EGFR Protein Expression of KRAS Wild-Type Colorectal Cancer: Predictive Value of the Sidedness for Efficacy of Anti-EGFR Therapy.

Right- and left-sided colorectal cancers (RSCRC and LSCRC, respectively) are different developmentally, genetically and prognostically. Clinical data also indicate that they respond differently to anti-EGFR therapies. The role of EGFR protein expression in KRAS wild type colorectal cancer is also controversial. Here we have used a cohort of anti-EGFR antibody treated KRAS-wild type colorectal cancer patients (n = 97) to analyse the prognostic role of EGFR protein expression in relation to sidedness. In our cohort EGFR copy number, determined by FISH, was not associated with the level of EGFR protein, assessed by immunohistochemistry and measured by H-scoring. There was a significantly higher EGFR H-score detected in RSCRC as compared to LSCRC in primary tumors (p = 0.04). Furthermore, in a proportion of cases (n = 31) metastatic tissues were also available and their analysis also found a significantly higher EGFR H-score in metastases of RSCRC compared to LSCRC (p = 0.018). Kaplan Meyer survival analysis demonstrated that anti-EGFR antibody therapies were more effective in case of LSCRC compared to RSCRC. Although in case of progression-free survival data just indicated a trend (p = 0.065), in case of overall survival the difference was significant favouring LSCRC (p = 0.047). These data demonstrated for the first time that the EGFR protein expression is significantly higher in KRAS wild type RSLCL as compared to LSCRC. Meanwhile it is somewhat unexpected that the lower EGFR protein expression was found to be associated with better efficacy of anti-EGFR antibody therapies of colorectal cancer, the finding of which must be further validated.

Genetic progression of malignant melanoma.

Malignant melanoma of the skin is the most aggressive human cancer given that a primary tumor a few millimeters in diameter frequently has full metastatic competence. In view of that, revealing the genetic background of this potential may also help to better understand tumor dissemination in general. Genomic analyses have established the molecular classification of melanoma based on the most frequent driver oncogenic mutations (BRAF, NRAS, KIT) and have also revealed a long list of rare events, including mutations and amplifications as well as genetic microheterogeneity. At the moment, it is unclear whether any of these rare events have role in the metastasis initiation process since the major drivers do not have such a role. During lymphatic and hematogenous dissemination, the clonal selection process is evidently reflected by differences in oncogenic drivers in the metastases versus the primary tumor. Clonal selection is also evident during lymphatic progression, though the genetic background of this immunoselection is less clear. Genomic analyses of metastases identified further genetic alterations, some of which may correspond to metastasis maintenance genes. The natural genetic progression of melanoma can be modified by targeted (BRAF or MEK inhibitor) or immunotherapies. Some of the rare events in primary tumors may result in primary resistance, while further new genetic lesions develop during the acquired resistance to both targeted and immunotherapies. Only a few genetic lesions of the primary tumor are constant during natural or therapy-modulated progression. EGFR4 and NMDAR2 mutations, MITF and MET amplifications and PTEN loss can be considered as metastasis drivers. Furthermore, BRAF and MITF amplifications as well as PTEN loss are also responsible for resistance to targeted therapies, whereas NRAS mutation is the only founder genetic lesion showing any association with sensitivity to immunotherapies. Unfortunately, there are hardly any data on the possible organ-specific metastatic drivers in melanoma. These observations suggest that clinical management of melanoma patients must rely on the genetic analysis of the metastatic lesions to be able to monitor progression-associated changes and to personalize therapies.