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© 2002 American Society for Clinical Oncology
Does HER-2 Status Predict Only a Decreased Response to Hormone Therapy in Advanced Breast Cancer, or Does It Also Predict the Extent of Metastatic Disease?Institut Català Oncologia, Girona, Spain To the Editor:In the March 15, 2002, issue of the Journal of Clinical Oncology, Lipton et al1 reported that elevated serum HER-2 levels predict a decreased response to hormone therapy in metastatic breast cancer. Their clinical study, the largest about the topic of HER-2 oncogene expression and hormone resistance, included 719 postmenopausal women with advanced breast cancer who participated in three randomized trials of second-line endocrine therapy. Two of the trials compared the aromatase inhibitor fadrozole with megestrol acetate, and one compared the aromatase inhibitor letrozole with megestrol acetate.2,3 The efficacy end points evaluated in the analysis by Lipton et al were overall response, clinical benefit, time to treatment failure, and time to progression. All four end points were significantly worse in the patients overexpressing HER-2 when compared with patients not expressing HER2. Their data support the results of other retrospective studies, in which clinical lack of response to hormone therapy was also correlated with HER2 overexpression.4,5 The article concludes that HER-2 is a molecular marker for predicting a decreased response to endocrine therapy in advanced breast cancer. However, this may not fully take into consideration some factors that are known to relate to prognosis in advanced breast cancer and that might also have an effect on HER-2 serum levels. These factors include site of metastases and metastatic tumor burden. In Lipton et al’s article,1 the site of metastases was recorded. The proportion of a visceral dominant site of metastasis, a characteristic associated with poor prognosis and poorer response to therapy, was significantly larger in patients with elevated serum HER-2 levels than in patients with normal HER-2 levels (59% v 39%, respectively). Conversely, fewer patients with elevated HER-2 levels had soft tissue/bone metastasis, which is usually associated with a favorable prognosis (41% v 61%).1 HER-2 status may therefore reflect the aggressiveness of advanced cancer, as suggested by others.6-8 An association between HER-2 status and visceral disease has been observed by some authors,4 although not by others.9 Tumor burden, measured either with the number of metastatic sites or with the levels of a tumor marker such as CA 15-3,10 is not reported in relation to HER-2 status in Lipton et al’s article. The addition in the analysis of the variable "tumor burden" might have shown that serum HER-2 is related to the amount of metastatic disease. In fact, we have shown previously that serum HER-2 in advanced breast cancer is related to HER-2 status in the primary breast carcinoma and also to metastatic tumor burden.11 Therefore, part of the decreased response in HER-2–positive patients may be attributed either to more aggressive tumor sites or to larger burden of metastatic disease. A multivariate analysis of prognostic factors, a statistical procedure that may correct the significance of competing variables, is not shown in Lipton et al’s report. However, in previous communications of the same material, the investigators did perform multivariate analyses, which included, in addition to HER-2 status, age, race, disease-free interval, performance status, visceral versus nonvisceral metastasis, and estrogen receptor and progesterone receptor status, although not tumor burden.11,12 A multivariate analysis in the present report would have increased the confidence of investigators in the predictive value of serum HER2 and in its independence from the site of metastatic disease and tumor burden. Retrospective studies such as this report can provide predictive information, but the limitations are large. Prospective studies are needed that address the issue of HER2 expression and hormone resistance. Since the logistics of a randomized clinical trial may not be applicable here, we recommend the design of prospective cohort studies, in which patients are treated with a defined endocrine therapy, serum HER-2 levels are determined initially, and patients are followed up for relapse. The preliminary results of such a trial have been reported.13 Until prospective data are available, it is not advisable to withhold endocrine therapy in patients with estrogen receptor–positive, HER2-positive advanced breast cancer. Finally, although combinations of endocrine therapy plus anti-HER-2 antibodies are a logical approach, they should be used with caution, since some preclinical research has reported that such combinations may be less than additive.14 REFERENCES
1. Lipton A, Ali SM, Leitzel K, et al: Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer. J Clin Oncol 20: 1467-1472, 2002 2. Buzdar AU, Smith R, Vogel C, et al: Fadrozole HCL (CGS-16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: Results of two randomized double blind controlled multiinstitutional trials. Cancer 77: 2503-2513, 1996[CrossRef][Medline]
3. Buzdar A, Douma J, Davidson N, et al: Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19: 3357-3366, 2001 4. Yamauchi H, O’Neill A, Gelman R, et al: Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of the HER-2/c-neu protein. J Clin Oncol 7: 2518-2525, 1997 5. Houston SJ, Plunkett TA, Barnes DM, et al: Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 79: 1220-1226, 1999[CrossRef][Medline]
6. Hayes DF, Yamauchi H, Broadwater G, et al: Circulating HER-2/erbB-2/c-neu (HER-2) extracellular domain as a prognostic factor in patients with metastatic breast cancer: Cancer and Leukemia Group B Study 8662. Clin Cancer Res 7: 2703-2711, 2001
7. Yamauchi H, Stearns V, Hayes DF: When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol 19: 2334-2356, 2001
8. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 19: 3808-3816, 2001
9. Colomer R, Montero S, Lluch A, et al: Circulating HER2 extracellular domain and resistance to chemotherapy in advanced breast cancer. Clin Cancer Res 6: 2356-2362, 2000 10. Colomer R, Ruibal A, Salvador L: Circulating tumor marker levels in advanced breast carcinoma correlate with the extent of metastatic disease. Cancer 64: 1674-1681, 1989[CrossRef][Medline] 11. Ali S, Leitzel K, Chinchilli V, et al: Serum HER-2/neu and response to megace vs an aromatase inhibitor. Proc Am Soc Clin Oncol 20: 23a, 2001 (abstr 87) 12. Lipton A, Ali SM, Leitzel K, et al: Elevated serum HER-2/neu level predicts decreased response to hormone therapy in advanced breast cancer. Proc Am Soc Clin Oncol 19: 71a, 2000 (abstr 274) 13. Colomer R, Llombart A, Ramos M, et al: Serum HER-2 ECD and the efficacy of letrozole in ER+/PR+ metastatic breast cancer: Preliminary results of a prospective study. Presented at the 24th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 10-13, 2001 (abstr 223) 14. Ropero S, Menendez JA, Montero S, et al: Tamoxifen-induced up-regulation of HER2 impairs the sensitivity to Herceptin in ER+HER2+ breast carcinoma cells. Proc Am Assoc Cancer Res 41: 1004, 2002 (abstr 4978)
ResponsePenn State College of Medicine, Hershey, PA In Reply:We respond to Drs Beltràn and Colomer’s important concerns regarding our article1 as follows:
So the answer to Drs Beltràn and Colomer’s question is yes, serum HER-2 status predicts decreased response to hormone therapy when adjusted for visceral metastatic disease, tumor burden, and, in a multivariate model, other traditional covariates. REFERENCES
1. Lipton A, Ali SM, Leitzel K, et al: Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer. J Clin Oncol 20: 1467-1472, 2002
2. Panasci LC: HER-2/neu serum levels vis-à-vis hormonal response in metastatic breast cancer. J Clin Oncol 20: 3357, 2002 (letter)
3. Ali SM, Leitzel K, Chinchilli V, et al: Relationship of serum HER-2/neu to serum CA 15-3 in patients with metastatic breast cancer. Clin Chem 48: 1314-1320, 2002
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2 analysis and a multivariate analysis within the two strata of visceral disease and nonvisceral disease. According to the 
