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Re: Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer.

In a recent article in the Journal, Cappuzzo et al. (1) presented data that Akt activation, as assessed by the phosphorylation status of S473 (pAkt), was associated with sensitivity to gefitinib in patients with non–small-cell lung cancer (NSCLC). Patients whose tumors were positive for pAkt had a better response rate, “disease control rate,” and time to progression than patients whose tumors were negative for pAkt. Despite the authors’ encouraging interpretation, we believe these data are confounded by two important factors. First, the scoring for phosphorylation of Akt in immunohistochemical analysis was not consistent with published data [for example, see (2,3), references within] (1–6), and may have led to false negative interpretations of samples that actually contained active Akt. The authors’ criteria for positive staining considered only nuclear staining of S473 phosphorylation. Distribution and intensity criteria for nuclear staining were not mentioned, and it is not clear how the presence of membranous and/or cytoplasmic staining was handled. We believe that excluding tumors with positive membranous or cytoplasmic staining is inappropriate because Akt activation occurs at the plasma membrane, the location where the components involved in Akt activation are assembled. Moreover, after activation at the plasma membrane, Akt translocates through the cytoplasm to subcellular organelles, such as the nucleus or mitochondria. Therefore, the methodology used by Cappuzzo et al. (1) for scoring raises the possibility that the number of tumors with increased pAkt may have been underestimated, which could have resulted in an overestimation of the strength of the association between response rate and pAkt status. In support of potential underreporting of Akt activity, the prevalence of S473 phosphorylation in their study was lower than that reported previously in other studies that assessed S473 phosphorylation in NSCLC specimens (4–6). Of note, these other studies characterized S473 phosphorylation as being predominantly cytoplasmic. The second confounding factor in the study by Cappuzzo et al. (1) is that the authors did not mention whether patients received other therapies after gefitinib. This omission is important because their current study was originally part of a separate study evaluating EGFR and HER2 expression (7). The contribution of other therapies to the clinical endpoints including time to progression and overall survival could be substantial. Until the issues of immunohistochemical scoring and other therapies are settled, we believe that caution should be observed when interpreting the results of the study by Cappuzzo et al. (1).