HER2 Mutation and Response to Trastuzumab Therapy in Non–Small-Cell Lung Cancer
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Trastuzumab is a monoclonal antibody against HER2, a member of the epidermal growth factor receptor (EGFR) family, that improves the outcome of HER2-positive breast cancer.1 Preclinical data have demonstrated that trastuzumab is effective in non–small-cell lung cancer, with additive or synergistic effects with various cytotoxic agents. However, trials of trastuzumab or other HER2-targeted agents, such as pertuzumab, failed to demonstrate clinical benefit in non–small-cell lung cancer when administered as monotherapy or combined with chemotherapy.2
In these studies, HER2 status was assessed by immunohistochemical analysis, a method that is not optimal.3 Moreover, the few patients whose tumors had HER2 gene amplification and who were treated with trastuzumab had a response to trastuzumab.2 Recently, activating mutations in HER2 were reported in lung adenocarcinomas, offering the potential for therapy targeted at the altered protein.4 Here, we report the case of a 60-year-old female nonsmoker with metastatic adenocarcinoma of the lung that responded to trastuzumab.
The patient's disease was refractory or resistant to cisplatin, taxane, and tyrosine kinase–inhibitor therapy. Fluorescence in situ hybridization (FISH) of a tumor specimen that was collected at the time of the original diagnosis showed increased numbers of copies of the EGFR and HER2 genes (Figure 1A).5 The patient was treated with weekly trastuzumab (at a dose of 2 mg per kilogram of body weight) and paclitaxel (at a dose of 60 mg per square meter of body-surface area). After two months of this combined therapy, a partial response was detected (Figure 1B and 1C) and confirmed after an additional two months (Figure 1D). DNA sequencing performed on the same tissue analyzed by FISH detected an EGFR exon 21 mutation (A859T) and a HER2 exon 20 mutation (G776L) (Figure 1E).
Figure 1. Response to Trastuzumab in a Patient with Non–Small-Cell Lung Cancer.
Adenocarcinoma of the right lung was diagnosed in August 2002. After incomplete surgical resection, the patient was treated with three courses of gemcitabine–cisplatin and radical radiotherapy. Lung metastases were found in July 2003, and four courses of gemcitabine–cisplatin were administered, which resulted in a five-month stabilization of disease. In March 2004, the patient received six courses of docetaxel (75 mg per square meter of body-surface area every 21 days) with no evidence of a response. In November 2004, computed tomography (CT) of the chest showed disease progression, and therapy with gefitinib (250 mg per day) was started. Although progressive disease was verified two months later, gefitinib was continued because of symptomatic improvements and the lack of better therapy. In June 2005, the HER2-positive status on FISH (Panel A) and the absence of standard treatment led to the proposal of therapy with weekly trastuzumab (at a dose of 2 mg per kilogram) and paclitaxel (at a dose of 60 mg per square meter). At that time, chest CT showed multiple lung metastases (Panel B), and the level of carcinoembryonic antigen (CEA) was 44 ng per milliliter. After two months of trastuzumab therapy, chest CT showed a partial response (Panel C), and the CEA level was 12 ng per milliliter. Disease assessment performed after an additional two months showed almost complete disappearance of lung metastases (Panel D), and the CEA level was 1.4 ng per milliliter. HER2 gene sequencing (Panel E) showed the presence of the exon 20 mutation. The base pairs 2327–2329 contain an insert of the bases TAT; base pair 2326 is a transversion from G to T. This mutation results in the replacement of glycine at amino acid 776 with leucine and an insertion of cysteine.
The HER2 mutation was similar to that previously described.4 The resistance to tyrosine kinase–inhibitor therapy in a case with all clinical and biologic features indicative of sensitivity to such treatment and the response to trastuzumab suggest that HER2 genomic gain and mutation are critical for the survival of tumor cells in some patients with non–small-cell lung cancer.
Federico Cappuzzo, M.D.
Bellaria Hospital
40139 Bologna, Italy
federico.cappuzzo@ausl.bo.it
Lynne Bemis, Ph.D.
