Implications of miRNA in oncology and clinical perspectives: the example of colorectal cancer

Les microARN (miARN) sont de petits ARN capables de moduler la traduction d’un ARN messager. Depuis leur découverte en 1993, leur biosynthèse, leur mécanisme d’action et les processus physiologiques et pathologiques dans lesquels ils sont impliqués ont été largement éclaircis, ce qui a conduit à évaluer leur intérêt dans plusieurs domaines dont la cancérologie. Cette revue a pour objectifs d’expliquer les mécanismes par lesquels les miARN sont impliqués dans la genèse des cancers, et d’exposer les applications cliniques potentielles de ces miARN dans la prise en charge des patients atteints de cancer, tant sur le plan diagnostique que pronostique et thérapeutique, en prenant comme exemple le cancer colorectal.MicroRNAs (miRNAs) are small RNA that can modulate translation of a messenger RNA. Since their discovery in 1993, their biosynthesis, mechanism of action and the physiological and pathological processes in which they are involved have been largely clarified, leading to evaluate their interest in several areas, including oncology. This review aims to explain the mechanisms by which miRNAs are involved in carcinogenesis and to expose the potential clinical applications of these miRNAs on the management of cancer patients, in terms of diagnosis, prognosis and treatment, using the example of colorectal cancers

Is the gene encoding Chibby implicated as a tumour suppressor in colorectal cancer ?

BACKGROUND: A novel member of the Wnt signalling pathway, Chibby, was recently identified. This protein inhibits Wnt/β-catenin mediated transcriptional activation by competing with Lef-1 (the transcription factor and target of β-catenin) to bind to β-catenin. This suggests that Chibby could be a tumour suppressor protein. The C22orf2 gene coding Chibby is located on chromosome 22, a region recurrently lost in colorectal cancer. Activation of the Wnt pathway is a major feature of colorectal cancer and occurs through inactivation of APC or activation of β-catenin. All of this led us to analyse the possible implication of Chibby in colorectal carcinogenesis. METHODS: First, 36 tumour and matched normal colonic mucosa DNA were genotyped with five microsatellite markers located on chromosome 22 to search for loss of heterozygosity. Then, mutation screening of the C22orf2 coding sequence and splice sites was performed in the 36 tumour DNA. Finally, expression of Chibby was analysed by quantitative RT-PCR on 10 patients, 4 with loss of heterozygosity (LOH) on chromosome 22. RESULTS: Loss of heterozygosity involving the C22orf2 region was detected in 11 out of 36 patients (30%). Sequencing analysis revealed a known variant, rs3747174, in exon 5: T321C leading to a silent amino acid polymorphism A107A. Allelic frequencies were 0.69 and 0.31 for T and C variants respectively. No other mutation was detected. Among the 10 patients studied, expression analysis revealed that Chibby is overexpressed in 2 tumours and underexpressed in 1. No correlations were found with 22q LOH status. CONCLUSION: As no somatic mutation was detected in C22orf2 in 36 colorectal tumour DNA, our results do not support the implication of Chibby as a tumour suppressor in colorectal carcinogenesis. This was supported by the absence of underexpression of Chibby among the tumour samples with 22q LOH. The implication of other Wnt pathway members remains to be identified to explain the part of colorectal tumours without mutation in APC and β-catenin

Review of the current status of RAS mutation testing in patients with metastatic colorectal cancer (mCRC): Flash-RAS study

