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Retrospective subgroup analyses of previous trials in the first-line therapy of RAS wt metastatic colorectal cancer (mCRC) suggested a predictive impact of primary tumour side on the efficacy of anti-epidermal growth factor receptor (EGFR) agents. Recently, new head-to-head trials of doublets/bevacizumab versus doublets/anti-EGFR, PARADIGM and CAIRO5 were presented. We searched for phase II and III trials comparing doublet chemotherapy plus an anti-EGFR or bevacizumab as the first-line treatment for RAS wt mCRC patients. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and radical resection rate result in the overall study populations and, according to the primary side, were pooled together in a two-stage analysis with random effects and fixed effect models. The interaction between sidedness and treatment effect was then analysed. We identified five trials (PEAK, CALGB/SWOG 80405, FIRE-3, PARADIGM and CAIRO5), including 2739 patients, 77% left- and 23% right-sided. Among patients with left-sided mCRC, the use of anti-EGFRs was associated with higher ORR (74% versus 62%, OR = 1.77 [95% confidence interval {CI} 1.39–2.26–0.88], p < 0.0001), longer OS (hazard ratio [HR] = 0.77 [95% CI 0.68–0.88], p < 0.0001) and not significantly longer PFS (HR = 0.92, p = 0.19). Among patients with right-sided mCRC, the use of bevacizumab was associated with longer PFS (HR = 1.36 [95% CI 1.12–1.65], p = 0.002) and not significantly longer OS (HR = 1.17, p = 0.14). A subgroup analysis confirmed a significant interaction effect between the primary tumour side and treatment arm in terms of ORR (p = 0.02), PFS (p = 0.0004) and OS (p = 0.001). No differences in the radical resection rate were found according to treatment and sidedness. Our updated metanalysis corroborates the role of the primary tumour location in the choice of the upfront therapy for RAS wt mCRC patients, leading to strongly recommend anti-EGFRs in left-sided tumours and to prefer bevacizumab in the right-sided. • Doublet/anti-epidermal growth factor receptor (EGFRs) or bevacizumab are both valuable first-line options for RAS wt metastatic colorectal cancer (mCRC). • Left-sided mCRC achieves a better overall survival and overall response rate benefit from anti-EGFRs versus bevacizumab. • Right-sided mCRC patients achieve better progression-free survival , with a trend for overall survivalwith bevacizumab. • Anti-EGFRs should be recommended only in the left-sided RAS wt mCRC. • Bevacizumab should be preferred in the right-sided RAS wt mCRC. [ABSTRACT FROM AUTHOR]

Encorafenib plus cetuximab is efficient in anti-EGFR-naïve patients with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC). No data are available concerning the efficacy of BRAF inhibitors associated with anti-EGFRs (B + E) in patients previously treated with an anti-EGFR agent. We retrospectively collected a series of patients with BRAFm mCRC treated with B + E after previous anti-EGFR treatment, in 14 centers. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment, and we reported objective response and disease control rates (ORR, DCR; RECIST V1.1). Twenty-five BRAFm mCRC patients were enrolled. Prior to B + E treatment, 4/10/11 patients were treated with 1/2/> 2 previous treatment lines. Ten patients received previous panitumumab, 14 cetuximab, 1 both. Immediate progression with previous anti-EGFR was reported for 7 patients. Anti-BRAF was encorafenib for 21 patients, dabrafenib for 4 patients, with cetuximab for 24 patients and panitumumab for 1 patient. ORR was 40% (10 patients) and DCR was 80% (20 patients). Median PFS and OS were 4.8 months (95% CI, 4.01–7.95) and 10.1 months (95% CI, 7.75-NR). DCR amongst patients with previous primary resistance to anti-EGFR (N = 7) was 100%. Two patients discontinued B + E due to drug-related adverse event. Though in a limited retrospective series of patients, these results show the efficacy of the combination of anti-BRAF and anti-EGFRs in BRAFm mCRC patients previously treated with an anti-EGFR. The use of this combination should thus not be ruled out in this population with limited therapeutic options. • Series of 25 non anti-EGFR-naïve patients treated by anti-BRAF + anti-EGFR for a colorectal cancer. • Median progression free survival and overall survival were 4.8 and 10.1 months. • Ten out of 24 patients had an objective response rate. • These results are very close to those reported in BEACON trial. • This proves the efficacy of encorafenib + cetuximab in non-naïve anti-EGFR patients. [ABSTRACT FROM AUTHOR]

In clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs evaluation, taking into account chronic low-grade AEs, single patient's perspective, and time-related information, such as ToxT analysis, should be considered especially for less intense but potentially long-lasting treatments, such as maintenance strategies in metastatic colorectal cancer (mCRC). We applied ToxT (Toxicity over Time) evaluation to a large cohort of mCRC patients enroled in randomised TRIBE, TRIBE2, and VALENTINO studies, in order to longitudinally describe AEs throughout the whole treatment duration and to compare AEs evolution over cycles between induction and maintenance strategies, providing numerical and graphical results overall and per single patient. After 4–6 months of combination therapy, 5-fluorouracil/leucovorin (5-FU/LV) + bevacizumab or panitumumab was recommended in all studies except for the 50% of patients in the VALENTINO trial who received panitumumab alone. Out of 1400 patients included, 42% received FOLFOXIRI (5-FU/LV, oxaliplatin, and irinotecan)/bevacizumab, 18% FOLFIRI/bevacizumab, 24% FOLFOX/bevacizumab, 16% FOLFOX/panitumumab. Mean grade of general and haematological AEs was higher in the first cycles, then progressively decreasing after the end of induction (p < 0.001), and always remaining at the highest levels with FOLFOXIRI/bevacizumab (p < 0.001). Neurotoxicity became more frequent over the cycles with late high-grade episodes (p < 0.001), while the incidence but not the grade of hand-and-foot syndrome gradually increased (p = 0.91). Anti-VEGF-related AEs were more severe in the first cycles, then setting over at low levels (p = 0.03), while anti-EGFR-related AEs still affected patients during maintenance. Most of chemotherapy-related AEs (except for HFS and neuropathy) reach the highest level in the first cycles, then decrease, probably due to their active clinical management. Transition to maintenance allows relief from most AEs, especially with bevacizumab-based regimens, while anti-EGFR-related AEs may persist. • ToxT analysis longitudinally evaluates AEs, overall and per single patient. • ToxT was applied for the first time to different upfront treatments of mCRC. • Most AEs are worse during the first cycles, then progressively ameliorate. • Transition to maintenance allows a considerable relief. • Some AEs draw peculiar trajectories, not perceived in traditional safety reports. [ABSTRACT FROM AUTHOR]

Background: Retrospective series suggest that bevacizumab-induced hypertension (HTN) is a prognostic and potentially predictive biomarker of efficacy of the antiangiogenic drug in the upfront treatment of metastatic colorectal cancer (mCRC) patients. The immortal-time bias and the effect of pre-existing HTN might affect these findings. We conducted a pooled, post hoc analysis of 2 prospective randomized trials of chemotherapy plus bevacizumab in mCRC, and performed a systematic review of the available literature focusing on how the immortal-time bias was taken into account and how pre-existing HTN potentially requiring the use of antihypertensive drugs was managed.Methods: The pooled-analysis included patients enrolled in the phase III TRIBE and TRIBE-2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively. Association between HTN and survival outcomes was assessed by incorporating a time-dependent Cox regression model to consider the time-dependency of the probability of HTN onset during the treatment. The systematic review was conducted according to PRISMA guidelines.Results: The systematic review retrieved 14 eligible and highly heterogeneous studies. A positive prognostic impact of bevacizumab-induced HTN was reported in the 58% of the analyses reporting Progression Free Survival (PFS) and in the 54% of the analyses reporting Overall Survival (OS) data. Immortal-time bias was incorporated in 4 studies (28%). In TRIBE and TRIBE-2 study populations (N = 1175), patients experiencing ≥ G2 HTN during first-line bevacizumab administration showed longer PFS (median: 14.7 versus 10.3 months, p < 0.001) and OS (median: 31.7 versus 24.2 months, p < 0.001). The association with OS retained statistical significance after correction for time-dependency (p = 0.003) and was confirmed in the multivariable model including HTN as a time-dependent variable (p = 0.02). Moreover, in patients with pre-existing HTN, no difference in terms of PFS and OS was observed compared with the subgroup of patients who never experienced ≥G2 HTN (HR 1.01, p = 0.86 and HR 1.02, p = 0.78 respectively.Conclusions: Bevacizumab-induced HTN during the first-line treatment of mCRC is an independent prognostic factor, also adopting a time-dependency correction. Toxicity should be interpreted as a time-dependent variable when exploring its association with clinical outcome. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Early increase of Ang-2 levels predicts outcome with regorafenib but not with trifluridine/tipiracil. • Baseline Ang-2 plasma levels are an independent prognostic biomarker in refractory metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

