Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial
A partir d'échantillons tumoraux prélevés sur 182 patients atteints d'un cancer colorectal métastatique et inclus dans un essai d'évaluation d'un traitement de première ligne combinant cétuximab et une chimiothérapie FOLFIRI, cette étude met en évidence une hétérogénéité de la présence de mutations des gènes KRAS, NRAS, BRAF et PIK3CA
Background : Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intra-tumor heterogeneity. We performed a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications. Patients and Methods : Tumor samples (n.182) from the CAPRI-GOIM trial of first-line cetuximab+FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation. Results : The KRAS HS ranged between 12 and 260 with mean value of 87,1 and median value of 84,4, suggesting that in most CRC the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35,5-146,7; mean 102,8; median 117,1). In contrast, in BRAF (HS range 17,1-120; mean 54,8; median 54,3) and PIK3CA (HS range 14,3-120; mean 59,5; median 47,3) mutant cases only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS<33 (low-KRAS; n.10) and 45,7% in KRAS HS>33 patients (high-KRAS; n.35); median progression free survival (PFS) were 7,97 and 8,37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA as compared with high-KRAS (6/10 vs 8/35). Conclusions : KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load.
Annals of Oncology 2015