Correspondence
HER2 Status and Benefit from Adjuvant Trastuzumab in Breast Cancer
N Engl J Med 2008; 358:1409-1411March 27, 2008
- Article
To the Editor:
Trastuzumab, an antibody against the protein product of the human epidermal growth factor receptor type 2 (HER2) gene, improves progression-free survival and overall survival when added to chemotherapy in patients with metastatic breast cancer.1 Initial trials enrolled patients with tumors that had a staining intensity of 2+ or 3+ for HER2 on immunohistochemical analysis, but in subsequent studies, the benefit was limited to tumors with HER2 amplification as determined by fluorescence in situ hybridization (FISH). Trastuzumab also improves disease-free survival and overall survival in the adjuvant setting.2
On the basis of its mechanism of action, the HER2 gene copy number was expected to predict benefit from adjuvant trastuzumab. National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31, which compared standard chemotherapy of four cycles of doxorubicin and cyclophosphamide followed by four cycles of paclitaxel (ACT) with ACT plus trastuzumab (ACTH) in the adjuvant setting, provided an opportunity to test this hypothesis.2 Available tissue blocks were examined at a central site by means of a Food and Drug Administration–approved HER2 FISH assay. We found no significant association between HER2 copy number and benefit (P=0.60). Even patients with normal gene copy numbers appeared to benefit (relative risk for disease-free survival, 0.40; 95% confidence interval [CI], 0.18 to 0.89; P=0.026).
HER2 status according to immunohistochemical analysis with the use of Herceptest (Dako) was also determined at a central site. Tumors that were negative on FISH and had an immunohistochemical staining intensity of less than 3+ were defined as “central HER2-negative,” as in our previous report.3 Among the 1787 patients with follow-up data, 174 patients had breast cancers that were found to be central HER2-negative (9.7%), yet these patients also appeared to benefit from trastuzumab (relative risk for disease-free survival, 0.34; 95% CI, 0.14 to 0.80; P=0.014) (Table 1Table 1
Relative Risks of Disease Progression and Death among Patients in the ACTH Group as Compared with the ACT Group.).To address the technical problems inherent in current testing methods,3,4 we examined levels of expression of HER2 messenger RNA (mRNA) in a subgroup of 638 patients that included all 167 patients who had central HER2-negative tumors with enough tissue remaining in the blocks. The mRNA levels of HER2 in tumors that were central HER2-negative were significantly lower than those in HER2-positive tumors, and they were similar to those in HER2-negative tumors from another NSABP trial (B-30) (Figure 1Figure 1
Scatter Plot of HER2 mRNA Levels in Each Category Defined by Centrally Performed HER2 Assays.). The mRNA data provide strong evidence that the central HER2-negative tumors in the B-31 trial are indeed HER2-negative. Independent validation of the central FISH testing and immunohistochemical findings from the B-31 trial is being initiated.Assuming that the validation studies are confirmatory, our findings suggest that the benefit of adjuvant trastuzumab may not be limited to patients with HER2 amplification. Since our findings are based on an exploratory analysis, they should not alter current criteria used for selecting patients for adjuvant trastuzumab. Validation of the findings from central testing would justify a phase 3 trial of adjuvant trastuzumab in women with breast cancers that do not meet established criteria for therapy.
Soonmyung Paik, M.D.
Chungyeul Kim, M.D.
Norman Wolmark, M.D.
NSABP Operations Center, Pittsburgh, PA 15212
soon.paik@nsabp. org Supported in part by a grant from the Pennsylvania Department of Health, which disclaims responsibility for any analysis, interpretations, or conclusions in this letter.
Dr. Paik reports serving on advisory boards for Genentech and GlaxoSmithKline. No other potential conflict of interest relevant to this letter was reported.
4 References1
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