Combination of a BRAF inhibitor (BRAFi) and an anti-epidermal growth factor receptor (EGFR), with or without a MEK inhibitor (MEKi), improves survival in BRAF - V600E-mutant metastatic colorectal cancer (mCRC) over standard chemotherapy. However, responses are heterogeneous and there are no available biomarkers to assess patient prognosis or guide doublet- or triplet-based regimens. In order to better characterize the clinical heterogeneity observed, we assessed the prognostic and predictive role of the plasmatic BRAF allele fraction (AF) for these combinations. A prospective discovery cohort including 47 BRAF- V600E-mutant patients treated with BRAFi–anti-EGFR ± MEKi in clinical trials and real-world practice was evaluated. Results were validated in an independent multicenter cohort (n = 29). Plasmatic BRAF- V600E AF cut-off at baseline was defined in the discovery cohort with droplet digital PCR (ddPCR). All patients had tissue-confirmed BRAF- V600E mutations. Patients with high AF have major frequency of liver metastases and more metastatic sites. In the discovery cohort, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 10.1 months, respectively. Patients with high BRAF AF (≥2%, n = 23) showed worse PFS [hazard ratio (HR) 2.97, 95% confidence interval (CI) 1.55-5.69; P = 0.001] and worse OS (HR 3.28, 95% CI 1.58-6.81; P = 0.001) than low- BRAF AF patients (<2%, n = 24). In the multivariable analysis, BRAF AF levels maintained independent significance. In the validation cohort, high BRAF AF was associated with worse PFS (HR 3.83, 95% CI 1.60-9.17; P = 0.002) and a trend toward worse OS was observed (HR 1.86, 95% CI 0.80-4.34; P = 0.15). An exploratory analysis of predictive value showed that high-BRAF AF patients (n = 35) benefited more from triplet therapy than low-BRAF AF patients (n = 41; PFS and OS interaction tests, P < 0.01). Plasmatic BRAF AF determined by ddPCR is a reliable surrogate of tumor burden and aggressiveness in BRAF- V600E-mutant mCRC treated with a BRAFi plus an anti-EGFR with or without a MEKi and identifies patients who may benefit from treatment intensification. Our results warrant further validation of plasmatic BRAF AF to refine clinical stratification and guide treatment strategies. • Plasmatic BRAF AF has a prognostic role for survival in mCRC treated with BRAF inhibitors. • ddPCR, applied in a cohort including a real-world population, mirrored those of the BEACON clinical trial using next-generation sequencing (NGS). • ddPCR detects BRAF AF in circulating tumor DNA (ctDNA) with high reproducibility and sensitivity, offering a validated alternative to NGS. • Identifying prognostic factors in BRAF-mutant mCRC is crucial to stratify patients and guide treatment strategies. [ABSTRACT FROM AUTHOR]

