Correspondence
HER2 Mutation and Response to Trastuzumab Therapy in Non–Small-Cell Lung Cancer
N Engl J Med 2006; 354:2619-2621June 15, 2006
- Article
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 1AFigure 1
Response to Trastuzumab in a Patient with Non–Small-Cell Lung Cancer.).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).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.
5 ReferencesFederico 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 800451
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