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Purpose of Review: This narrative review explores the efficacy and applicability of anti-EGFR therapy as the first-line treatment for patients with RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC). It critically examines current guidelines, along with recent evidence in the literature, to assess whether it should be universally applied., Recent Findings: Recent evidences highlight the variability of the response to anti-EGFR therapies due to molecular diversity and several clinical factors, such as RAS mutational status and primary tumor location. Anti-EGFR plus chemotherapy is the standard first-line treatment for most patients with MSS, RAS-WT, left-sided mCRC. Whether this combination is the best treatment for these patients remains an open question. This review delves into the role of EGFR inhibition in mCRC, focusing on clinical factors and the knowledge of biology, molecular targets, and biomarkers. It underscores the crucial role of a personalized approach, empowering healthcare providers and equipping them with the confidence to make informed decisions., Competing Interests: Declarations. Competing interests: Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors. Conflict of Interest: Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors. Conflict of Interest: Armano Santoro reports honoraria and advisory board consultancy from BMS (Bristol Myers Squibb), Servier, Gilead, Pfizer, Eisai, Bayer, and MSD (Merck Sharp and Dohme); speaker honoraria from Takeda, BMS, Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD (all outside the submitted work). The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. The other authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mismatch repair (MMR) immunohistochemical (IHC) evaluation has entered pathology routine practice as the first-line screening method to identify patients with MMR deficient (MMRd)/microsatellite instability (MSI) colorectal cancer (CRC), and its misdiagnosis may significantly impact the personalization of CRC patient care. To determine the prevalence of MMR protein intratumor heterogeneity in real-world practice, we collected a series of 8282 CRCs tested for MMR proteins in the setting of Lynch syndrome universal screening. Four heterogenous cases were also investigated for tumor infiltrating lymphocytes count, MSI status, and consensus molecular subtypes by Nanostring nCounter® Platform. Overall, 1056 (12.8%) CRCs showed a MMR altered status, with 46 cases showing a heterogeneous MMR profile (0.56% of the total, and 4.36% of all MMRd cases). To conclude, the authors make some critical remarks regarding the approach to MMR heterogeneity in clinical practice and routine diagnostics., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: The Lynch syndrome (LS) screening algorithm requires BRAF testing as a fundamental step to distinguish sporadic from LS-associated colorectal carcinomas (CRC). BRAF testing by immunohistochemistry (IHC) has shown variable results in the literature. Our aim was to analyse concordance between BRAF V600E IHC and BRAF molecular analysis in a large, mono-institutional CRC whole-slide, case series with laboratory validation., Methods and Results: MisMatch repair (MMR) protein (hMLH1, hPMS2, hMSH2, and hMSH6) and BRAF V600E IHC were performed on all unselected cases of surgically resected CRCs (2018-2023). An in-house validation study for BRAF V600E IHC was performed in order to obtain optimal IHC stains. BRAFV V600E IHC was considered negative (score 0), positive (scores 2-3), and equivocal (score 1). Interobserver differences in BRAF V600E IHC scoring were noted in the first 150 cases prospectively collected. Nine-hundred and ninety CRCs cases (830 proficient (p)MMR/160 deficient (d)MMR) were included and all cases performed BRAF V600E IHC (BRAF V600E IHC-positive 13.5% of all series; 66.3% dMMR cases; 3.4% pMMR cases), while 333 also went to BRAF mutation analysis. Optimal agreement in IHC scoring between pathologists (P < 0.0001) was seen; concordance between BRAF V600E IHC and BRAF molecular analysis was extremely high (sensitivity 99.1%, specificity 99.5%; PPV 99.1%, and NPV 99.5%). Discordant cases were reevaluated; 1 score 3 + IHC/wildtype case was an interpretation error and one score 0 IHC/mutated case was related to heterogenous BRAF V600E IHC expression. Among the 12 IHC-equivocal score 1+ cases (which require BRAF molecular analysis), three were BRAF-mutated and nine BRAF-wildtype., Conclusion: BRAF V600E IHC can be used as a reliable surrogate of molecular testing after stringent in-house validation., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Introduction: Available treatments for colorectal cancer are limited. However, in the last few years several advances and new treatment options became available and expanded the continuum of care in metastatic colorectal cancer (mCRC)., Areas Covered: Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both. Preclinical studies have shown that fruquintinib inhibits with high selectivity VEGFR 1-2-3, leading to a blockade in angiogenesis process, but also acts, with weak inhibition, on RET, FGFR-1, and c-kit kinases. Fruquintinib demonstrated good efficacy and tolerance in chemorefractory mCRC in two phase III trial: FRESCO and FRESCO 2. These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy., Expert Opinion: Fruquintinib is a valid therapeutic option for heavily pretreated mCRC patients. However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRAS G12C or HER2 amplification) and in non-oncogenic driven patients.

