Treating metastatic colorectal cancer (mCRC) is becoming increasingly challenging especially after the development of new therapeutic agents targeting Epidermal Growth Factor Receptor (EGFR) and angiogenesis. Cetuximab and panitumumab, the monoclonal antibodies that bind to the extracellular domain of the EGFR, have shown efficacy both as monotherapy and in combination with chemotherapy in patients withKRASwild-type mCRC.KRAS is part of the intracellular pathway RAS/RAF/MAPK and mutation of this oncogene constitutively activates the RAS/RAF pathway independent from EGFR activation by binding of the ligand,
Nevertheless, only 50% of patients withKRASwild-type tumours will respond to anti-EGFR therapy.BRAForPIK3CAmutation, loss ofPTENexpression, discordance in mutation status between primary and metastatic site, according to the early dissemination model, or intratumoral heterogeneity may be further explanations for this limited action of anti-EGFR antibodies.
Current data concerning the concordance of mutations in primary CRC and metastases are conflicting and this may attributed to the relative low number of paired cases leading to underpowered studies, the comparison of different metastatic sites (lymph nodes, liver and lung) with the primary tumor and technical issues concerningKRASanalysis,
In the study of Knijn et al., investigators have tried to highlight this issue comparing the mutation status in the primary tumor with the liver metastases in 305 mCRC patients who underwent surgical resection of the primary tumor and biopsy or surgical resection of the corresponding liver metastasis.KRASmutation was detected in 108 out of 305 primary tumours (35.4%). In 11 cases (3.6%), discordance between primary tumour and metastasis was found: 5 primary tumours had aKRASmutation with a wild-type metastasis, 1 primary tumour was wild type with aKRASmutation in the metastasis, and in 5 cases the primary tumour and the metastasis had a differentKRASmutation. This means a high concordance ofKRASmutation status of 96.4% (95% CI 93.6–98.2%) between primary colorectal tumours and their corresponding liver metastases while in only six patients (2.0%; 95% CI 0.7–4.2%), the discordance was clinically relevant.
Authors indicate this is the first adequately powered study in CRC that comparesKRASmutation status between primary tumours and their corresponding liver metastases and that both tissue of primary tumour or liver metastasis may be used forKRASmutation analysis. It is also important to emphasize that lymph node metastases are not suitable to determineKRASmutation status due to the high discordance rate reaching 30%, confirmed in this study as well.
Finally, we should try to identify other predictive markers to account for the failure of anti-EGFR therapy in patients withKRASwild-type tumors. In this context it would be interesting to further exploreBRAFandPIK3CAmutation status in primary and metastatic sites once the existing studies seem to be underpowered due to the small number of paired cases.