FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer

Loupakis, Fotios; Cremolini, Chiara; Salvatore, Lisa; Masi, Gianluca; Sensi, Elisa; Schirripa, Marta; Michelucci, Angela; Pfanner, E.; Brunetti, I.; Lupi, Cristiana; Antoniotti, Carlotta; Bergamo, Francesca; Lonardi, Sara; Zagonel, Vittorina; Simi, Paolo; Fontanini, Gabriella; Falcone, Alfredo

doi:10.1016/j.ejca.2013.08.024

Cited by 168 publications

(122 citation statements)

References 21 publications

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“…These malignancies represent, at present, a real clinical challenge as they are insensitive to both traditional chemotherapeutics and new anti-EGFR agents (44). Although recent findings suggest that only the combination of a triple chemotherapy regimen (i.e., 5-fluorouracil, irinotecan, and oxaliplatin) with the anti-VEGF agent, bevacizumab, may affect the progression of BRAF-mutated metastatic colorectal carcinomas (45), our data provide a strong rationale for the evaluation of TRAP1-targeting agents in these tumors.…”

Section: Discussionmentioning

confidence: 99%

TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors

et al. 2014

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Human BRAF-driven tumors are aggressive malignancies with poor clinical outcome and lack of sensitivity to therapies. TRAP1 is a HSP90 molecular chaperone deregulated in human tumors and responsible for specific features of cancer cells, i.e., protection from apoptosis, drug resistance, metabolic regulation, and protein quality control/ubiquitination. The hypothesis that TRAP1 plays a regulatory function on the BRAF pathway, arising from the observation that BRAF levels are decreased upon TRAP1 interference, was tested in human breast and colorectal carcinoma in vitro and in vivo. This study shows that TRAP1 is involved in the regulation of BRAF synthesis/ubiquitination, without affecting its stability. Indeed, BRAF synthesis is facilitated in a TRAP1-rich background, whereas increased ubiquitination occurs upon disruption of the TRAP1 network that correlates with decreased protein levels. Remarkably, BRAF downstream pathway is modulated by TRAP1 regulatory activity: indeed, TRAP1 silencing induces (i) ERK phosphorylation attenuation, (ii) cell-cycle inhibition with cell accumulation in G 0 -G 1 and G 2 -M transitions, and (iii) extensive reprogramming of gene expression. Interestingly, a genome-wide profiling of TRAP1-knockdown cells identified cell growth and cell-cycle regulation as the most significant biofunctions controlled by the TRAP1 network. It is worth noting that TRAP1 regulation on BRAF is conserved in human colorectal carcinomas, with the two proteins being frequently coexpressed. Finally, the dual HSP90/TRAP1 inhibitor HSP990 showed activity against the TRAP1 network and high cytostatic potential in BRAF-mutated colorectal carcinoma cells. Therefore, this novel TRAP1 function represents an attractive therapeutic window to target dependency of BRAF-driven tumors on TRAP1 translational/quality control machinery. Cancer Res; 74(22); 6693-704. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors

et al. 2014

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“…The risk of neutropenia was certainly lower based on the favourable clinical characteristics of patients. Moreover, the absence of significant neutropenia is typical of our COI regimen, since capecitabine has a lower myelotoxicity than 5-FU and is given for only 5 consecutive days [18].…”

Section: Discussionmentioning

confidence: 99%

“…Initially, triplet chemotherapy with FOLFOXIRI plus bevacizumab gained popularity as conversion strategy in potentially resectable CRC liver metastases [17] or in selected, poor-prognosis patient populations, such as those with BRAF-mutated tumours [18]. However, this strategy of upfront treatment intensification was recently established as a palliative treatment option due to improvement of patients' survival [4].…”

Section: Discussionmentioning

confidence: 99%

DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

Falvella

Cheli

Martinetti

et al. 2015

Brit J Clinical Pharma

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AIMSTriplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations. METHODSGermline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3-4 AEs. RESULTSNone of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pharmacogenetic testing of DPYD and UGT1A1 is recommended in clinical practice prior to administration of fluoropyrimidines and irinotecan, respectively. respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3-4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c

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“…Quellen: [1060,1117] Konsens Hintergrund Eine BRAF-V600-Mutation wird bei 8 -12 % der mKRK-Patienten beobachtet. Häufiger sind Frauen betroffen, das Erkankungsalter ist meist höher.…”

Section: Level Of Evidenceunclassified

S3-Leitlinie – Kolorektales Karzinom

Schmiegel

Buchberger

Follmann³

et al. 2017

Z Gastroenterol

147

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FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer

Cited by 168 publications

References 21 publications

TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors

TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors

DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan

S3-Leitlinie – Kolorektales Karzinom

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