CORRESPONDENCE

Re: Quantitative Association Between HER-2/neu and Steroid Hormone Receptors in Hormone Receptor-Positive Primary Breast Cancer

Frédérique Spyratos, Cécile Bouchet, Magali Ferrero-Poüs, Michèle Tubiana-Hulin, Kamel Hacène

Affiliations of authors: F. Spyratos (Laboratoire d‘Oncobiologie), C. Bouchet, M. Ferrero-Poüs (Département de Biologie), M. Tubiana-Hulin (Département de Médecine), K. Hacène (Département de Statistiques Médicales), Centre René Huguenin de Lutte Contre le Cancer, Saint Cloud, France.

Correspondence to: Dr. Frédérique Spyratos, Centre René Huguenin de Lutte Contre le Cancer, Laboratoire d’Oncobiologie, 35 rue Dailly, 92210 Saint Cloud, France (e-mail: f.spyratos{at}stcloud-huguenin.org).

Recent clinical data (1) suggest that c-erbB-2 overexpression/amplification might be associated with tamoxifen resistance in patients with estrogen receptor (ER)-positive tumors. This association is controversial, however, and the question of the efficacy of hormone therapy in these patients is still a matter of debate. In a recent issue of the Journal, Konecny et al. (2) provided some answers to this question. After considering c-erbB-2, ER, and progesterone receptors (PRs) as continuous variables, they reported that patients with higher levels of c-erbB-2 overexpression had statistically significantly lower ER and PR levels than patients with lower levels of c-erbB-2 overexpression. They suggested that this finding might explain the relative resistance of c-erbB-2–positive, hormone receptor–positive tumors to hormone therapy.

Given the small number of retrospective studies offering data relevant to this question, we strictly reproduced the methodology of Konecny et al. (2) in a retrospective series of 488 patients with primary breast cancer and a median follow-up of 10 years for whom c-erbB-2, ER, and PR expression had been measured by quantitative biochemical methods, allowing them to be analyzed as continuous variables. The patients’ characteristics have been published elsewhere (3). For this analysis, 101 (20.7%) of the 488 patients were considered to be c-erbB-2–positive (protein levels above 350 IU/mg protein), providing separation of patients with regard to disease-free survival (P = .002) and overall survival (P<.001). This c-erbB-2 positivity frequency is in the range of published values (2,4).

Our results were as follows. First, among patients with c-erbB-2–overexpressing tumors (n = 101), we found a negative correlation between c-erbB-2 and ER and PR levels (ER: r = –0.41, P<.001; PR: r = –0.24, P = .01). Second, patients with c-erbB-2–positive tumors had statistically significantly lower absolute ER and PR levels than patients whose tumors did not overexpress c-erbB-2 (Table 1Go). Third, when we divided the 101 patients with c-erbB-2–positive tumors into two subgroups of approximately equal size, the median ER level was statistically significantly lower in the 52 patients with higher c-erbB-2 overexpression than in the 49 patients with weaker c-erbB-2 overexpression. Fourth, when we restricted this analysis to patients with hormone receptor–positive tumors (Table 1Go), those with higher c-erbB-2 overexpression had a lower median ER level than those with lower c-erbB-2 overexpression. Differences in PR levels were not statistically significant.


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Table 1. Median estrogen receptor (ER) and progesterone receptor (PR) levels according to c-erbB-2 expression using data from (3)
 
Thus, by applying the methodology of Konecny et al. retrospectively to an independent population, we confirmed their results, i.e., the higher the level of c-erbB-2 overexpression, the lower the ER level, both in the overall population and in the subset of patients with hormone receptor–positive tumors. Because the response to endocrine therapy depends on ER and PR levels, not only on arbitrarily defined ER and PR status (positive versus negative), the lower ER and PR expression in c-erbB-2–positive/ER-positive tumors could explain the failure of this treatment in such patients. Indeed, there is compelling evidence that cross-talk between ER and growth factor receptor pathways, such as those involving the EGFR/c-erbB-2 family, can alter ER function and thereby contribute to tumor growth and tamoxifen resistance (5–7). Taken together, these results emphasize the importance of considering the quantitative levels of c-erbB-2 and ER rather than using dichotomous systems.

REFERENCES

1 Stal O, Borg A, Ferno M, Kallstrom AC, Malmstrom P, Nordenskjold B. ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer. Ann Oncol 2000;11:1545–50.[Abstract]

2 Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 2003;95:142–53.[Abstract/Free Full Text]

3 Ferrero-Pous M, Hacène K, Bouchet C, Le Doussal V, Tubiana-Hulin M, Spyratos F. Relationship between c-erbB-2 and other tumor characteristics in breast cancer prognosis. Clin Cancer Res 2000;6:4745–54.[Abstract/Free Full Text]

4 Hayes DF, Thor AD. C-erbB-2 in breast cancer: development of a clinically useful marker. Semin Oncol 2002;29:231–45.[CrossRef][ISI][Medline]

5 Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, et al. Elevated levels of epidermal growth factor receptor/ c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 2003;144:1032–44.[Abstract/Free Full Text]

6 Kurokawa H, Arteaga CL. ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. Clin Cancer Res 2003;9:511S–5S.[Abstract/Free Full Text]

7 Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, et al. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 2003;95:353–61[Abstract/Free Full Text]



             
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