Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study

Abstract

Background We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). Patients and methods VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF / PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m 2 then 250 mg/m 2 weekly) plus FOLFIRI [irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 , 5-fluorouracil 400 mg/m 2 (bolus) then 2400 mg/m 2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. Results Two hundred and forty patients with BRAF / PIK3CA wild-type ( n = 196) or BRAF- and/or PIK3CA- mutated tumours ( n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF / PIK3CA wild-type and BRAF / PIK3CA -mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA -mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF / PI3KCA -mutated ( n = 8), BRAF -mutated/ PI3KCA wild-type ( n = 16) and BRAF wild-type/ PI3KCA -mutated ( n = 20) tumours, respectively ( P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF / PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF / PIK3C A-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. Conclusions BRAF ...

Prognostic value of gender and primary tumor location in metastatic colon cancer

“…Concerning sidedness, our findings emphasize the poor outcome of patients with RCC, compared to those with LCC, as reported in several clinical studies 4 - 6 . The aggressive behavior of RCC has been attributed to a higher occurrence of BRAF mutations 37 , PIK3CA mutations 38 - 40 or CpG island methylation phenotype (CIMP) 41 - 43 , all factors associated with shorter survival 44 - 47 . However, thus far, no study has focused on sex disparities relative to RCC.…”

Targeted Treatment against Cancer Stem Cells in Colorectal Cancer

“…In multivariate analysis, patients with a PIK3A mutation and LGR5 expression had poor outcomes for both DFS and OS [ 58 ]. PI3KCA mutations are present in 13% of mCRC cases and are associated with right-sided tumors, older patients, and poor prognosis [ 58 , 59 , 60 ].…”

BRAF Mutations in Colorectal Liver Metastases: Prognostic Implications and Potential Therapeutic Strategies

“…Compared to mFOLFOXIRI alone, mFOLFOXIRI combined with bevacizumab increased the incidence of clinical NED and tended to improve survival. In another study (Visnu-2), which was a multicenter, randomized, phase II study [ 63 ], investigators studied the effect of BRAF and PIK3CA mutation status on first-line treatment with bevacizumab or cetuximab in combination with 5-fluorouracil/calcium folate and irinotecan (FOLFIRI) in patients with RAS wild-type mCRC. The findings suggested that BRAF/PIK3CA status affects the outcomes of patients with RAS wild-type mCRC, but does not appear to contribute to the selection of first-line targeted therapy.…”