorectal cancer (mCRC), but no validated factors predicting longer survival are available., Patients and Methods: REALITY was a retrospective multicenter trial in regorafenib-treated mCRC patients with overall survival (OS) ≥ 6 months. We aimed to assess the association between clinical parameters and outcome to define a panel identifying long term survivors among regorafenib candidates. Primary and secondary endpoints were OS and progression free survival (PFS), respectively. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; independent role of significant variables at univariate analysis: logistic regression)., Results: Hundred regorafenib-treated mCRC patients with OS ≥ 6 months were enrolled. Median OS was 11.5 m (95%CI:9.60-12.96); median PFS was 4.2 months (95% CI:3.43-43.03). The absence of liver progression and of dose and/or schedule changes during the first 4 cycles (mainly for good tolerability) were independently correlated at multivariate analysis with OS (Exp(b)1.8869, P= .0277and Exp(b)2.2000, P = .0313) and PFS (Exp(b)2.1583, P = .0065 and Exp(b)2.3036, P= .0169). Patients with neither of these variables had a significantly improved OS (n = 14, 20.8 months; 95% CI:12.967-55.267) versus others (n = 86, 10 months; 95% CI:8.367-12.167; HR = 0.4902, P = .0045) and PFS (11.3 months, 95%CI:4.267-35.8 vs. 3.9 months, 95% CI:3.167-43.033; HR = 0.4648, P = .0086)., Conclusion: These 2 factors might allow clinicians to better identify patients more likely to benefit from regorafenib. Toxicity management remains crucial., (Copyright © 2021. Published by Elsevier Inc.)

Background: In mCRC, CEA is used to monitor response to systemic therapy together with imaging. After the end of induction, no major improvement in tumour shrinkage is expected, and the availability of a marker able to predict progressive disease (PD) versus no-PD might allow avoiding CT scans., Methods: We pooled data from patients with baseline CEA ≥ 10 ng/mL included in TRIBE and TRIBE2 studies with the aim of identifying a threshold for percent increase of CEA from nadir able to predict PD after the end of the induction therapy., Results: In total, 1178 paired CEA and radiological assessments from 434 patients were included. According to the optimal cut-off determined by ROC, a CEA increase of at least 120% from nadir differentiated between PD and no-PD with a sensitivity of 74% and a specificity of 78%, excluding PD in the 92% of radiological assessments and allowing to avoid the 67% of CT scans. However, CEA cut-off of 120% was not able to detect radiological PD in 26% of cases. In order to mitigate this issue, a different clinically relevant threshold was evaluated based on the best sensitivity cut-off. Therefore, using any CEA increase from nadir as a threshold, the sensitivity grew to 93% and only in the 7% of cases the radiological PD was not detected., Conclusions: In mCRC with baseline CEA ≥ 10 ng/mL, CEA values can accurately predict PD versus no-PD after the end of the first-line induction therapy., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Oligometastatic disease (OMD) identifies tumours with limited metastatic spread. OMD definition is not univocal and no data from clinical trials are available about the prognostic effect of OMD in metastatic colorectal cancer (mCRC), the impact of locoregional treatments (LRTs) and the effect of chemotherapy intensification in these patients. The role of tumour burden (TB) in driving therapeutic choices is also debated., Patients and Methods: We performed a pooled analysis of phase III TRIBE and TRIBE2 studies comparing FOLFOXIRI/bevacizumab (bev) to doublets (FOLFOX or FOLFIRI)/bev. Patients were grouped in OMD versus non-OMD based on the European Society for Medical Oncology definition. Among patients with OMD, those with OMD/low TB were compared with all the others., Results: Of 1187 patients enrolled, 1096 were classified as OMD (N = 312 [28%]) or non-OMD (N = 784 [72%]). Among patients with OMD, 126 (40%) were OMD/low TB. OMD was associated with longer progression-free survival (14.0 versus 10.1 months; p < 0.01) and overall survival (38.2 versus 22.0 months; p < 0.01). These results were confirmed in multivariable models. The benefit provided by FOLFOXIRI/bev compared with doublets/bev did not differ in accordance with OMD and TB (p for interaction >0.05). Patients with OMD underwent LRTs more frequently (p < 0.01) and those with OMD/low TB had higher chance to undergo LRTs after the first progression (p < 0.01)., Conclusions: OMD is a positive prognostic factor in mCRC. The benefit from the upfront treatment intensification is independent of the metastatic spread extent and TB. LRTs should be highly considered in these patients, mainly during the first-line therapy but also at later stages of treatment history in selected cases., Competing Interests: Conflict of interest statement S.L. reported receiving advisory board fees from Amgen, Eli Lilly, and Merck. F.P. reports having declared Honoraria/speaker's bureau from Roche, Amgen, Merck Serono, Lilly, Sanofi, Bayer, Servier; has received research grants from BMS. R.B. reports receiving fee payments by Bayer, Astra Zeneca, Sanofi, Novartis, Amgen, Roche, Pfizer, Janssen, Cilag, Bristol Meyers Squibb. G.A. reports receiving personal fees and has been a consultant or played an advisory role with Merck Serono, Amgen, Roche, and Servier. A.F. reports being a consultant/advisory board member for Bayer, Roche, Amgen, Eli Lilly, Merck Serono, Sanofi, Servier. C.C. is a consultant/advisory board member for Roche, Amgen, Bayer, Merck Serono, Servier. All the other authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To understand the immune landscape