Opinion Statement: Circulating tumor DNA (ctDNA) has already shown clinically relevant results in early-stage colon cancer patient management. Its prognostic value is by far much stronger than that of the available clinico-pathological biomarkers, therefore, has the potential to personalize the treatment after radical surgery through intensifying or de-intensifying the adjuvant therapy. Further developments and improvements should be pursued by (a) optimizing ctDNA assays and (b) validating its clinical utility in the different stages of this disease. Two main avenues of ctDNA testing are being pursued: tumor-informed vs tumor-agnostic assays. Two main clinical trial designs are under study: ctDNA-based strategy and ctDNA-by-treatment interaction. The former needs large sample sizes to address the main questions of the studies; thus, the target delta benefit may be the main challenge in these trial designs. The latter may be challenged by unavoidable contamination bias. To date, several clinical trials are ongoing worldwide. We believe that this large number of trials may provide an excellent common database for the demonstration of surrogacy of ctDNA for the classical 3-year disease-free survival endpoint. This would mark a huge methodological improvement to speed up new drug testing and development in the adjuvant treatment of this disease., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Signet ring cell carcinoma (SRCC) is rare: about 10% of gastric cancer (GC) and 1% of colorectal cancer (CRC). SRCC is associated with poor prognosis, however the underlying molecular characteristics are unknown. SRCCs were analyzed using NGS, immunohistochemistry, and in situ hybridization. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mutations, and microsatellite instability (MSI) was evaluated by NGS of known MSI loci. A total of 8500 CRC and 1100 GC were screened. Seventy-six SRCC were identified from the CRC cohort (<1%) and 98 from the GC cohort (9%). The most frequently mutated genes in CRC-SRCC were TP53 (47%), ARID1A (26%), APC (25%); in GC-SRCC were TP53 (42%), ARID1A (27%), CDH1 (11%). When compared to non-SRCC histology (N = 3522), CRC-SRCC (N = 37) more frequently had mutations in BRCA1 (11% vs 1%, P < 0.001) and less frequently mutations in APC (19% vs 78%, P < 0.001), KRAS (22% vs 51%, P = 0.001) and TP53 (47% vs 73%, P = 0.001). Among the GC cohort, SRCC (N = 54) had a higher frequency of mutations in CDH1, BAP1, and ERBB2, compared to non-SRCC (N = 540). Our data suggest that SRCCs harbor a similar molecular profile, regardless of the tumor location. Tailored therapy may become available for these patients., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Gene fusions involving R-spondin (RSPOfp) and RNF43 mutations have been shown to drive Wnt-dependent tumor initiation in colorectal cancer. Herein, we aimed to characterize the molecular features of RSPOfp/RNF43 mutated (mut) compared with wild-type (WT) colorectal cancers to gain insights into potential rationales for therapeutic strategies., Experimental Design: A discovery cohort was classified for RSPOfp/RNF43 status using DNA/RNA sequencing and IHC. An independent cohort was used to validate our findings., Results: The discovery cohort consisted of 7,245 colorectal cancer samples. RSPOfp and RNF43 mutations were detected in 1.3% (n = 94) and 6.1% (n = 443) of cases. We found 5 RSPO fusion events that had not previously been reported (e.g., IFNGR1-RSPO3). RNF43-mut tumors were associated with right-sided primary tumors. No RSPOfp tumors had RNF43 mutations. In comparison with WT colorectal cancers, RSPOfp tumors were characterized by a higher frequency of BRAF, BMPR1A, and SMAD4 mutations. APC mutations were observed in only a minority of RSPOfp-positive compared with WT cases (4.4% vs. 81.4%). Regarding RNF43 mutations, a higher rate of KMT2D and BRAF mutations were detectable compared with WT samples. Although RNF43 mutations were associated with a microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) phenotype (64.3%), and a tumor mutation burden ≥10 mt/Mb (65.8%), RSPOfp was not associated with MSI-H/dMMR. The validation cohort