Affiliations of authors: Divisions of Medical Oncology (FDB, TDP, GC, CN), Pathology (GP), and Thoracic Surgery (LS, GV), European Institute of Oncology, Milan, Italy
Correspondence to: Filippo de Braud, MD, Clinical Pharmacology and New Drugs Development Unit, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy (e-mail: Filippo.debraud{at}ieo.it).
We found the study by Cappuzzo et al. (1) to be very interesting, and we congratulate the authors on conducting this important clinical trial, which identified factors that were predictive of response to gefitinib. Cappuzzo et al. (1) designed the trial to assess the possible association between activation of epidermal growth factor receptor (EGFR) pathway downstream signaling components MAPK and Akt and response to gefitinib in patients with nonsmall-cell lung cancer (NSCLC).
Every year, more than 1 million patients are diagnosed with NSCLC worldwide. Most of the patients will be not curable by surgery. Consequently, even if a small percentage of patients would benefit from a targeted agent such as gefitinib, it would have a major impact on care. However, the best strategy for selecting patients who will respond to gefitinib is unclear.
The EGFR tyrosine kinase is still the only recognized target for gefitinib. However, the downstream components MAPK and Akt are activated in response to EGFR and to many other receptors. We believe that EGFR expression should always be analyzed initially as a factor that is predictive of response to an agent targeting EGFR. Indeed, some somatically acquired mutations in the EGFR gene are strongly associated with clinical responsiveness to gefitinib (2,3). For example, preliminary data from a mutation analysis of bronchioalveolar carcinoma (BAC)/adenocarcinoma tumors from patients enrolled in the SWOG 0126 trial showed that 43% of 14 patients had an EGFR mutation in exon 18, 19, or 21 (4). The BAC histotype was associated with gefitinib sensitivity.
An analysis of the relationship between EGFR mutations and activation of the downstream components should then clarify whether activation of MAPK and/or Akt is an independent factor that can increase the predictive value of EGFR mutations or whether activation of MAPK and/or Akt is just a less specific marker of a subgroup of gefitinib-responsive patients already selected by the analysis of EGFR itself. Thus, we are concerned about the missing data on lack of analysis of EGFR expression in the study by Cappuzzo et al. (1).
We are also concerned about the timing of the assessment for EGFR expression and MAPK and Akt activation in Cappuzzo et al. (1). It appears that most of the specimens were collected at the time of primary diagnosis, and that patients were treated with gefitinib after having received chemotherapy. We have found (5) that chemotherapy can induce EGFR expression in some patients with EGFR-negative tumors. In this analysis, we evaluated EGFR expression on mediastinal lymph nodes and/or primary tumors before and after chemotherapy in patients with stage IIIa/bpN2/3 NSCLC. Before chemotherapy, six patients had EGFR-negative mediastinal lymph nodes and five patients had EGFR-negative primary tumors. After chemotherapy, four of the six EGFR-negative mediastinal lymph nodes and three of the five EGFR-negative primary tumors were EGFR positive. Although this observation was very preliminary, it raised the possibility that systemic chemotherapy can change EGFR expression and activation of its downstream pathway. This possibility could explain the two responses observed among Akt-negative tumors in Cappuzzo et al. (1).
A prospective study is needed to assess the relationship between EGFR mutations and activation of downstream pathway components. The identification of a profile that is strongly predictive of the response to EGFR targeting agents will be important to increase the clinical impact of these agents in clinical care.
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 nonsmall-cell lung cancer. J Natl Cancer Inst 2004;96:113341.
(2) Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activatingmutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:21913.
(3) Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497500.
(4) Franklin WA, Chansky K, West H, Gumerlock PH, Hirsch FR, Gandara DR. Association between activation of ErbB pathway genes and survival following gefitinib treatment in advanced BAC (SWOG 0126). Presentation during the "Lung Cancer II" session at ASCO, New Orleans, LA, USA, June 58, 2004. Available at: http://www.asco.org/ac/1,1003,_12-002511-00_18-0026-00_19-0010095,00.asp. [Last accessed: August 23, 2004.]
(5) De Pas T, Pelosi G, de Braud F, Veronesi G, Curigliano G, Leon ME, et al. Modulation of epidermal growth factor receptor (EGFR) status by chemotherapy in patients with locally advanced nonsmall-cell lung cancer is rare.J Clin Oncol 2004;22:496670.
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