of deficient mismatch repair colorectal cancer (dMMR CRC) tumor microenvironment, gene expression profiling was performed by the nCounter PanCancer Immune Profiling Panel. This study was conducted retrospectively on 89 dMMR-CRC samples. The expression of CD3, CD8, programmed death-1, and programmed death ligand-1 protein was evaluated on a subset of samples by immunohistochemistry, and lymphocyte density was calculated. A subset of deregulated genes was identified. Functional clustering analysis performed on these genes generated four main factors: antigen processing and presentation, with its major histocompatibility complex-II-related genes; genes correlated with the cytotoxic activity of immune system; T-cell chemotaxis/cell adhesion genes; and T-CD4 + regulator cell-related genes. A deregulation score (DS) was calculated for each sample. On the basis of their DS, tumors were then classified as COLD (DS ≤ -3) to select the samples with a strong down-regulation of the immune system and NOT COLD (DS ≥ -2). The COLD group of patients showed a worse prognosis in terms of survival considering all patients (P = 0.0172) and patients with metastatic disease (P = 0.0031). These results confirm that dMMR-CRCs do not constitute a homogeneous group as concerns the immune system activity of tumor microenvironment. In particular, the distinction between COLD and NOT COLD tumors may improve the management of these two subsets of patients., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Biomarkers able to improve the cost/benefit ratio are urgently needed for metastatic colorectal cancer patients that are eligible to receive regorafenib. Here, we measured plasma levels of ten circulating microRNAs (c-miRNAs) and we investigated their early changes during treatment, as well as possible correlation with clinical outcome. Ten literature-selected c-miRNAs were quantified by qRT-PCR on plasma samples collected at baseline (d1) and after 15 days of treatment (d15). C-miRNAs showing significant changes were further analyzed to establish correlations with outcome. A decision tree-based approach was employed to define a c-miRNA signature able to predict the outcome. Results achieved in an exploratory cohort were tested in a validation group. In the exploratory cohort (n = 34), the levels of c-miR-21 (p = 0.06), c-miR-141 (p = 0.04), and c-miR-601 (p = 0.01) increased at d15 compared with d1. A c-miRNA signature involving c-miR-21, c-miR-221, and c-miR-760 predicted response to treatment (p < 0.0001) and was significantly associated to PFS (HR = 10.68; 95% CI 3.2-35.65; p < 0.0001). In the validation cohort (n = 36), the increase in c-miR-21 (p = 0.02) and c-miR-601 (p = 0.02) levels at d15 was confirmed, but the associations with outcome were not. Our data indicate that early changes of c-miRNA levels might be influenced by regorafenib treatment. However, further studies are needed to establish the predictive power of such modifications.

Background: Adenocarcinoma with mucinous histology or mucinous component are histologic subtypes of metastatic colorectal cancers (mCRCs) with limited benefit from cytotoxic agents. Their sensitivity to anti-epithelial growth factor receptors (EGFRs) is not clear., Patients and Methods: The activity and efficacy of anti-EGFRs was retrospectively evaluated among patients with RAS and BRAF wild-type mCRC with or without mucinous histology or mucinous component. Subgroup analyses according to primary tumor location were conducted., Results: Overall, the study population included 22 mucinous or with mucinous component tumors (11 right- and 11 left-sided tumors) and 83 not mucinous tumors. One patient experienced partial response among mucinous tumors, whereas in the not mucinous group, 42 patients experienced partial response, with an overall response rate of 4% and 51%, respectively (P = .003). The median progression-free survival was 2.8 versus 6.7 months (hazard ratio, 0.28; 95% confidence interval, 0.13-0.59; P < .001), and the median overall survival was 6.5 and 16.7 months (hazard ratio, 0.58; 95% confidence interval, 0.33-1.00; P = .022), for the mucinous and not mucinous groups, respectively. Similar results were observed in subgroup analysis according to primary tumor location., Conclusion: Anti-EGFRs may not provide clinically meaningful benefit in mCRCs with mucinous histology or mucinous component compared with those without mucinous component, irrespective of sidedness., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Tumors bearing homologous recombination deficiency are extremely sensitive to DNA double strand breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA damage response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive and prognostic biomarker has not been fully investigated. We carried out a multicenter effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational profiles were obtained by means of next-generation sequencing. Overall, 35 out of 227 samples (15%) carried an ATM mutation. At a median follow-up of 56.6 months, patients with ATM mutated tumors showed a significantly longer median overall survival (OS) versus ATM wild-type ones (64.9 vs 34.8 months; HR, 0.50; 95% CI, 0.29-0.85; P = 0.01). In the multivariable model, ATM mutations confirmed the association with longer OS (HR, 0.57; 95% CI, 0.33-0.98; P = 0.04). The prognostic impact of ATM mutations was independent from TP53 mutational status and primary tumor location. High heterogeneity score for ATM mutations, possibly reflecting the loss of wild-type allele, was associated with excellent prognosis. In conclusion, we showed that ATM mutations are independently associated with longer OS in patients with mCRC.