replicated our genetic findings., Conclusions: This is the largest series of RSPOfp/RNF43-mut colorectal cancers reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO/RNF43 and suggested potential alternative strategies to overcome the low clinical impact of Wnt-targeted agents and immunotherapy., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Low socioeconomic status (SES) has been linked to worse survival in patients with colorectal cancer (CRC); however, the impact of SES on early-onset CRC remains undescribed., Materials and Methods: Retrospective analysis of data from the National Cancer Database (NCDB) between 2004 and 2016 was conducted. We combined income and education to form a composite measure of SES. Logistic regression and χ 2 testing were used to examine early-onset CRC according to SES group. Survival rates and Cox proportional hazards models compared stage-specific overall survival (OS) between the SES groups., Results: In total, 30,903 patients with early-onset CRC were identified, of whom 78.7% were White; 14.5% were Black. Low SES compared with high SES patients were more likely to be Black (26.3% vs. 6.1%) or Hispanic (25.3% vs. 10.5%), have T4 tumors (21.3% vs. 17.8%) and/or N2 disease (13% vs. 11.1%), and present with stage IV disease (32.8% vs. 27.7%) at diagnosis (p < .0001, all comparisons). OS gradually improved with increasing SES at all disease stages (p < .001). In stage IV, the 5-year survival rate was 13.9% vs. 21.7% for patients with low compared with high SES. In multivariable analysis, SES (low vs. high group; adjusted hazard ratio [HR adj ], 1.35; 95% confidence interval [CI], 1.26-1.46) was found to have a significant effect on survival (p < .0001) when all of the confounding variables were adjusted. Insurance (not private vs. private; HR adj , 1.38; 95% CI, 1.31-1.44) mediates 31% of the SES effect on survival., Conclusion: Patients with early-onset CRC with low SES had the worst outcomes. Our data suggest that SES should be considered when implementing programs to improve the early detection and treatment of patients with early-onset CRC., Implications for Practice: Low socioeconomic status (SES) has been linked to worse survival in patients with colorectal cancer (CRC); however, the impact of SES on early-onset CRC remains undescribed. In this retrospective study of 30,903 patients with early-onset CRC in the National Cancer Database, a steady increase in the yearly rate of stage IV diagnosis at presentation was observed. The risk of death increased as socioeconomic status decreased. Race and insurance status were independent predictors for survival. Implementation of programs to improve access to care and early diagnostic strategies among younger adults, especially those with low SES, is warranted., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

KRAS status serves as a predictive biomarker of response to treatment in metastatic colorectal cancer (mCRC). We hypothesize that complex interactions between multiple pathways contribute to prognostic differences between KRAS wild-type and KRAS mutant patients with mCRC, and aim to identify polymorphisms predictive of clinical outcomes in this subpopulation. Most pathway association studies are limited in assessing gene-gene interactions and are restricted to an individual pathway. In this study, we use a random survival forests (RSF) method for identifying predictive markers of overall survival (OS) and progression-free survival (PFS) in mCRC patients treated with FOLFIRI/bevacizumab. A total of 486 mCRC patients treated with FOLFIRI/bevacizumab from two randomized phase III trials, TRIBE and FIRE-3, were included in the current study. Two RSF approaches were used, namely variable importance and minimal depth. We discovered that Wnt/β-catenin and tumor associated macrophage pathway SNPs are strong predictors of OS and PFS in mCRC patients treated with FOLFIRI/bevacizumab independent of KRAS status, whereas a SNP in the sex-differentiation pathway gene, DMRT1, is strongly predictive of OS and PFS in KRAS mutant mCRC patients. Our results highlight RSF as a useful method for identifying predictive SNPs in multiple pathways.