Marileila Varella-Garcia, Ph.D.
Colorado Cancer Center
Aurora, CO 80045
References
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-1684.
Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol 2004;15:19-27.
Hirsch FR, Varella-Garcia M, Franklin WA, et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer 2002;86:1449-1456.
Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 2005;65:1642-1646.
Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643-655.
In these studies, HER2 status was assessed by immunohistochemical analysis, a method that is not optimal.3 Moreover, the few patients whose tumors had HER2 gene amplification and who were treated with trastuzumab had a response to trastuzumab.2 Recently, activating mutations in HER2 were reported in lung adenocarcinomas, offering the potential for therapy targeted at the altered protein.4 Here, we report the case of a 60-year-old female nonsmoker with metastatic adenocarcinoma of the lung that responded to trastuzumab.
The patient's disease was refractory or resistant to cisplatin, taxane, and tyrosine kinase–inhibitor therapy. Fluorescence in situ hybridization (FISH) of a tumor specimen that was collected at the time of the original diagnosis showed increased numbers of copies of the EGFR and HER2 genes (Figure 1A).5 The patient was treated with weekly trastuzumab (at a dose of 2 mg per kilogram of body weight) and paclitaxel (at a dose of 60 mg per square meter of body-surface area). After two months of this combined therapy, a partial response was detected (Figure 1B and 1C) and confirmed after an additional two months (Figure 1D). DNA sequencing performed on the same tissue analyzed by FISH detected an EGFR exon 21 mutation (A859T) and a HER2 exon 20 mutation (G776L) (Figure 1E).
Figure 1. Response to Trastuzumab in a Patient with Non–Small-Cell Lung Cancer.
Adenocarcinoma of the right lung was diagnosed in August 2002. After incomplete surgical resection, the patient was treated with three courses of gemcitabine–cisplatin and radical radiotherapy. Lung metastases were found in July 2003, and four courses of gemcitabine–cisplatin were administered, which resulted in a five-month stabilization of disease. In March 2004, the patient received six courses of docetaxel (75 mg per square meter of body-surface area every 21 days) with no evidence of a response. In November 2004, computed tomography (CT) of the chest showed disease progression, and therapy with gefitinib (250 mg per day) was started. Although progressive disease was verified two months later, gefitinib was continued because of symptomatic improvements and the lack of better therapy. In June 2005, the HER2-positive status on FISH (Panel A) and the absence of standard treatment led to the proposal of therapy with weekly trastuzumab (at a dose of 2 mg per kilogram) and paclitaxel (at a dose of 60 mg per square meter). At that time, chest CT showed multiple lung metastases (Panel B), and the level of carcinoembryonic antigen (CEA) was 44 ng per milliliter. After two months of trastuzumab therapy, chest CT showed a partial response (Panel C), and the CEA level was 12 ng per milliliter. Disease assessment performed after an additional two months showed almost complete disappearance of lung metastases (Panel D), and the CEA level was 1.4 ng per milliliter. HER2 gene sequencing (Panel E) showed the presence of the exon 20 mutation. The base pairs 2327–2329 contain an insert of the bases TAT; base pair 2326 is a transversion from G to T. This mutation results in the replacement of glycine at amino acid 776 with leucine and an insertion of cysteine.
The HER2 mutation was similar to that previously described.4 The resistance to tyrosine kinase–inhibitor therapy in a case with all clinical and biologic features indicative of sensitivity to such treatment and the response to trastuzumab suggest that HER2 genomic gain and mutation are critical for the survival of tumor cells in some patients with non–small-cell lung cancer.
Federico Cappuzzo, M.D.
Bellaria Hospital
40139 Bologna, Italy
federico.cappuzzo@ausl.bo.it
Lynne Bemis, Ph.D.
Marileila Varella-Garcia, Ph.D.
Colorado Cancer Center
Aurora, CO 80045
References
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-1684.
Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol 2004;15:19-27.
Hirsch FR, Varella-Garcia M, Franklin WA, et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer 2002;86:1449-1456.
Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 2005;65:1642-1646.
Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 2005;97:643-655.