Background: TAS-102 is indicated for patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, available therapies. Given the complete inefficacy in half of patients, the lack of predictive factors, the palliative setting, and the financial and clinical toxicity, optimizing the cost-benefit ratio is crucial. The "ColonLife" nomogram allows an estimate of the 12-week life expectancy of patients with refractory mCRC., Materials and Methods: We collected data from patients treated at eight Italian centers in the compassionate use program. Baseline characteristics of patients who were or were not progression free at 6 months were compared. The discriminative ability of the ColonLife nomogram was assessed. Among patients who received both TAS-102 and regorafenib, clinical outcomes of the two sequences were compared., Results: This study included 341 patients. Six (2%) and 93 (27%) patients achieved response and disease stabilization, respectively. The median progression-free survival (PFS) was 2.4 months with an estimated 6-month PFS rate of 19%; the median overall survival (OS) was 6.2 months. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, normal lactate dehydrogenase (LDH), and a time from the diagnosis of metastatic disease of >18 months were independently associated with higher chances of a patient being progression free at 6 months. The discriminative ability of ColonLife was confirmed. Among 121 patients who received both regorafenib and TAS-102, no differences in first or second PFS or OS were reported between the two sequences., Conclusion: One out of five patients achieves clinical benefit with TAS-102. ECOG PS, LDH, and time from diagnosis of metastatic disease may help to identify these patients. Excluding patients with very short life expectancy appears a reasonable approach., Implications for Practice: Improving the cost-efficacy ratio of TAS-102 in metastatic colorectal cancer is needed to spare useless toxicities in a definitely palliative setting. Eastern Cooperative Oncology Group performance status, lactate dehydrogenase levels, and time from the diagnosis of metastatic disease may help to identify patients more likely to achieve benefit. Properly designed prognostic tools (i.e., the "ColonLife" nomogram) may enable excluding from further treatments patients with very limited life expectancy., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Background: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs., Methods: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials., Results: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615)., Conclusions: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.

Secondary resection is a chance of cure for a subgroup of metastatic colorectal cancer (mCRC) patients with unresectable liver-limited disease. Medical treatment has a dual goal: to induce tumour shrinkage and to prevent disease relapse. The aims of the present analysis were to assess the efficacy of FOLFOXIRI plus bevacizumab in this setting, and to investigate whether this regimen could revert the poor prognosis of high-risk patients defined by clinical and molecular factors. We performed a pooled analysis of patients with unresectable and liver-limited mCRC, treated with first-line FOLFOXIRI plus bevacizumab in three prospective clinical trials by Gruppo Oncologico del Nord Ovest. 205 (37.9%) patients with liver-limited disease were selected, out of 541 treated patients. Liver metastases were synchronous, ≥4 and bilobar in 90%, 61%, and 79% of cases, respectively. The largest diameter was >5 cm in 42% of cases, and ≥6 segments were involved in 25%. Seventy-four patients (36.1%) underwent R0 or R1 resection of metastases. R2 resections were performed in 17 cases (8.3%). Having <6 involved segments (p < 0.001) and achieving RECIST response (p = 0.019) were associated with higher chances of resection. R0/R1 resected patients had significantly longer median progression-free survival (PFS) (18.1 versus 10.7 months, HR: 0.48 [0.35-0.66], p < 0.001) and overall survival (OS) (44.3 versus 24.4 months, HR: 0.32 [0.22-0.48], p < 0.001) compared with other patients, both in the univariate and multivariate analyses (PFS p = 0.025; OS p < 0.001). The 5-year PFS and OS rate in R0 resected patients were 12% and 43%, respectively. Neither negative baseline characteristics nor high clinical risk scores or RAS/BRAF mutations were associated with poor post-resection outcomes. In conclusion, FOLFOXIRI plus bevacizumab demonstrates efficacy in the conversion setting with considerable long-term outcome results independent of clinical and molecular prognostic factors (NCT00719797, NCT01163396 and NCT02271464)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)