Research Papers:

KRAS, NRAS and BRAF mutations detected by next generation sequencing, and differential clinical outcome in metastatic colorectal cancer (MCRC) patients treated with first line FIr-B/FOx adding bevacizumab (BEV) to triplet chemotherapy

Gemma Bruera, Francesco Pepe, Umberto Malapelle, Pasquale Pisapia, Antonella Dal Mas, Daniela Di Giacomo, Giuseppe Calvisi, Giancarlo Troncone and Enrico Ricevuto _

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Oncotarget. 2018; 9:26279-26290. https://doi.org/10.18632/oncotarget.25180

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Gemma Bruera1,2,*, Francesco Pepe3,*, Umberto Malapelle3, Pasquale Pisapia3, Antonella Dal Mas4, Daniela Di Giacomo1,2, Giuseppe Calvisi4, Giancarlo Troncone3 and Enrico Ricevuto1,2

1Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy

2Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

3Department of Public Health, University Federico II, Napoli, Italy

4Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy

*These authors equally contributed to this work

Correspondence to:

Enrico Ricevuto, email: [email protected]

Keywords: FIr-B/FOx intensive first line triplet chemotherapy plus bevacizumab; metastatic colorectal cancer; next generation sequencing; RAS/BRAF mutations; 50 genes panel

Received: October 06, 2017     Accepted: April 05, 2018     Published: May 29, 2018


Background: First line triplet chemotherapy/BEV significantly improved clinical outcome of MCRC. KRAS/NRAS/BRAF mutations were evaluated by next generation sequencing (NGS) in MCRC patients treated with first line FIr-B/FOx.

Methods: KRAS exons 2-4 (KRAS2-4), NRAS2-4, BRAF15 were evaluated in 67 tumours by ION Torrent platform. Mutation detection criteria: >500×sequence coverage (cov); >1% mutant allelic fraction (AF). Clinical outcomes were compared by log-rank.

Results: In 63 samples, KRAS2-4/NRAS2-4/BRAF15 wild-type (wt) were 14 (22.2%), mutant (mut) 49 (77.8%): KRAS2-4 42 (66.7%); NRAS2-4 11 (16.4%); BRAF15 5 (7.5%). Sixty mutations were detected, range 1-3 mut: 43 (71.7%) >1000×cov/>5% AF; 9 (15%) >500×cov/>5% AF; 8 (13.3%) >1000×cov/<5% AF. Mut distribution in KRAS2-4/NRAS2-4/BRAF15: 40 (63.5%) >1000×cov/>5% AF, 8 (12.7%) >500×cov/>5% AF, 1 (1.6%) >1000×cov/<5% AF; BRAF15 1 (1.5%) >500×cov/>5% AF, 4 (6%) >1000×cov/<5% AF. Prevalence of ≥2 mut samples: KRAS2-4/NRAS2-4/BRAF15 8 (12.7%); KRAS2-4 7 (11.1%); NRAS2-4 5 (7.5%). BRAF15 mutant were all ≥2 mut (7.5%), atypical and associated to KRAS and/or NRAS mut: c.1405 G>A; c.1406 G>C; c.1756 G>A, 2 samples; c.1796 C>T. At 21 months (m) follow-up, clinical outcome wt compared to mut was not significantly different: in KRAS2-4/NRAS2-4/BRAF15, progression-free survival (PFS) 18/12 m, overall survival (OS) 28/22 m; 1/≥2 mutations, PFS 14/11, OS 37/22. PFS was trendy worse in RAS/BRAF wt vs ≥2 mut genes (P 0.059).

Conclusions: Most MCRC harboured KRAS2-4/NRAS2-4/BRAF15 mutations by NGS, often multiple and affecting few tumoral clones; 22% were triple wt. Clinical outcome is not significantly affected by KRAS2-4/NRAS2-4/BRAF15 genotype, trendy different in triple wt, compared with KRAS2-4/NRAS2-4/BRAF15 ≥2 mut.

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