Background: ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC., Methods: We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry., Results: ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell-inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples., Conclusions: Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status., Competing Interests: Conflict of interest statement P.A.P. reports receiving speaker bureau honoraria from Merck, Celgene, Halozyme, Ipsen, Bristol-Myers Squibb and Bayer and reports being a consultant/advisory board member for Halozyme, Caris and Merck. A.S. reports being a consultant/advisory board member for Caris Life Sciences. A.F.S. reports being is a consultant/advisory board member for and reports receiving commercial research grants from Caris. J.L.M. reports being an employee of and having ownership interests (including patents) at Caris; reports receiving speaker bureau honoraria from Genentech, Amgen, Celgene, Tailho and Bayer and reports being a consultant/advisory board member for Caris SAB. H.B. reports receiving speaker bureau honoraria from Eli Lilly Japan K.K. W.M.K. reports having ownership interests (including patents) at Caris Life Sciences and reports being a consultant/advisory board member for Merck and Lilly. H.-J.L. reports receiving speaker bureau honoraria from and reports being a consultant/advisory board member for Merck Serono, Bayer and Genentech. All other authors declare no potential conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The incidence of colorectal cancer (CRC), particularly left-sided tumors (LT), in adolescents and young adults (AYA) is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in younger patients. We compared molecular features of LT to right-sided tumors (RT) in AYA., Materials and Methods: A total of 246 LT and 56 RT were identified in a cohort of 612 AYA with primary CRC. Tumors were examined by next-generation sequencing (NGS), protein expression, and gene amplification. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined based on NGS data., Results: RT showed higher mutation rates compared with LT in several genes including BRAF (10.3% vs. 2.8%), KRAS (64.1% vs. 45.5%), PIK3CA (27% vs. 11.2%), and RNF43 (24.2% vs. 2.9%). Notably, additional mutations in distinct genes involved in histone modification and chromatin remodeling, as well as genes associated with DNA repair and cancer-predisposing syndromes, were characteristic of RT; most frequently KMT2D (27.8% vs. 3.4%), ARID1A (53.3% vs. 21.4%), MSH6 (11.1% vs. 2.3%), MLH1 (10.5% vs. 2.3%), MSH2 (10.5% vs. 1.2%), POLE (5.9% vs. 0.6%), PTEN (10.8% vs. 2.3%), and BRCA1 (5.4% vs. 0.6%). MSI was seen in 20.8% of RT versus 4.8% of LT. RT had a higher frequency of TMB-high regardless of MSI status., Conclusion: Molecular profiling of AYA CRC revealed different molecular characteristics in RT versus LT. Epigenetic mechanisms and alteration in DNA repair genes warrant further investigation and may be a promising treatment target for CRC in AYA., Implications for Practice: Colorectal cancer (CRC) in adolescents and young adults (AYA) comprises a distinct entity with different clinicopathologic features and prognosis compared with older patients. Molecular profiling of right- and left-sided tumors in AYA is needed to gain novel insight into CRC biology and to tailor targeted treatment in this age group. This study found that right- and left-sided CRC show distinct molecular features in AYA, overall and in subgroups based on microsatellite instability status. Alterations in DNA double-strand break repair and homologous recombination repair, as well as epigenetic mechanisms, appear to play a critical role. The present molecular profiling data may support the development of personalized treatment strategies in the AYA population., (© AlphaMed Press 2019.)

