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BACKGROUND: MicroRNAs (miRs) are frequently altered in colorectal cancer (CRC) and can be used as prognostic factors. OBJECTIVE: To confirm in stage III CRC patients a reported miR signature that was associated to the presence of metastatic disease. To correlate miR expression with microsatellite instability (MSI) and mutations in RAS and BRAF. METHODS: miR-21, miR-135a, miR-206, miR-335 and miR-Let-7a expression was analyzed by RT-qPCR in 150 patients out of the 329 patients used to analyze MSI and RAS and BRAF mutations. Association with disease free survival (DFS) and overall survival (OS) was analyzed. Data was confirmed by a multivariate analysis. RESULTS: MiR-21 high expression (p= 0.034) and miR-335 low expression (p= 0.0061) were significantly associated with MSI-H. A positive trend (p= 0.0624) between miR-135a high expression and RAS mutations was found. Lower miR-21 expression levels are associated with DFS (HR = 2.654, 95% CI: 1.066–6.605, p= 0.036) and a trend with OS (HR = 2.419, 95% CI: 0.749–7.815, p= 0.140). MiR-21 high expression significantly improves DFS of the poor prognosis group (T4 or N2) (p= 0.03). CONCLUSIONS: Association of increased expression of miR-21 and better prognosis in the poor prognostic group may be of interest and could be explored in future prospective clinical trials.

Retrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy.Survival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling.Of 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15-1.48; p 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13-1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00-1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05-1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21-1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13-1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08-1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS.Considering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.

Background Patients with metastatic colorectal cancer (mCRC) and KRAS mutations have a poor prognosis, seemingly dependent on the location of the mutation. This multicenter, retrospective, cohort study assessed the frequency and prognostic value of specific KRAS mutation codon locations in mCRC patients, and survival outcomes in relation to treatment. Materials and Methods Data from mCRC patients treated in 10 Spanish hospitals between January 2011 and December 2015 were analyzed. The main objective was to investigate (1) the impact of KRAS mutation location on overall survival (OS), and (2) the effect of targeted treatment plus metastasectomy and primary tumor location on OS in patients with KRAS mutations. Results The KRAS mutation location was known for 337/2002 patients. Of these, 177 patients received chemotherapy only, 155 received bevacizumab plus chemotherapy, and 5 received anti-epidermal growth factor receptor therapy plus chemotherapy; 94 patients underwent surgery. The most frequent KRAS mutation locations were G12A (33.8%), G12D (21.4%), and G12V (21.4%). Compared with other locations, patients with a G12S mutation had the shortest median OS (10.3 [95% CI, 2.5-18.0] months). OS was longer in patients who underwent surgery versus those who did not, with a trend toward prolonged survival with bevacizumab (median OS 26.7 [95% CI, 21.8-31.7] months) versus chemotherapy alone (median OS 23.2 [95% CI, 19.4-27.0] months). Conclusion These findings confirm that KRAS mutation location may predict survival outcomes in patients with mCRC, and suggest that pre-/post-operative bevacizumab plus metastasectomy provides survival benefits in patients with KRAS mutations.

TPS3641 Background: Colorectal cancer (CRC) is one of the most commonly occurring cancers with high recurrence and mortality rate. Circulating tumor DNA (ctDNA) can be used as a marker of minimal residual disease after completion of surgical resection of stage II/III CRC, where detectable ctDNA levels (positive) post-AdCTx are associated with an increased risk of disease recurrence and novel therapies are needed. Autogene cevumeran is an investigational individualized neoantigen-specific immunotherapy that is designed to harness an immune response against patient-specific, tumor neoantigens. This clinical trial is in progress in patients with Stage II (high risk) / Stage III colorectal cancer who are ctDNA positive following resection. Methods: Autogene cevumeran is being evaluated in an open-label, Phase 2, randomized, controlled trial in patients with Stage II / III CRC patients who are ctDNA positive following resection. Patients are randomized to adjuvant therapy followed by autogene cevumeran compared to adjuvant therapy followed by watchful waiting. The primary endpoint is disease-free survival (DFS). The trial has a Biomarker Cohort of 15 patients who will receive autogene cevumeran irrespective of the ctDNA status to pursue exploratory objectives. The main study of the phase 2 trial consists of a randomized (1:1) design comparing the experimental arm (autogene cevumeran) with the observational arm (watchful waiting) in ctDNA positive CRC patients. A third Exploratory Cohort explores the efficacy and safety of autogene cevumeran in ctDNA positive CRC patients with early recurrence/relapse during or after completion of AdCTx. Patients enrolled onto the experimental group, the biomarker and exploratory cohorts will receive autogene cevumeran 6x q1w, followed by 2x q2w, followed by 7 “booster” doses q6w, to receive a total of 15 doses (dosed at 25μg). AEs are assessed according to CTCAE v5. DFS will be determined by an independent central radiology assessment. Key eligibility criteria include 1) Patients must have stage II/III rectal cancer or stage II (high risk)/III colon cancer that has been surgically resected (R0 confirmed by pathology report); 2) patients must be ctDNA positive following resection; and 3) at least 5 tumor neoantigens must be identified in the provided tumor sample for autogene cevumeran manufacturing (RNA lipoplex, RNA-LPX). ClinicalTrials.gov identifier: NCT04486378.