Affiliation of authors: Division of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles.
Correspondence to: Dennis Slamon, MD, PhD, Division of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Factor Building, Rm. 11-934, Los Angeles, CA 90095-1678 (e-mail: dslamon{at}mednet.ucla.edu).
The role of HER-2/neu in influencing steroid hormone receptor status is an area of some controversy. Spyratos et al. have confirmed our findings using a large cohort of primary breast cancer patients and different antibodies than we used for the quantitative measurement of HER-2/neu expression. This confirmatory study strengthens the conclusion that HER-2/neu amplification/overexpression is associated with lower tumor estrogen and progesterone receptor levels, even in those patients otherwise classified as hormone receptorpositive. These data add to the growing body of biologic and molecular evidence of critical cross-talk between the HER-2/neu and steroid hormone receptor pathways (1). More important, such data have substantial clinical therapeutic implications because response to tamoxifen therapy is closely associated with the absolute levels of estrogen or progesterone receptor expression.
Our results and those of Spyratos et al. provide a possible explanation for the reduced response to tamoxifen in women with hormone receptorpositive tumors containing HER-2/neu amplification/overexpression. Furthermore, the data argue against the interpretation of the results of two recently published retrospective studies whose authors have proposed that estrogen withdrawal, whether by treatment with aromatase inhibitors (such as letrozole) in postmenopausal patients (2) or by oophorectomy in premenopausal breast cancer patients (3), might be the preferred treatment choice for women with hormone receptorpositive tumors containing HER-2/neu amplification/overexpression. In the first study, postmenopausal women with hormone receptorpositive primary breast cancer were randomly assigned to receive preoperative letrozole or tamoxifen (2). Overall, there was a higher response to letrozole than to tamoxifen, but the difference was statistically significant only in the pooled subpopulation of patients with tumors classified as EGFR or HER-2/neupositive, and not in those patients with EGFR and HER-2/neunegative tumors. In the second study, premenopausal women with estrogen receptorpositive, operable breast cancer were randomly assigned to receive adjuvant surgical oophorectomy and tamoxifen daily for 5 years or to observation. Adjuvant endocrine therapy was superior to observation in terms of disease-free and overall survival, but women with HER-2/neuoverexpressing tumors were more likely to benefit from endocrine therapy than those with HER-2/neu non-overexpressing tumors.
Although these two studies appear to indicate that women with hormone receptorpositive tumors containing HER-2/neu amplification/overexpression are likely to benefit from estrogen withdrawal therapy, both studies had shortcomings in that they were retrospective studies performed in small cohorts. (The studies included only 36 EGFR/HER-2/neu and 73 HER-2/neupositive patients, respectively, and in the latter study, only 27 HER-2/neupositive patients received the endocrine therapy, and even fewer events were reported.) Thus, the data from both studies are not sufficiently robust to allow us to conclude that HER-2/neu measurements can be used to select an aromatase inhibitor or oophorectomy as the preferred treatment for women with hormone receptorpositive tumors containing HER-2/neu amplification/overexpression. Furthermore, the reduced expression of the hormone receptors in tumors containing HER-2/neu amplification/overexpression makes it unlikely that estrogen ablation will be substantially more active than tamoxifen in HER-2/neupositive breast cancer. Finally, a recent large retrospective study (4) in 562 patients (164 HER-2/neupositive) with metastatic breast cancer showed that patients with HER-2/neupositive tumors had a lower response to both tamoxifen and letrozole than patients with HER-2/neunegative tumors. The findings of this study are precisely what would be predicted from the quantitative inverse relationship between HER-2/neu and estrogen receptor expression presented by our group and now confirmed by Spyratos et al. Additional retrospective analyses of sufficiently powered studies with patients who are correctly analyzed for the quantitative levels of HER-2/neu gene amplification and hormone receptor expression will be necessary to fully characterize the predictive value of hormone receptor levels in women with hormone receptorpositive tumors containing HER-2/neu amplification/overexpression.
REFERENCES
1 Pietras RJ, Arboleda J, Reese DM, Wongvipat N, Pegram MD, Ramos L, et al. HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 1995;10:243546.[ISI][Medline]
2 Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cussac A, Jänicke F, et al. Letrozole is more effective neoadjuvant therapy than tamoxifen for ErbB-1- and ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. J Clin Oncol 2001;19:380816.
3 Love RR, Duc NB, Havighurst TC, Mohsin SK, Zhang Q, DeMets DL, et al. Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer. J Clin Oncol 2003;21:4537.
4 Lipton A, Ali SM, Leitzel K, Demers L, Harvey HA, Chaudri-Ross HA, et al. Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol 2003;21:196772.
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