Challenging chemoresistant metastatic colorectal cancer: Therapeutic strategies from the clinic and from the laboratory

As survival has improved for patients with metastatic colorectal cancer (mCRC), there is an increasing need for effective and well-tolerated third-line and subsequent-lines of treatment. Despite recent advances with the development of new-targeted therapies in this setting, there remains an unmet need to exploit oncogenic drivers of colorectal cancer and overcome acquired resistance. Potential treatment strategies include revisiting old targets such as human epidermal growth factor receptor 2, RAS, and BRAF and investigating new targets such as c-MET, the PI3 kinase, and Wnt pathways, and also the use of immune-checkpoint inhibitors. Here, we review recent phase III trials exploring approved agents, early trials investigating new drugs for chemorefractory mCRC, and the potential of capturing tumour dynamics during its evolution by liquid biopsy analysis

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

Objective: Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients. Methods: With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival). Results: No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1). Conclusion: Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens

Reply: KRAS status analysis and anti-EGFR therapies: is comprehensiveness a biologist's fancy or a clinical necessity?

We thank Dr Lopez-Crapez et al 2010 to have taken cue fro

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

Pharmacokinetics, a main actor in a many-sided approach to severe 5-FU toxicity prediction

Based on this clinical experience, we detail the principles that should guide the decision-making process regarding the prevention of 5-FU severe toxicity and propose a diagnostic algorithm in order to screen candidate patients to fluoropyrimidine therapy. In the suggested diagnostic algorithm, the predictive 5-FU test dose could be regarded as a triage test, allowing detection of the fraction of patients with normal, impaired or absent fluoropyrimidine metabolism. Other analyses, such as DPD genotyping or even DPD PBMC activity, could be used later as add-on tests and, limited to the still undiagnosed subgroup, to detect those degrees of enzyme activity impairment suitable for possible reduction of 5-FU dose or different treatments. Overall, the published data strongly suggest the use of a diagnostic algorithm based on the sequential application of a 5-FU pharmacokinetic test followed by DPD genotyping and activity in order to make a highly probable diagnosis of altered 5-FU metabolism. Moreover, the application of this model could result in a consistent reduction of costs and morbidity, by limiting genotyping and PBMC DPD activity analysis to only selected subgroups of patients

Molecular and pathological characterization of the EZH2 rs3757441 single nucleotide polymorphism in colorectal cancer

Background The enhancer of zeste-homolog 2 (EZH2) is involved in cancer development through gene silencing by trimethylation of lysine 27 of histone 3 (H3K27me3). The C/C genotype for the EZH2 rs3757441 single-nucleotide polymorphism (SNP) is linked with poor prognosis in metastatic colorectal cancer (CRC), but molecular and pathological characterization of this SNP is lacking. Methods 119 primary CRCs were analyzed. SNP was evaluated by real-time PCR from colonic healthy tissue, while EZH2 and H3K27me3 expression were studied by immunohistochemistry. We primarily looked for correlation between EZH2 rs3757441 genotypes and EZH2/H3K27me3 expression. Potential associations between EZH2/H3K27me3 expression and clinico-pathological features or KRAS exon 2 and BRAF exon 15 mutations were secondary endpoints. Statistical analysis was performed by chi-square test, T-test or ANOVA. Results The C/C genotype was significantly associated with higher EZH2 (100 vs. 44 %; P = 0.019) and H3K27me3 (100 vs. 38 %; P = 0.009) staining intensity compared with C/T and T/T. EZH2 3+ staining significantly correlated with stronger H3K27me3 expression (P = 0.039). KRAS and BRAF mutations were not associated with EZH2 or H3K27me3 expression. Conclusion EZH2 rs3757441 C/C genotype is associated with stronger EZH2 and H3K27me3 immunoreactivity in primary CRC: this SNP may serve as a promising biomarker for EZH2-targeting agents and may add independent information to KRAS and BRAF testing

Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer

BACKGROUND: The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC). METHODS: Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF: -2578A/C, -1498C/T, -1154A/G, -634C/G and 936C/T; and VEGFR-2: -604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients. RESULTS: Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found. CONCLUSION: Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies

Dicer and Drosha expression and response to Bevacizumab-based therapy in advanced colorectal cancer patients

PURPOSE: The miRNA-regulating enzymes Dicer and Drosha exhibit aberrant expression in several cancer types. Dicer and Drosha play a crucial role during the angiogenetic process in vitro and, for Dicer, in vivo. We aimed to investigate the potential role of Dicer and Drosha in predicting response to Bevacizumab-based therapy in advanced colorectal cancer (CRC) patients. METHODS: Dicer and Drosha mRNA levels were analysed in formalin-fixed paraffin-embedded specimens from patients affected by advanced CRC treated with or without Bevacizumab-containing regimens (n=116 and n=50, respectively) and from patients with diverticulosis as control group (n=20). The experimental data were obtained using qRT-PCR, analysed comparing Dicer and Drosha expression levels in tumour samples versus normal mucosa and then compared to clinical outcome. RESULTS: The tumour samples from Bevacizumab-treated patients showed a significantly higher Drosha expression (P<.001) versus normal mucosa, while Dicer levels did not differ. Intriguingly, we found that low Dicer levels predicted a longer progression-free survival (PFS) (P<.0001) and overall survival (OS) (P=.009). In addition, low Dicer levels were associated with better response to Bevacizumab-based treatments versus high Dicer levels (1.7% complete responses and 53.4% partial responses versus 0% and 32.7%, respectively; P=.0067). Multivariate analysis identified three independent predictors of improved OS: high performance status (PS) (relative risk (RR) 1.45; P=.011), lower organs involvement (RR 0.79; P=.034) and low Dicer expression (RR 0.71; P=.008). Conversely, Drosha levels were not associated with prognosis and outcome associated with treatment. In non-Bevacizumab-treated patients, Dicer and Drosha expression did not correlate with outcome. CONCLUSION: These findings suggest that low Dicer mRNA levels seem to be independent predictors of favourable outcome and response in patients affected by advanced CRCs treated with Bevacizumab-based therapy