Présentation PosterInternational audienceOBJECTIVES: In 2013, it was shown that mutations in KRAS exons 3 and 4, or NRAS exons 2 to 4 had a similar effect. The primary objective was to assess the practices in conducting RAS testing in 2014. The secondary objectives were to describe the evolution of the RAS testing prescription rates from 2011, the process and time required to obtain the results, and to analyze their impact on the therapeutic strategy. METHODS: FLASH-RAS is an observational retrospective French multicenter study. RESULTS: 375 mCRC patients diagnosed and initiating a 1st line treatment (L1) between March and June 2014 were analyzed. For 90.1% of the patients (IC95%= [87.1%; 93.2%]), a genotyping request for RAS biomarkers was made in L1, i.e. a significantly increased rate compared to 2011 (81.1% in 2011, p<0.001). For 75% of the patients, the request was made before or at least one month after the diagnosis of the first metastases (1st M). No increase was observed in the median and mean times to obtain the test results between 2011 and 2014 despite the increased number of exons tested. CONCLUSIONS: In 2014, the rate of RAS genotyping requests has been increasing since 2011. For a majority of patients, the request is made before or at the latest one month after 1st M diagnosis. Nevertheless, for 24.5% of the patients, the request is made more than one month after 1st M diagnosis, which is not compatible with an informed treatment decision in L1

Influence of cirrhosis on outcomes of patients with advanced intrahepatic cholangiocarcinoma receiving chemotherapy

International audienceBackground: Cirrhosis is a risk factor for intrahepatic cholangiocarcinoma (iCC). However, its exact prevalence is uncertain and its impact on the management of advanced disease is not established.Methods: Retrospective analysis of patients treated with systemic chemotherapy for advanced iCC in the 1st-line setting at 2 tertiary cancer referral centres. Cirrhosis was diagnosed based on at least one element prior to any treatment: pathological diagnosis, baseline platelets &lt;150 × 109/L, portal hypertension and/or dysmorphic liver on imaging.Results: In the cohort of patients (n = 287), 82 (28.6%) had cirrhosis (45 based on pathological diagnosis). Patients with cirrhosis experienced more grade 3/4 haematologic toxicity (44% vs 22%, respectively, P = 0.001), and more grade 3/4 non-haematologic toxicity (34% vs 14%, respectively, P = 0.001) than those without. The overall survival (OS) was significantly shorter in patients with cirrhosis: median 9.1 vs 13.1 months for those without (HR = 1.56 [95% CI: 1.19-2.05]); P = 0.002), confirmed on multivariable analysis (HR = 1.48 [95% CI: 1.04-2.60]; P = 0.028).Conclusion: Cirrhosis was relatively common in patients with advanced iCC and was associated with increased chemotherapy-induced toxicity and shorter OS. Formal assessment and consideration of cirrhosis in therapeutic management is recommended

Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study

<p>Abstract</p> <p>Background</p> <p>The anti-VEGF antibody bevacizumab associated with an irinotecan or oxaliplatin-based chemotherapy was proved to be superior to the chemotherapy alone in first or second line treatment of metastatic colorectal cancer (mCRC). However, it was reported to have no efficacy in 3^rdor later-line, alone or with 5FU. The aim of this study was to evaluate the activity of bevacizumab combined with FOLFIRI or FOLFOX in mCRC who have failed prior chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin.</p> <p>Methods</p> <p>Thirty one consecutive patients treated between May 2005 and October 2006 were included in this retrospective study. All of them have progressed under a chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin and received bevacizumab (5 mg/kg) in combination with FOLFIRI or simplified FOLFOX4 every 14 days.</p> <p>Results</p> <p>Ten patients (32.2%) had an objective response (1 CR, 9 PR) and 12 (38.8%) were stabilized. The response and disease control rates were 45.4% and 100% when bevacizumab was administered in 2^ndor 3^rdline and 25% and 55% in 4^thor later line respectively (p = 0.024 and p = 0.008). Among the patients who had previously received the same chemotherapy than that associated with bevacizumab (n = 28) the overall response rate was 35.7% and 39.3% were stabilized. Median progression free survival (PFS) and overall survival (OS) were of 9.7 and 18.4 months respectively. Except a patient who presented a hypertension associated reversible posterior leukoencephalopathy syndrome, tolerance of bevacizumab was acceptable. A rectal bleeding occurred in one patient, an epistaxis in five. Grade 1/2 hypertension occurred in five patients.</p> <p>Conclusion</p> <p>This study suggests that bevacizumab combined with FOLFOX or FOLFIRI may have the possibility to be active in chemorefractory and selected mCRC patients who did not receive it previously.</p

