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

Abstract

BackgroundFirst 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.MethodsKRAS 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.ResultsIn 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).ConclusionsMost 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.

Toxicity Syndromes, Patient-Related Clinical Indicator of Toxicity Burden Induced by Intensive Triplet Chemotherapy-Based Regimens in Gastrointestinal Cancers With Metastatic Disease

“…In the era of precision oncology, integrating molecular characterization of cancer affecting the individual patient to specifically address targeted treatments, such as in mCRC (30)(31)(32), the addition of LTS could integrate the description of cumulative toxicities, toward a precision toxicity evaluation, even to better evaluate innovative drugs as intensive combinations of multiple drugs, favoring the dissemination of innovative treatments in clinical practice.…”

Development of an AmpliSeqTM Panel for Next-Generation Sequencing of a Set of Genetic Predictors of Persisting Pain

“…Due to the costs of assay development (for details, see second paragraph of the Discussion), the Ampliseq TM panel was established in a limited number of n = 72 DNA samples. This corresponds to the number of samples used in comparable recent studies for NGS assay establishment and validation ( Bruera et al, 2018 ; De Luca et al, 2018 ; Mustafa et al, 2018 ; Shah et al, 2018 ). To further limit the project costs, the Ampliseq TM panel was established in a subset of samples originating from a clinical cohort of 1,000 women who had undergone breast cancer surgery ( Kaunisto et al, 2013 ; Lötsch et al, 2018 ).…”

Relevance of Pharmacogenomics and Multidisciplinary Management in a Young-Elderly Patient With KRAS Mutant Colorectal Cancer Treated With First-Line Aflibercept-Containing Chemotherapy

“…Because of the elderly status and secondary CIRS stage, the patient underwent adjuvant chemotherapy according to the following schedule: oxaliplatin (120 mg/m 2 ) d1, capecitabine (825 mg/m 2 bid) d1-14, cycles repeated every 21 days, for six cycles. Safety profile was characterized by LTS-ms, specifically G2 HFS associated with G2 anemia (1,4,12,13). At disease-free survival (DFS) 10 months and disease-free interval (DFI) 4 months after completion of adjuvant chemotherapy, CT scan showed bilateral lung metastases at left antero-basal (8 mm), right inferior (7 mm), and posterior-superior lobe (3 mm), confirmed by PET.…”

“…High activity correlated with 26% secondary liver resections and 15% pathologic complete response (CR) (3). Integrated multidisciplinary treatments significantly improved clinical outcome of liver-limited patients (PFS 17 months, OS 44 months), compared with other/multiple metastatic sites (O/MM) (3), not significantly affected by KRAS/NRAS/BRAF genotype (4). In non-elderly RAS wild-type patients, FIr-C/FOx-C triplet chemotherapy plus cetuximab was highly active and tolerable at recommended doses, with PFS 12 months, confirming that intensive first-line regimens increase efficacy, also by increasing secondary resection of liver metastases (5).…”