Background: Through enhancement of the Wnt signalling pathway, R-spondins are oncogenic drivers in colorectal cancer. Experimental data suggest that the R-spondin/Wnt axis stimulates vascular endothelial growth factor (VEGF)-dependent angiogenesis. We therefore hypothesise that variations within R-spondin genes predict outcome in patients with metastatic colorectal cancer (mCRC) treated with upfront FOLFIRI and bevacizumab., Patients and Methods: 773 patients with mCRC enrolled in the randomised phase III FIRE-3 and TRIBE trials and receiving either FOLFIRI/bevacizumab (training and validation cohorts) or FOLFIRI/cetuximab (control group) were involved in this study. The impact of six functional single-nucleotide polymorphisms (SNPs) within the R-spondin 1-3 genes on outcome was evaluated., Results: RAS and KRAS wild-type patients harbouring any G allele of the RSPO2 rs555008 SNP had a longer overall survival compared with those having a TT genotype in both the training (FIRE-3) and validation (TRIBE) cohorts (29.0 vs 23.6 months, P = 0.009 and 37.8 vs 19.4 months, P = 0.021 for RAS wild-type patients and 28.4 vs 22.3 months, P = 0.011 and 36.0 vs 23.3 months, P = 0.046 for KRAS wild-type patients). Conversely, any G allele carriers with KRAS and RAS mutant tumours exhibited a shorter progression-free survival compared with TT genotype carriers, whereas the results were clinically more evident for KRAS mutant patients in both the training and validation cohorts (8.1 vs 11.2 months, P = 0.023 and 8.7 vs 10.3 months, P = 0.009)., Conclusion: Genotyping of the RSPO2 rs555008 polymorphism may help to select patients who will derive the most benefit from FOLFIRI/bevacizumab dependent on (K)RAS mutational status., Competing Interests: Conflict of interest statement The authors declare no conflict of interest regarding the content discussed in the manuscript., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Colorectal cancer treatment has undergone a paradigm shift. We no longer see this disease as a singular, anatomic tumor type but rather a set of disease subgroups. Largely because of a better understanding of cancer biology and the introduction and integration of molecular biomarkers-the premise of precision therapy-we are beginning to direct treatments toward the right tumor target(s) in the right patients. The field of molecular profiling is continually evolving, and new biomarkers are constantly being discovered that have investigational, therapeutic, and/or prognostic implications-negative or positive. To date, only a few biomarkers have sufficient actionable, clinical implication to earn international guideline-recommended routine testing. Hence, it is vital that the treating oncologist should know which biomarkers to assess, when in the treatment course to test for them, and how the test is to be done. Correct interpretation of profiling results is imperative. Herein, we focus on international guideline-recommended mutation testing for patients prior to their colorectal cancer treatment initiation. The clinical applications of circulating tumor DNA (ctDNA) in patients with metastatic disease, based on our current knowledge and capabilities, are also addressed.

AMP-activated protein kinase (AMPK) is a key sensor of energy homeostasis and regulates cell metabolism, proliferation and chemotherapy/radiotherapy sensitivities. This study aimed to explore the relationship between the AMPK pathway-related single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with metastatic colorectal cancer (mCRC). We analyzed a total of 884 patients with mCRC enrolled in three randomized clinical trials (TRIBE, MAVERICC and FIRE-3: where patients were treated with FOLFIRI, mFOLFOX6 or FOLFOXIRI combined with bevacizumab or cetuximab as the first-line chemotherapy). The association between AMPK pathway-related SNPs and clinical outcomes was analyzed across the six treatment cohorts, using a meta-analysis approach. Our meta-analysis showed that AMPK pathway had significant associations with progression-free survival (PFS; p < 0.001) and overall survival (OS; p < 0.001), but not with tumor response (TR; p = 0.220): PRKAA1 rs13361707 was significantly associated with favorable PFS (log HR = -0.219, SE = 0.073, p = 0.003), as well as PRKAA1 rs10074991 (log HR = -0.215, SE = 0.073, p = 0.003), and there were suggestive associations of PRKAG1 rs1138908 with unfavorable OS (log HR = 0.170, SE = 0.083, p = 0.041), and of UBE2O rs3803739 with unfavorable PFS (log HR = 0.137, SE = 0.068, p = 0.042) and OS (log HR = 0.210, SE = 0.077, p = 0.006), although these results were not significant after false discovery rate adjustment. AMPK pathway-related SNPs may be predictors for chemotherapy in mCRC. Upon validation, our findings would provide novel insight for selecting treatment strategies., (© 2019 UICC.)

