HER-2/neu Expression and Response to Tamoxifen in ER-Positive Breast Cancer
HER-2/neu Expression and Response to Tamoxifen in ER-Positive Breast Cancer
ABSTRACT & COMMENTARY
Synopsis: HER-2/neu is an oncogene that encodes a growth factor receptor. Thus, it is no surprise that overexpression of HER-2/neu by breast cancer cells is associated with more aggressive behavior, including more rapid tumor growth and greater resistance to chemotherapy. However, there have been conflicting reports about the influence of HER-2/neu expression on response of estrogen-receptor positive (ER+) tumors to tamoxifen. In this analysis of ER+ breast cancer patients enrolled on a Southwest Oncology Group trial in which all patients received tamoxifen, archival tissue was prepared for HER-2 analysis. In contrast to chemotherapy response, there was no correlation between expression of this gene and response to therapy (tamoxifen), disease-free survival, or survival. Thus, in patients with metastatic ER+ breast cancer, the presence of increased expression of the HER-2 gene does not imply refractoriness to tamoxifen therapy.
Source: Elledge RM, et al. Clin Cancer Res 1998;4: 7-12.
Her-2 (also known as erbb-2) is a growth factor receptor that, when found to be over-expressed in tumor cells, is associated with resistance to chemotherapy.1 For example, in chemotherapy-treated (cyclophosphamide, methotrexate and 5 fluorouracil) breast cancer patients, overexpression of HER-2 correlated with resistance to treatment and poorer clinical outcomes.2 There has been speculation that HER-2 expression might also adversely affect the response to tamoxifen treatment. The current study examines this question.
Primary or metastatic tissue from patients with estrogen-receptor (ER) positive, metastatic breast cancer who were enrolled in a Southwest Oncology Group protocol more than a decade ago were examined by immunohistochemistry for the presence of HER-2/neu expression. No patients on this trial had received prior therapy for their metastatic disease and all patients received tamoxifen. Tissue blocks were available for 205 patients and this group was representative of the overall study (SWOG 8228 enrolled 349 patients) with equivalent demographic characteristics and clinical responses. Unlike what had previously been demonstrated for HER-2/neu expression and response to chemotherapy, HER-2/neu expression was not significantly associated with response rate, time to treatment failure, or survival in ER+ tamoxifen-treated patients. These findings run counter to the speculation that this marker of aggressive breast cancer cells would predict response to hormonal manipulation in a manner similar to its predictive value for chemotherapy response. Elledge and colleagues speculate that earlier suggestions to the contrary may have been due to failure to rigorously exclude ER- tumors, which are much less likely to respond to tamoxifen and more likely to have high HER-2/neu expression.
COMMENTARY
It has been suspected that tamoxifen exerts at least some of its therapeutic effect through growth factor pathways. Thus, it was expected that overexpression of HER-2 would be associated with tamoxifen resistance. In fact, poor response to tamoxifen was observed in some, but not all of previously reported retrospective series.3,4 The confusion may be because there is an association of increased HER2 with ER- tumors, and prior studies were less rigorous in restricting the analysis to ER+ patients. It is quite clear from this report that HER2 expression in ER+ tumors does not indicate resistance to tamoxifen. Inasmuch as it is not common clinical practice to measure HER-2, the finding is of more biological interest than practical interest. Nonetheless, it is interesting that this growth factor receptor, HER-2/neu, indicative of highly proliferative tumor cells and associated with chemotherapy resistance, does not predict tamoxifen resistance. Perhaps this clinical observation provides some clues to tumor biologists studying the mechanisms of action of the anti-estrogens.
Another important feature of this study is the use of archival tissue obtained a decade or more ago to answer a clinical question that wasn't even pondered when the samples were frozen. It is another example of the value of coordinated clinical research provided by the cooperative oncology groups. It is likely that similar studies employing banked tissue to correlate genes of proposed importance in tumor biology or drug resistance will be examined by a similar retrospective/prospective design.
References
1. Allred DC, et al. J Clin Oncol 1992;10:599-605.
2. Gusterson BA, et al. J Clin Oncol 1992;10:1049-1056.
3. Borg A, et al. Cancer Lett 1994;8:137-144.
4. Archer SG, et al. Br J Cancer 1995;72:1259-1266.
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