Responsiveness to Cetuximab without Mutations in EGFR
http://www.100md.com
《新英格兰医药杂志》
To the Editor: A large amount of information suggests that mutations in the kinase domain of epidermal growth factor receptor (EGFR) are critical for the efficacy of EGFR kinase inhibitors.1,2,3 However, the effect of EGFR mutations on the response to cetuximab has not been directly investigated. Barber et al.4 reported the absence of EGFR mutations in colorectal cancers and speculated that EGFR mutations were not required for the response to cetuximab, since it was an efficacious agent against this type of tumor.5 We sequenced the kinase domain of EGFR (exons 18, 19, and 21) in tumor samples from 38 patients participating in a cetuximab-monotherapy study for recurrent non–small-cell lung cancer and tumor samples from 39 patients participating in a cetuximab-monotherapy study for refractory colorectal cancer. Mutations previously detected in non–small-cell lung cancer1,2,3 were identified in 3 of the 38 patients with non–small-cell lung cancer. Of 13 patients with non–small-cell lung cancer whose disease was stable, 2 carried a del746-750, and of 21 patients with progressive disease, 1 had an L861Q mutation. No mutations were identified in other patients with non–small-cell lung cancer who had a partial response (one patient) or for whom response data were unavailable (three patients). No mutations were detected in the samples from the 39 patients with colorectal cancer, including those from 20 patients who had a partial response and 1 who had a complete response.
From these results, it appears that the presence of an EGFR mutation is not a major determining factor for a positive response to cetuximab. Absence of an EGFR mutation in the samples of colorectal cancer, including those from patients who had a response to cetuximab, supports the speculation by Barber et al.4 that EGFR mutations are not required for the efficacy of cetuximab in colorectal cancer. (Some of the samples were chosen for sequence analysis on the basis of the clinical response, and thus the numbers we mention in this letter do not reflect the response rates in the trials.) In addition, we sequenced 160 biopsy samples of previously untreated colorectal cancer (provided by Dr. Sina Dorudi, Royal London Hospital, London) from patients outside the cetuximab trial and could not identify any mutation in exons 18, 19, and 21. This further confirms the general absence of EGFR mutations in colorectal cancer. Our results suggest that in contrast to the correlation of mutations with responses to the EGFR kinase inhibitors gefitinib and erlotinib, EGFR mutations are not critical for the response of a tumor to cetuximab.
Zenta Tsuchihashi, Ph.D.
Shirin Khambata-Ford, Ph.D.
Bristol-Myers Squibb
Princeton, NJ 08543-5400
zenta.tsuchihashi@bms.com
Nasser Hanna, M.D.
Indiana University
Indianapolis, IN 46202
Pasi A. J?nne, M.D., Ph.D.
Dana–Farber Cancer Institute
Boston, MA 02115
Dr. Hanna reports having received grant support from Bristol-Myers Squibb. Dr. J?nne reports having received an unrestricted gift from Genentech and being a participant in a patent application for EGFR mutation detection.
References
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-13311.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Barber TD, Vogelstein B, Kinzler KW, Velculescu VE. Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 2004;351:2883-2883.
Ng M, Cunningham D. Cetuximab (Erbitux) -- an emerging targeted therapy for epidermal growth factor receptor-expressing tumours. Int J Clin Pract 2004;58:970-976.
From these results, it appears that the presence of an EGFR mutation is not a major determining factor for a positive response to cetuximab. Absence of an EGFR mutation in the samples of colorectal cancer, including those from patients who had a response to cetuximab, supports the speculation by Barber et al.4 that EGFR mutations are not required for the efficacy of cetuximab in colorectal cancer. (Some of the samples were chosen for sequence analysis on the basis of the clinical response, and thus the numbers we mention in this letter do not reflect the response rates in the trials.) In addition, we sequenced 160 biopsy samples of previously untreated colorectal cancer (provided by Dr. Sina Dorudi, Royal London Hospital, London) from patients outside the cetuximab trial and could not identify any mutation in exons 18, 19, and 21. This further confirms the general absence of EGFR mutations in colorectal cancer. Our results suggest that in contrast to the correlation of mutations with responses to the EGFR kinase inhibitors gefitinib and erlotinib, EGFR mutations are not critical for the response of a tumor to cetuximab.
Zenta Tsuchihashi, Ph.D.
Shirin Khambata-Ford, Ph.D.
Bristol-Myers Squibb
Princeton, NJ 08543-5400
zenta.tsuchihashi@bms.com
Nasser Hanna, M.D.
Indiana University
Indianapolis, IN 46202
Pasi A. J?nne, M.D., Ph.D.
Dana–Farber Cancer Institute
Boston, MA 02115
Dr. Hanna reports having received grant support from Bristol-Myers Squibb. Dr. J?nne reports having received an unrestricted gift from Genentech and being a participant in a patent application for EGFR mutation detection.
References
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-13311.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Barber TD, Vogelstein B, Kinzler KW, Velculescu VE. Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 2004;351:2883-2883.
Ng M, Cunningham D. Cetuximab (Erbitux) -- an emerging targeted therapy for epidermal growth factor receptor-expressing tumours. Int J Clin Pract 2004;58:970-976.