Purpose: The natural history and prognosis of appendiceal adenocarcinomas differ from those of adenocarcinomas arising in other large bowel sites. We aimed to compare the molecular profiles exhibited by appendiceal adenocarcinomas and colorectal cancers, or between the histopathologic subtypes of appendiceal adenocarcinoma., Experimental Design: A total of 183 samples from appendiceal adenocarcinoma [46 adenocarcinoma, not otherwise specified (NOS), 66 pseudomyxoma peritonei (PMP), 44 mucinous adenocarcinoma (MU), and 27 signet ring cell carcinoma (SR)], 994 from right-sided colorectal cancer (R-CRC), and 1,080 from left-sided CRC (L-CRC) were analyzed by next-generation sequencing (NGS) and IHC markers. Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and programmed death ligand 1 (PD-L1) by IHC., Results: We observed high mutation rates in appendiceal adenocarcinoma samples for KRAS (55%), TP53 (40%), GNAS (31%), SMAD4 (16%), and APC (10%). Appendiceal adenocarcinoma exhibited higher mutation rates in KRAS and GNAS , and lower mutation rates in TP53, APC , and PIK3CA (6%) than colorectal cancers. PMP exhibited much higher mutation rates in KRAS (74%) and GNAS ( 63%), and much lower mutation rates in TP53 (23%), APC (2%), and PIK3CA (2%) than NOS. Alterations associated with immune checkpoint inhibitor response (MSI-high, TMB-high, PD-L1 expression) showed similar frequency in appendiceal adenocarcinoma compared with L-CRC, but not R-CRC, and those of NOS were higher than other subtypes of appendiceal adenocarcinoma and L-CRC., Conclusions: Molecular profiling of appendiceal adenocarcinoma revealed different molecular characteristics than noted in R-CRC and L-CRC, and molecular heterogeneity among the histopathologic subtypes of appendiceal adenocarcinoma. Our findings may be critical to developing an individualized approach to appendiceal adenocarcinoma treatment., (©2019 American Association for Cancer Research.)

Background: CpG island DNA hypermethylation and global DNA hypomethylation are hallmark characteristics of colorectal cancer (CRC). Therefore, we aim to explore the effect of genetic variations within the genes that regulate the DNA methylation and demethylation pathways on outcomes in patients with metastatic CRC (mCRC) treated with first-line therapy and enrolled in three independent, randomised, open-label clinical trials., Methods: A total of 884 patients with mCRC enrolled in TRIBE, MAVERICC and FIRE-3 trials were included. Single-nucleotide polymorphisms (SNPs) within genes involved in DNA methylation and demethylation pathways were analysed. The prognostic value of each SNP across all treatment arms was quantified using the inverse-variance-weighted effect size, a meta-analysis approach implemented in the METASOFT software., Results: In the meta-analysis, DNMT3A rs11681717 was significantly associated with overall survival (hazard ratio = 1.26; 95% confidence interval [CI] 1.08-1.46; P = 0.002; false discovery rate [FDR] = 0.016), accounting for seven tests in the DNA methylation pathway. In addition, there was suggestive evidence of association for ten-eleven translocation (TET) genes variance with tumour response (TET1 rs3814177, odds ratio [OR] = 0.76, 95% CI 0.59-0.97, P = 0.025, FDR = 0.087; TET3 rs7560668, OR = 1.44; 95% CI 1.10-1.89; P = 0.009; FDR = 0.062)., Conclusions: We showed that polymorphisms within the genes responsible for the DNA methylation and demethylation machineries are correlated with outcomes in patients with mCRC who were enrolled in three independent, randomised, open-label, phase II/III clinical trials. In addition, we demonstrated the feasibility of a meta-analysis approach to identify stronger and more convincing association between gene polymorphisms and outcome, potentially leading the way to a new method of analysis for similar data set., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy., Patients and Methods: We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE (ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed., Results: In the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95% CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95% CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort., Conclusion: Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Previous studies have found significant relationships between height and colorectal cancer (CRC) risk. Increased growth has been associated with activated pathways such as insulin-like growth factor 1. This study examined the impact of height on outcomes in metastatic CRC patients enrolled onto the FIRE-3 study, a randomized phase 3 clinical trial., Patients and Methods: A total of 695 patients with metastatic CRC were studied and height was measured in centimeters. Male patients were grouped as ≤ 165, 166-175, 176-185, and ≥ 186 cm in height; female patients were grouped as ≤ 154, 155-164, 165-174, and ≥ 175 cm in height. Primary end