© 2004 by Oxford University Press
© 2004 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Akt Phosphorylation and Gefitinib Efficacy in Patients With Advanced Non–Small-Cell Lung Cancer
Correspondence to: Federico Cappuzzo, MD, Division of Medical Oncology, Bellaria-Maggiore Hospital, Oncology Department, Via Altura 3, Bologna, 40139, Italy (federico.cappuzzo{at}ausl.bo.it)
In their letter, Tsurutani and Dennis identify two possible confounding factors (scoring system used for phospho-Akt analysis and therapies given after gefitinib treatment) that they suggest could impact our results regarding Akt phosphorylation in non–small-cell lung cancer (NSCLC) in patients treated with gefitinib (1).
When we analyzed our specimens for phospho-Akt, we observed nuclear, cytoplasmic, and membrane staining. Because of the absence of any validated scoring system, in our initial analysis we adopted the same scoring criteria for phospho-MAPK and phospho-Akt, and we considered samples that had at least a moderate stain (2+) in more than 10% of cells, regardless of staining localization, as positive. Because Akt activation results in its nuclear translocation (2), we decided to take into account only nuclear staining. Importantly, when we analyzed the data for subsets of patients categorized by staining patterns (i.e., nuclear versus extranuclear versus nuclear plus extranuclear), we did not find any statistically significant differences among the patient groups because exclusive nuclear or extranuclear localization rarely occurred. Therefore, we believe that our findings do not underestimate the number of tumors with activated Akt. Moreover, in our study, activated Akt was observed in 49.5% of patients, which is less than the 67% reported by Lee et al. (3) but is similar to the 53% reported by Mukohara et al. (4), who used a scoring system that considered specimens with moderate staining (2+) in more than 5% of cells as positive.
The possibility that therapies given after gefitinib could interfere with our results is unlikely. I agree that additional therapies could affect survival, but unless other treatments are given concomitantly, they cannot interfere with the time to progression. As we clearly indicated, our cohort consisted of only those patients who were not suited to receive standard therapies because they werepretreated or had medical conditions contraindicating chemotherapy. These patients did not receive chemotherapy or any other antineoplastic drug concomitantly with gefitinib, and the only treatment proposed after gefitinib failed was best supportive care.
In conclusion, we believe that our results do not overestimate the impact of Akt phosphorylation in response to gefitinib therapy, and that no confounding factor, such as other treatments, affected any of the study end points.
REFERENCES
1 Cappuzzo F, Magrini E, Ceresoli GL, Bartolini S, Rossi E, Ludovini V, et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non–small-cell lung cancer. J Natl Cancer Inst1 2004;96: 1133–41.
2 Meier R, Alessi DR, Cron P, Andjelkovic M, Hemmings BA. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. J Biol Chem 1997;272:30491–7.
3 Lee SH, Kim HS, Park WS, Kim SY, Lee KY, Kim SH, et al. Non-small cell lung cancers frequently express phosphorylated Akt; an immunohistochemical study. Apmis 2002;110:587–92.[CrossRef][ISI][Medline]
4 Mukohara T, Kudoh S, Yamauchi S, Kimura T, Yoshimura N, Kanazawa H, et al. Expression of epidermal growth factor receptor (EGFR) and downstream-activated peptides in surgically excised non-small-cell lung cancer (NSCLC). Lung Cancer 2003;41:123–30.[ISI][Medline]
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J Natl Cancer Inst 2004 96: 1795.
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