MRI-Based Radiomics Input for Prediction of 2-Year Disease Recurrence in Anal Squamous Cell Carcinoma

International audiencePurpose: Chemo-radiotherapy (CRT) is the standard treatment for non-metastatic anal squamous cell carcinomas (ASCC). Despite excellent results for T1-2 stages, relapses still occur in around 35% of locally advanced tumors. Recent strategies focus on treatment intensification, but could benefit from a better patient selection. Our goal was to assess the prognostic value of pre-therapeutic MRI radiomics on 2-year disease control (DC). Methods: We retrospectively selected patients with non-metastatic ASCC treated at the CHU Bordeaux and in the French FFCD0904 multicentric trial. Radiomic features were extracted from T2-weighted pre-therapeutic MRI delineated sequences. After random division between training and testing sets on a 2:1 ratio, univariate and multivariate analysis were performed on the training cohort to select optimal features. The correlation with 2-year DC was assessed using logistic regression models, with AUC and accuracy as performance gauges, and the prediction of disease-free survival using Cox regression and Kaplan-Meier analysis. Results: A total of 82 patients were randomized in the training (n = 54) and testing sets (n = 28). At 2 years, 24 patients (29%) presented relapse. In the training set, two clinical (tumor size and CRT length) and two radiomic features (FirstOrder_Entropy and GLCM_JointEnergy) were associated with disease control in univariate analysis and included in the model. The clinical model was outperformed by the mixed (clinical and radiomic) model in both the training (AUC 0.758 versus 0.825, accuracy of 75.9% versus 87%) and testing (AUC 0.714 versus 0.898, accuracy of 78.6% versus 85.7%) sets, which led to distinctive high and low risk of disease relapse groups (HR 8.60, p = 0.005). Conclusion: A mixed model with two clinical and two radiomic features was predictive of 2-year disease control after CRT and could contribute to identify high risk patients amenable to treatment intensification with view of personalized medicine

Genetic polymorphisms of MMP1, MMP3 and MMP7 gene promoter and risk of colorectal adenoma

BACKGROUND: Matrix metalloproteinases (MMP) have been shown to play a role in colorectal cancer (CRC). More recently, MMP1, MMP3 and MMP7 functional gene promoter polymorphisms have been found to be associated with CRC occurrence and prognosis. To document the role of MMP polymorphisms in the early step of colorectal carcinogenesis, we investigated their association with colorectal adenoma risk in a case-control study comprising 295 patients with large adenomas (LA), 302 patients with small adenomas (SA) and 568 polyp-free (PF) controls. METHODS: Patients were genotyped using automated fragment analysis for MMP1 -1607 ins/del G and MMP3 -1612 ins/delA (MMP3.1) polymorphisms and allelic discrimination assay for MMP3 -709 A/G (MMP3.2) and MMP7 -181 A/G polymorphisms. Association between MMP genotypes and colorectal adenomas was first tested for each polymorphism separately and then for combined genotypes using the combination test. Adjustment on relevant variables and estimation of odds ratios were performed using unconditional logistic regression. RESULTS: No association was observed between the polymorphisms and LA when compared to PF or SA. When comparing SA to PF controls, analysis revealed a significant association between MMP3 -1612 ins/delA polymorphism and SA with an increased risk associated with the 6A/6A genotype (OR = 1.67, 95%CI: 1.20–2.34). Using the combination test, the best association was found for MMP3.1-MMP1 (p = 0.001) with an OR of 1.88 (95%CI: 1.08–3.28) for the combined genotype 2G/2G-6A/6A estimated by logistic regression. CONCLUSION: These data show a relation between MMP1 -1607 ins/del G and MMP3 -1612 ins/delA combined polymorphisms and risk of SA, suggesting their potential role in the early steps of colorectal carcinogenesis

Anti-PD-1 for pretreated advanced anal carcinoma: which patients will benefit?

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