point was overall survival (OS); secondary end point was progression-free survival., Results: When patients' heights were categorized into 4 groups, the tallest group showed a worse OS compared to the shortest group; however, there was no linear relationship between height and OS. To investigate this, we showed the association between height as a continuous variable and OS. Patients shorter than 172 cm had a worse OS as their height decreased. Patients taller than 172 cm had a worse OS as their height increased. Moreover, patients with heights between 165 and 179 cm had a better OS compared to other patients (P = .05). This effect was independent of treatment arm and gender., Conclusion: Patients shorter than 165 cm and taller than 179 cm have a worse OS, while those between 165 and 179 cm have a better OS. Hence, clinicians should consider height as an important prognostic factor when treating metastatic CRC patients. Future prospective studies are warranted to shed light on the mechanisms underlying the worse OS in taller patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed using direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by IHC. Interestingly, right-sided colon and small-bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high was strongly associated with MSI-H ( P < 0.0001). However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS). Higher PD-L1 expression was more likely to be seen in MSI compared with MSS tumors (20.6% vs. 7.8%, P < 0.0001). Implications: TML-high rate varied widely among gastrointestinal cancers. Although MSI is conceivably the main driver for TML-high, other factors may be involved. Future clinical trials are needed to evaluate whether the integration of TML, MSI, and PD-L1 could better identify potential responders to immunotherapy. Mol Cancer Res; 16(5); 805-12. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Introduction: Angiogenesis is a complex process regulated by several pro- and anti-angiogenic factors, thus the loss of its fine equilibrium plays a key role in colorectal cancer (CRC) development and progression. Therapeutic agents targeting VEGF/VEGFR signaling, the main regulator of this process, proved to be effective across different treatment lines in metastatic CRC (mCRC) and contributed greatly to improve patients' survival in recent years. Areas covered: This review aimed to summarize the actual body of knowledge available on the VEGF pathway in CRC, including currently available anti-angiogenic drugs and treatment challenges, mechanisms of resistance, promising predictive biomarkers and future perspectives. Expert commentary: Angiogenesis inhibition in subsequent lines of treatment is a valid strategy in the continuum of care of mCRC patients. In this scenario, the availability of multiple agents warrants to tailor therapy to an individualized approach. However, the validation of predictive biomarkers to aid therapeutic decisions remains an issue. Intrinsic and adaptive resistance to anti-angiogenic agents comprises distinct and intertwined processes, eventually leading to treatment failure and disease progression. The expanding knowledge on the mechanisms underlying the angiogenesis pathway, different potential treatment targets and mechanisms of tumor resistance, may lead to promising new perspectives in this field.

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab. Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes ( GC, CYP24A1, CYP27B1, VDR, DKK1, CST5 ) were analyzed. Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D-binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable ( P = 0.001) and multivariable analyses ( P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable ( P = 0.033) and multivariable analyses ( P = 0.046). Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784-93. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular and clinical features, which reflects the wide range of prognostic outcomes and treatment responses observed among CRC patients worldwide. Our understanding of the CRC epigenome has been largely developed over the last decade and it is now believed that among thousands of epigenetic alterations present in each tumor, a small subgroup of these may be considered as a CRC driver event. DNA methylation profiles have been the most widely studied in CRC, which includes a subset of patients with distinct molecular and clinical features now categorized as CpG island methylator phenotype (CIMP). Major advances have been made in our capacity to detect epigenetic alterations, providing us with new potential biomarkers for diagnostic, prognostic and therapeutic purposes. This review aims to summarize our current knowledge about epigenetic alterations occurring in CRC, underlying their potential future clinical implications in terms of diagnosis, prognosis and therapeutic strategies for CRC patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)