Circulating microRNAs in metastatic colorectal cancer (mCRC) patients (pts) treated with regorafenib

Introduction: Regorafenib is indicated for the treatment of mCRC patients who have failed all other therapies. Nevertheless a substantial percentage of patients experiences rapid disease progression (PD) and serious adverse events may occur. For these reasons, clinical and/or molecular markers able to improve the cost/benefit ratio are urgently needed. Circulating microRNAs (c-miRNAs) have been recognized as possible prognostic and diagnostic markers in mCRC. The aim of this study was to describe the early changes in plasma levels of 10 selected c-miRNAs during the treatment with regorafenib and to investigate their correlation with clinical outcome.Methods: Plasma samples of patients treated with regorafenib at our Institution were collected at baseline (D1) and after 15 days of treatment (D15). Plasma levels of c-miR-17, c-miR-21, c-miR-29, c-miR-34, c-miR-92, c-miR-126, c-miR-141, c-miR-221, c-miR-601, c-miR-760 were analysed by means of real-time PCR. Paired levels at D1 and D15 were compared by means of Wilcoxon test for each c-miRNA. C-miRNAs showing significant changes were further analysed in order to identify possible correlations with outcome.Results: Thirty-four patients were included in the present study. Main characteristics were the following: M/F = 50%/50%; median age = 65 (range 48-78 years); ECOG-PS 0/1-2 = 71%/29%; time from diagnosis of metastases </ ? 18 months 15%/85%. Median PFS and OS were 2.4 and 6.5 months, respectively. One (3%) patient achieved a response and 16 (47%) had disease stabilization (disease control rate: 50%). As compared to D1, the following c-miRNAs increased at D15: c-miR-601 (p = 0.01), c-miR-141 (p = 0.04) and c-miR-21 (p = 0.06). Despite a median increase in the overall population, 12 (35%) out of 34 patients showed reduced level of c-miR-21 at D15. Nine out of 12 (75%) patients with reduced levels of c-miR-21 achieved disease control, as compared to 8 out of 23 (35%) patients with increased levels (Fisher \u27s Exact Test, p = 0.035). Median PFS of patients with increased and decreased level of levels of c-miR-21 were 2.1 and 3.9 months, respectively (HR = 1.89 95%CI 0.92-4.14 p = 0.08). Data on OS are not yet mature. Early modifications of c-miR-21 levels showed a sensitivity of 82% in predicting benefit from regorafenib.Conclusion: The early modulation of c-miR-21 levels may predict benefit from regorafenib in terms of disease control. These results need validation in independent series

Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO

Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status

Duration of oxaliplatin‐based adjuvant chemotherapy in patients with Stage III or high‐risk Stage II resected colon cancer

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Immune checkpoint inhibitors in pmmr metastatic colorectal cancer: A tough challenge

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of “immune-competent” TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies

Exome-wide somatic mutation characterization of small bowel adenocarcinoma

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (Al) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.Peer reviewe

Negative Hyperselection of Patients with HER2+ and RAS Wild-Type Metastatic Colorectal Cancer Receiving Dual HER2 Blockade: the PRESSING-HER2 Study

Hyperselection; Metastatic colorectal cancerHiperselección; Cáncer colorrectal metastásicoHiperselecció; Càncer colorectal metastàticPurpose: To demonstrate the negative prognostic impact of a panel of genomic alterations (PRESSING-HER2 panel) and lack of HER2 amplification by next-generation sequencing (NGS) in patients with HER2+, RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade. Experimental Design: The PRESSING-HER2 panel of HER2 mutations/rearrangements and RTK/MAPK mutations/amplifications was assessed by NGS. HER2 amplification was confirmed by NGS if copy-number variation (CNV) was ≥ 6. With a case–control design, hypothesizing 30% and 5% PRESSING-HER2 positivity in resistant [progression-free survival (PFS) <4 months and no RECIST response] versus sensitive cohorts, respectively, 35 patients were needed per group. Results: PRESSING-HER2 alterations included HER2 mutations/rearrangements, EGFR amplification, and BRAF mutations and had a prevalence of 27% (9/33) and 3% (1/35) in resistant versus sensitive patients (P = 0.005) and 63% predictive accuracy. Overall, HER2 nonamplified status by NGS had 10% prevalence. Median PFS and overall survival (OS) were worse in PRESSING-HER2+ versus negative (2.2 vs. 5.3 months, P < 0.001; 5.4 vs. 14.9 months, P = 0.001) and in HER2 nonamplified versus amplified (1.6 vs. 5.2 months, P < 0.001; 7.4 vs. 12.4 months, P = 0.157). These results were confirmed in multivariable analyses [PRESSING-HER2 positivity: PFS HR = 3.06, 95% confidence interval (CI), 1.40–6.69, P = 0.005; OS HR = 2.93, 95% CI, 1.32–6.48, P = 0.007]. Combining PRESSING-HER2 and HER2 CNV increased the predictive accuracy to 75%. Conclusions: PRESSING-HER2 panel and HER2 nonamplified status by NGS warrant validation as potential predictive markers in this setting.This study was supported by AIRC IG 23624 (to F. Pietrantonio), and by the NIH Cancer Center Core Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center