Molecular testing in lung carcinoma: Quo vadis?

The development of molecular targeted therapies with small-molecule inhibitors of the epidermal growth factor receptor (EGFR) has resulted in new therapeutic options for patients with advanced stage lung cancer. Certain clinical characteristics have been associated with an increased likelihood of response to EGFR tyrosine kinase inhibitors (TKIs; women, never smokers, East Asian ethnicity, and adenocarci-noma histology). Furthermore, several molecular events can also affect the efficacy of these therapies. Activating mutations in EGFR exons 18 through 21 (insert deletions in exon 19 and the single L858R point mutation in exon 21 being the most common) seem to be more reliable predictors of response than clinical features and are associated with increased response and survival after TKI therapy. 1-3 In contrast, K-ras mutations , insertion mutations or T790M point mutations in exon 20 of EGFR, and MET amplification are negative predictors of response. 4-6 These observations have resulted in numerous retrospective studies that correlate patient response to the molecular profile of lung adenocarcinomas. Unfortunately, different methodological approaches have been used for EGFR assessment, including DNA mutational analysis, fluo-rescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) for gene copy number changes, and immunohistochemical analysis for protein expression. Not surprisingly, reported results are inconsistent, reflecting the lack of standardization of the method and interpretation criteria. In general, EGFR FISH and DNA mutation analyses are the 2 most extensively studied methods for selection of candidates for EGFR TKI therapy. There is a large body of literature addressing the issue of usefulness of EGFR FISH or CISH in the selection of patients for EGFR TKI therapy. 7-9 Most of the confusion about the best choice between EGFR FISH or mutation arose from the observation that EGFR mutations are frequently associated with increased EGFR gene copy numbers. Cappuzzo et al 7 demonstrated that 33% of cases interpreted as FISH+ had a higher response rate to gefitinib (36%) than FISH– cases (3%) and that there was a longer median survival (18.7 vs 7.0 months). Within the same cohort, 17% of cases were positive for the EGFR mutation, which was associated with a response rate of 53%, compared with 5% in wild-type cases. 7 In contrast , in FISH studies in East Asian patients with non–small cell lung cancer (NSCLC) treated with EGFR TKIs, 41% of patients were FISH+, but FISH positivity was not associated with survival benefit, suggesting a difference between Asian and Caucasian ethnicity. …