The availability of new drugs in the chemo-refractory setting opened the way to the concepts of treatment sequencing in mCRC. However, the impact of later line options in the therapeutic route of metastatic colorectal cancer (mCRC) patients and the attrition rate across subsequent lines of therapy are not well established. We performed a pooled analysis of treatments administered after the 2nd disease progression in 1187 mCRC patients enrolled in the randomized phase III TRIBE and TRIBE2 studies, where upfront FOLFOXIRI/bev was compared with FOLFOX or FOLFIRI/bev. Per each line, we assessed the attrition rate, treatment choices and clinical outcomes. 625 (53%), 326 (27%) and 136 (11%) patients received a systemic treatment after the 2nd, 3rd and 4th disease progression, respectively. PFS and objective response rate decreased along each line. RAS/BRAF wild-type patients received more likely a 3rd line (75%) compared with RAS (66%, p = 0.005) and BRAF (66%, p = 0.11) mutants. In 3rd line, 67% of RAS/BRAF wild-type patients received anti-EGFRs, achieving longer PFS with respect to other therapies (6.4 vs 3.9 months, p = 0.02). A trend towards longer 3rd line OS was observed in TRIBE patients (9.9 vs 7.2 months, p = 0.05). A relevant attrition rate across subsequent lines of therapy is evident, and more pronounced in RAS and BRAF mutated patients, thus highlighting the relevance of the choice of the upfront treatment. The efficacy of anti-EGFR agents among RAS/BRAF wild-type patients unexposed to anti-EGFRs is higher than other options. The reintroduction of chemotherapy remains frequent in clinical practice. Clinicaltrials. gov Identifiers NCT00719797, NCT02339116. • 53% of mCRC patients treated with upfront doublets/triplet + bev receive a 3rd line. • RAS/BRAF wild-type patients achieve more likely a 3rd line versus RAS/BRAF mutants. • In 3rd line, RAS/BRAF wild-type patients reach longer disease control with anti-EGFRs. • Regorafenib and Tas-102 show modest efficacy, and chemotherapy re-challenge is frequent. • The pronounced funnel effect in BRAF mutants endorses early blockade of BRAF + EGFR. [ABSTRACT FROM AUTHOR]

We performed a pooled analysis of TRIBE and TRIBE2 studies to assess the efficacy and safety of the intensification of upfront chemotherapy backbone – from doublets to the triplet FOLFOXIRI – in combination with bevacizumab (bev) in patients with early-onset metastatic colorectal cancer (EO-mCRC; aged <50 years) and to explore whether EO-mCRCs have a peculiar tumour genomic profiling. Subgroup analyses according to age (<50 versus ≥50 years) and treatment (FOLFOXIRI/bev versus doublets/bev) were carried out for rates of any grade and grade ≥3 (≥G3) overall and singular adverse events, progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Tumour genomic profiling was obtained using a DNA-based next-generation sequencing platform. Of 1187 patients included, 194 (16%) patients were aged <50 years. Females were more frequently diagnosed with EO-mCRC (P = 0.04). Patients aged <50 years showed a lower risk of ≥G3 neutropenia (P = 0.07), diarrhoea (P = 0.04), asthenia (P = 0.008) and a higher risk of any grade nausea (P < 0.01) and vomiting (P < 0.01). Patients receiving FOLFOXIRI/bev more frequently experienced ≥G3 chemotherapy-related adverse events respect to doublets/bev, regardless of age (P interaction = 0.60). FOLFOXIRI/bev was associated to a lower incidence of neutropenia (P = 0.04) and asthenia (P = 0.01) in patients <50 years old, than those aged ≥50 years. PFS, OS and ORR did not differ according to age (PFS P = 0.81, OS P = 0.44, ORR P = 0.50) and no interaction between age and the benefit from the intensification of upfront chemotherapy was observed (PFS P interaction = 0.72, OS P interaction = 0.54, ORR P interaction = 0.65). Genomic profiling was assessed in 296 patients, showing an enrichment of FBXW7 and POLE mutations in EO-mCRC. Upfront FOLFOXIRI/bev shows a favourable efficacy/safety balance in EO-mCRC. Clinicaltrials.gov Identifiers NCT00719797, NCT0233-9116. • Early-onset metastatic colorectal cancer (EO-mCRC) – diagnosed < 50 years – is not related to poor prognosis. • EO-mCRC does not have peculiar clinical and genomic features. • The efficacy of upfront FOLFOXIRI/bev is similar in patients aged < and ≥50 years. • FOLFOXIRI/bev is associated with a favourable safety profile in patients with EO-mCRC. [ABSTRACT FROM AUTHOR]

To unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF - mutated and microsatellite stable (MSS) metastatic colorectal cancer. In this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression. Left-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6–20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3–7.29] versus 3 [IQR, 1.26–3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07–4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02–4.81, P = 0.044). Despite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF -mutated mCRC deserves prospective validation. • Primary resistance to BRAF inhibitors in BRAF -mutated metastatic colorectal cancer (mCRC) is as high as 25%. • No established biomarkers predict primary resistance. • TMB reflects elevated intra-tumour heterogeneity in microsatellite stable (MSS) tumours. • Higher TMB is associated with primary resistance to EGFR/BRAF blockade in MSS mCRC. • Higher TMB predicts inferior PFS and OS following EGFR/BRAF blockade in MSS mCRC. [ABSTRACT FROM AUTHOR]

We performed a comprehensive genomic profiling of tumour samples from metastatic colorectal cancer (mCRC) patients enrolled in the TRIBE2 study to assess the concordance among different techniques to evaluate mismatch repair (MMR) and microsatellite instability (MSI) status, to characterize tumours according to the tumour mutational burden (TMB) and explore the clinical relevance of different TMB cutpoints, and to investigate the prevalence of alterations actionable with targeted approaches or immune checkpoint inhibitors. Tumour samples of 296 (44%) of 679 enrolled patients underwent 592-gene DNA next-generation sequencing (NGS). MMR status was assessed by immunohistochemistry (MMR-IHC), and MSI status was assessed by NGS (MSI-NGS). TMB was defined as low, intermediate, or high if <7, 7–16, or ≥17 mutations/megabase (mut/Mb) were found. The performance of TMB to predict MSI status was tested by receiver operating characteristic (ROC) curve. Actionable alterations included BRAF V600E, KRAS G12C, POLE mutations, HER2 amplification and mutations, and MSI-H. Of 216 paired cases, concordance between MMR-IHC and MSI-NGS was 98.6%. Among 11 TMB-high tumours, eight (73%) were MSI-H and three (27%) were microsatellite stable and harboured POLE or MSH6 mutations. High TMB had a trend for a better outcome than low/intermediate TMB (hazard ratio for overall survival 0.45, 95% confidence interval 0.28–1.33; P = 0.106). No interaction effect between TMB and treatment arm was observed. Seventeen mut/Mb was identified as the optimal threshold of TMB for predicting MSI status. Actionable alterations were found in 62 (21%) of 296 patients. Genomic profiling provides an overview of the genomic landscape of mCRC in a single analysis, including actionable targets and markers of immune sensitivity. • Microsatellite testing by next-generation sequencing is higly concordant with immunohistochemistry. • High tumour mutational burden (TMB) defines a clinical and molecular subtype of mCRC. • Alterations in DNA damage repair are rare in microsatellite stable mCRC with high TMB. • Potentially actionable alterations are detectable in a small percentage of mCRC. • Molecular characterisation of mCRC is helpful in adopting personalised treatments. [ABSTRACT FROM AUTHOR]

Recent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF -mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study. Clinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy. Of 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P < 0.001). Gene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment. • A restricted panel of 44 genes discerns BM1/BM2 subtypes of BRAF mut mCRC. • AXIN2 expression distinguishes LI versus LD Wnt pathway activation of BRAF mut mCRC. • No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. • No predictive effect of both BM1/BM2 and LI/LD subtypes was shown for FOLFOXIRI/bev. • ECOG-PS >0 and left-sidedness seem associated with no benefit from FOLFOXIRI/bev. [ABSTRACT FROM AUTHOR]

Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in V600E BRAF- mutated (BRAF mt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting. We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAF mt mCRCs with matched clinical and pathological information. Tumours were dichotomized as synaptophysin high and low. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier and log-rank tests. Thirty-five tumours (22.0%) showed any level of positivity for synaptophysin, and 18 (11.3%) were characterized by positivity in at least 20% of tumour cells. Four cases resulted 100% synaptophysin positive. The histotype of synaptophysin-positive tumours (i.e. ≥20%) was not otherwise specified in 11 cases (61.1%) and mucinous adenocarcinoma in 4 cases (22.2%). Four cases were DNA mismatch repair deficient (22.2%) and 7 (38.9%) were characterized by a high number of tumour-infiltrating lymphocytes. At multivariate analysis, high synaptophysin expression was a negative independent prognostic factor for both PFS (HR = 2.00, 95% confidence interval [CI] 1.21–3.33, p = 0.006) and OS (HR = 2.27, 95% CI 1.35–3.85, p = 0.001). Among BRAF mt mCRCs, synaptophysin-positive tumours are characterized by worse PFS and OS. Further studies should investigate the molecular mechanisms involved in the acquisition of the neuroendocrine phenotype to identify novel-targeted treatment strategies. • Neuroendocrine differentiation is associated with worse prognosis in several cancers. • Neuroendocrine differentiation is associated with secondary therapy resistance. • V600E BRAF colorectal cancers show high prevalence of neuroendocrine differentiation. • Synaptophysin-positive tumours are characterized by worse PFS and OS. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. • Patients with oligometastatic disease (OMD) (European Society for Medical Oncology definition) and low tumour burden (TB) have better prognosis. • The benefit from FOLFOXIRI/bev vs doublets/bev is independent of metastatic spread. • Patients with OMD are optimal candidates to an intensified upfront chemotherapy. • Locoregional treatments should be strongly considered in patients with OMD especially those with low TB. [ABSTRACT FROM AUTHOR]

RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC. AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR–based therapy; RAS mutant patients (N = 171) received anti-angiogenic–based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset. AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractory patients. AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients. • AXL, marker of epithelial to mesenchymal transition, is expressed in metastatic colorectal cancer (mCRC). • AXL is associated with poor prognosis and shorter progression-free survival in patients with RAS wild-type (WT) mCRC. • AXL is a biomarker of both primary and acquired resistance to anti-epidermal growth factor receptor therapies in RAS WT mCRC. [ABSTRACT FROM AUTHOR]

Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment. An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed. No substantial differences were reported in immunological parameters according to administered targeted agent, RAS / BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role. The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies. • Immune-tumour microenvironment (TME) influences prognosis of colorectal cancer. • 'Immunological scores' were built in resected colorectal liver metastasis after triplet and biologic. • These 'Immunological scores' affect prognosis independently of other features. • Triplet plus a biologic agent modify the immune-texture of TME. • Immune-TME should be considered for trials in the post-metastasectomy setting. [ABSTRACT FROM AUTHOR]

Background The phase III TRIBE and TRIBE2 studies randomized metastatic colorectal cancer patients to first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI or FOLFOX)/bevacizumab. The studies demonstrated a significant benefit from the triplet at the price of an increased incidence of chemotherapy-related adverse events (AEs). In both trials, males and females aged between 18 and 70 years with ECOG PS ≤2 and between 71 and 75 years with ECOG PS = 0 were eligible. We investigated the effect of FOLFOXIRI/bevacizumab versus doublets/bevacizumab according to age and gender. Patients and methods Subgroup analyses according to age (<70 versus 70–75 years) and gender were carried out for overall response rate (ORR), progression-free survival (PFS), and AE rates. Results Of 1187 patients, 1005 (85%) were aged <70 years and 182 (15%) 70–75 years; 693 (58%) were males and 494 (42%) females. There was no evidence of interaction between age or gender and the benefit provided by the intensification of the upfront chemotherapy in terms of ORR and PFS, or the increased risk of experiencing G3/4 AEs. Elderly patients and females experienced higher rates of overall G3/4 AEs (73% versus 60%, P  <   0.01 and 69% versus 57%, P  <   0.01, respectively). Notably, in the FOLFOXIRI/bevacizumab subgroup, G3/4 diarrhea and febrile neutropenia occurred in 27% and 16% of elderly patients, respectively, while females reported high incidences of any grade nausea (67%) and vomiting (50%). Conclusions The improvements in terms of ORR and PFS of FOLFOXIRI/bevacizumab versus doublets/bevacizumab are independent of gender and age, with a similar relative increase in AEs among elderly patients and females. Initial dose reductions and possibly primary G-CSF prophylaxis should be recommended for patients between 70 and 75 years old treated with FOLFOXIRI/bevacizumab, and a careful management of antiemetic prophylaxis should be considered among females. [ABSTRACT FROM AUTHOR]