AMeta-Analysis on the Interaction between HER-2 Expression and Response to EndocrineTreatment in Advanced Breast Cancer

Purpose: Experimental data suggest a complex cross-talk between HER-2 and estrogen receptor, and it has been hypothesized that HER-2-positive tumors may be less responsive to certain endocrine treatments. Clinical data, however, have been conflicting.We have conducted a metaanalysis on the interaction between the response to endocrine treatment and the overexpression of HER-2 inmetastatic breast cancer. Experimental Design: Studies have been identified by searching the Medline, Embase, and American Society of Clinical Oncology abstract databases. Selection criteria were (a) metastatic breast cancer, (b) endocrine therapy (any line of treatment), and (c) evaluation of HER-2 expression (any method). For each study, the relative risk for treatment failure for HER-2-positive over HER-2-negative patients with 95% confidence interval was calculated as an estimate of the predictive effect of HER-2. Pooled estimates of the relative risk were computed by the MantelHaenszel method. Results:Twelve studies (n = 2,379 patients) were included in the meta-analysis.The overall relative risk was 1.42 (95% confidence interval, 1.32-1.52; P < 0.00001; test for heterogeneity = 0.380). For studies involving tamoxifen, the pooled relative risk was1.33 (95% confidence interval, 1.20-1.48; P < 0.00001; test for heterogeneity = 0.97); for studies involving other hormonal drugs, a pooled relative risk of 1.49 (95% confidence interval, 1.36-1.64; P < 0.00001; test for heterogeneity = 0.08) was estimated. A second meta-analysis limited to tumors that were either estrogen receptor positive, estrogen receptor unknown, or estrogen receptor negative/progesterone receptor positive yielded comparable results. Conclusions: HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment. This effect holds in the subgroup of patients with positive or unknown steroid receptors. The HER-2 (also known as c-erbB-2 or neu) oncoprotein is one of the four transmembrane receptors of the erbB family. Different from the other receptors of the family, HER-2 has unique receptor features: it binds no known specific ligand, but it seems to exert its biological activity by serving as a preferential partner of the other erbB receptors. Indeed, it forms heterodimers with the other members of the erbB family after their binding to specific ligands, thus enhancing and prolonging cell signaling (1–4). Interestingly, overexpression of HER-2 also induces its spontaneous homodimerization thereby leading to activation of the tyrosine kinase moiety of the intracytoplasmic domain without the need for ligand (5). Proliferation of breast cells is dependent on the regulatory action of both steroid hormones and growth factors, and a body of experimental evidence suggests the presence of complex cross-talk and interactions between the HER-2/tyrosine kinase pathway and the estrogen receptor (ER) pathway (6–8). In particular, it seems that HER-2-overexpressing tumor cells might grow in estrogen-depleted condition and be resistant to selective ER modulators, such as tamoxifen, compared with HER-2-negative cells (8–11). Overexpression of HER-2, generally due to gene amplification, is found in 20% to 30% of human breast cancers and it has been postulated that this overexpression may modulate the clinical sensitivity of tumors to endocrine treatments. However, clinical studies have yielded conflicting results in both adjuvant and metastatic settings. Imaging, Diagnosis, Prognosis Authors’Affiliations: Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Universita' ‘‘Federico II’’; Cattedra di Oncologia Medica, Seconda Universita degli Studi di Napoli, Napoli, Italy; TheBreast Center at Baylor College ofMedicine and The Methodist Hospital; Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston,Texas; and Divisione di Oncologia Medica, Ospedale ‘‘G. Rummo,’’Benevento, Italy Received12/13/04; revised 4/7/05; accepted 4/14/05. Grant support: Associazione Italiana Ricerca sul Cancro, Ministero dell’Istruzione, dell’Universita' e della Ricerca-Cofin, and Consiglio Nazionale delle Ricerche. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints:Michele De Laurentiis, Dipartimento di Endocrinologia ed OncologiaMolecolare e Clinica, Universita' ‘‘Federico II,’’ via Sergio Pansini, 5, 80131 Napoli, Italy. Phone : 39-81-7464286; Fax : 39-81-2290150; E-mail : michele.delaurentiis@unina.it. F2005 American Association for Cancer Research. www.aacrjournals. org Clin Cancer Res 2005;11(13) July1, 2005 4741 Research. on July 8, 2017. © 2005 American Association for Cancer clincancerres.aacrjournals. org Downloaded from In particular, in the metastatic setting, several groups have identified a correlation between HER-2 overexpression and a lower response rate to endocrine treatment (12–21), whereas others have not (22–26). Instances of conflicting results may be related to the lack of a standardized methodology for HER-2 analysis, to flawed experimental designs, but also to the low statistical power of the single studies. We have conducted a meta-analysis of the pertinent published studies in an attempt to gain insights into the association between HER-2 and response to different types of endocrine therapy in metastatic breast cancer.