Is FISH floating or still swimming in the lung cancer ocean?

editorial Is FISH floating or still swimming in the lung cancer ocean? The epidermal growth factor receptor (EGFR) is a crucial factor in the development and growth of several human malignancies, including non-small-cell lung cancer (NSCLC). The main strategies aimed at inhibiting the EGFR pathway include agents directed against the extracellular domain of the receptor, such as monoclonal antibodies, and small molecules interfering with the tyrosine kinase activity of the intracellular domain, the tyrosine kinase inhibitors (TKIs). From the first clinical studies, it became clear that both strategies only seemed effective in a fraction of NSCLC patients, highlighting the need for patient preselection if these agents were to be optimally used. While no reliable biomarker has been yet identified for anti-EGFR monoclonal antibodies [1, 2], the presence of activating EGFR mutations and increased EGFR gene copy number detected by FISH emerged early on as the two most relevant predictors for EGFR-TKI sensitivity [3–5]. Potentially predictive biomarkers may predict for a higher likelihood of response, longer survival from the treatment, or both. Dahabreh and collaborators [6, 7] have recently published two meta-analyses on this subject. When analyzing the predictive value of EGFR mutation and copy number gain (CNG) for response to EGFR-TKIs, the authors concluded that EGFR mutation testing was both more sensitive and more specific than CNG [6]. In the current issue, these authors presented the first meta-analysis exploring the role of EGFR– CNG as a predictor of survival in NSCLC patients treated with EGFR-TKIs [7]. All patients were treated with the EGFR-TKIs erlotinib or gefitinib as monotherapy. EGFR CNG was evaluated using different methods and with different scoring systems, with the majority using FISH and the Colorado Classification System [5, 8]. Overall survival (OS), the primary end point of the study, was significantly associated with EGFR CNG as was progression-free survival (PFS) and time to progression. The association with survival benefit was detected in studies dominated by Caucasian patients but not in those dominated by East Asian patients. Taken at face value, the work of Dahabreh et al. concluded for evidence that the EGFR FISH is still swimming along smoothly as a predictive biomarker of OS from TKIs, especially in Caucasian populations. Yet the field of EGFR biomarkers in NSCLC has evolved significantly since many of the studies in these meta-analyses were conducted. EGFR mutations have recently emerged as the most dominant marker of benefit from EGFR-TKIs. We also …