Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05

L’objectif de ce travail était la recherche de biomarqueurs moléculaires prédictifs de la tolérance et de l’efficacité des chimio– thérapies utilisées dans le colorectal (CCR) métastatique. Nous avons effectué le génotypage de 20 polymorphismes présents au sein de 9 gènes connus ou suspectés d’être impliqués dans la voie du 5FU, de l’oxaliplatine, ou de l’irinotécan, à partir de l’ADN extrait du sang de 346 patients traités dans le cadre d’un essai de phase III. Cet essai comparait une chimiothérapie séquentielle par 5FU (schéma LV5FU2) suivie d’une association 5FU plus oxali– platine (schéma FOLFOX) à une chimiothérapie combinée de type FOLFOX d’emblée en première ligne de traitement. Nous avons trouvé un risque de toxicité hématologique sévère sous FOLFOX significativement augmenté chez les patients porteurs de l’allèle ERCC2-K751QC. La présence de l’allèle TS-5’UTR3RG du gène de la thymidylate synthase était associée à un taux de réponse significativement plus élevé sous LV5FU2. Le taux de réponse au FOLFOX en 2e ligne était significativement supérieur chez les patients porteurs de l’allèle ERCC1-IVS3+74G, et chez ceux ayant au moins un allèle de GSTT1 présent. L’analyse prédictive a montré un effet dépendant du traitement de certains polymorphismes. En effet, une survie sans progression significativement allongée par l’ajout de l’oxaliplatine en 1re ligne a été observée uniquement chez les patients ayant un génotype TS-5’UTR2R/2R ou 2R/3R, suggérant l’absence de bénéfice d’une bithérapie par FOLFOX d’emblée en première ligne chez les patients TS-5’UTR3R/3R. Ces résultats montrent que l’étude des polymorphismes constitutionnels permettent de prédire non seulement la toxicité mais aussi l’efficacité des chimiothérapies antitumorales du cancer colorectal, et ainsi (sous réserve d’une validation sur une population indépendante) d’orienter la stratégie thérapeutique à l’échelle de l’individu

UDP-glucuronosyltransferase UGT1A7 genetic polymorphisms in hepatocellular carcinoma: a differential impact according to seropositivity of HBV or HCV markers?

<p>Abstract</p> <p>Background:</p> <p>We conducted a case-control study to evaluate the role of UDP-glucuronosyltransferase 1A7 (UGT1A7) polymorphisms in the onset of hepatocellular carcinoma (HCC).</p> <p>Methods:</p> <p>The study included 165 patients with HCC, 134 with cirrhosis and 142 controls without liver disease, matched for age and hospital. All were men younger than 75 years. HCC and cirrhosis patients were stratified according to time since cirrhosis diagnosis.</p> <p>Results:</p> <p>We found a positive association between the UGT1A7*3/*3 genotype and HCC when the comparison was restricted to patients whose disease was of viral origin [OR = 3.4 (0.3–45)] but a negative association when it included only alcoholic patients [OR = 0.1 (0.02–0.6), p = 0.01].</p> <p>Conclusion:</p> <p>Our study shows that UGT1A7 may play a role in hepatocellular carcinogenesis and that this role may differ according to the primary cause of the cirrhosis.</p

Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients

BACKGROUND: RAS mutations have been shown to confer resistance to anti-EGFR treatment. We analyzed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. METHODS: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumors harboring RAS & BRAF WT and RAS mutations. The prognostic value of each individual mutation was also tested. RESULTS: Among the 2559 pts analyzed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2,3,4 or NRAS exon 2,3,4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS & BRAF WT tumors (HR 0.77 to 1.03, all P>0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. CONCLUSION: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favor of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting.Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores

MicroRNA Related Polymorphisms and Breast Cancer Risk

Peer reviewe

Formation des internes en Médecine de la douleur et Médecine palliative : bilan des étudiants

International audienc

Evaluation of the specialits training in palliative medecine : the students weigh

International audienc