CORRESPONDENCE

RESPONSE: Re: Italian Randomized Trial Among Women With Hysterectomy: Tamoxifen and Hormone-Dependent Breast Cancer in High-Risk Women

Umberto Veronesi, Patrick Maisonneuve, Nicole Rotmensz, Andrea Decensi, Giuseppe Viale, Peter Boyle

Affiliations of authors: U. Veronesi, P. Maisonneuve, N Rotmensz, A. Decensi, G. Viale, P Boyle, Divisions of Senology, Chemoprevention and Pathology and Department of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy; G. Viale, University of Milan, Milan, Italy.

Correspondence to: Professor Peter Boyle, Ph.D., Department of Epidemiology and Biostatistics, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy (e-mail: director.epi{at}ieo.it).

We concluded our recent publication (1) by noting that the effect of tamoxifen in chemoprevention appeared to be restricted to women predicted to be at high risk of the hormone-dependent form of the disease. We identified a subgroup of women in the Italian Randomized Trial of Tamoxifen at high risk of estrogen receptor (ER)-positive breast cancer on the basis of baseline measurements and emphasized that these results require confirmation from other trials before the clinical and public health implications are clear (1). We still believe this to be the case.

Narasimhadevara et al. make some interesting points; notably, that we did not attempt to identify a subgroup at high risk of ER-negative breast cancer. When we investigated the role of the hormonal variables as risk factors, none of the variables in Table 1Go of our original article (1) (i.e., use of hormone replacement therapy, height, ovary function, age at menarche, age at first birth) were statistically significantly associated with the risk of ER-negative breast cancer in the study cohort. Only breast cancer in a first-degree relative (odds ratio = 2.6, 95% confidence interval = 0.8 to 8.1) approached statistical significance. We agree that ER-negative breast cancer is a very important form of breast cancer and one that deserves a great deal of attention, especially in terms of prevention, both primary prevention and chemoprevention. However, it is counter intuitive to expect hormonal interventions with agents such as tamoxifen and other SERMs (selective estrogen receptor modulators) to have an impact on the risk of this form of the disease.


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Table 1. Number and proportion of HER2-overexpressing tumors per number of breast tumors in the various subgroups of patients in the Italian Tamoxifen Chemoprevention Trial
 
It must be clear when reading Menard et al., particularly the opening paragraph, that when we referred to "high risk" (1), we were referring to the high risk of hormone-dependent breast cancer and not high risk of breast cancer per se. When Menard et al. state that the frequency of ER-negative tumors was higher than expected, the statement should be interpreted with caution. In our study, 30% of the breast tumors in women receiving the placebo were ER-negative. This frequency may be different from that in a general population, because half of the women in our study had a bilateral oophorectomy before baseline (1). The higher proportion (40%) of ER-negative tumors in women receiving tamoxifen may reflect the ability of tamoxifen to prevent ER-positive tumors. In women in the placebo arm of our study, which is the only arm that can be compared with population based-studies, the cumulative incidence of ER-positive tumors was about four times higher for those in the high-risk group than for those in the low-risk group. The proportion of ER-positive tumors in the placebo arm was also higher in the high-risk group (73%) than in the low-risk group (66%) (1).

The evidence that tamoxifen protects against ER-positive breast cancer in a subset of subjects is quite compelling (2), but tamoxifen is still ineffective in subjects at low risk of developing the disease. There are many potential mechanisms that could be proposed to explain such a lack of effect, and Menard et al. have chosen to focus on one of these. In our study, we observed a higher proportion of tumors that over-expressed HER2 in the low-risk group than in the high-risk group, supporting the hypothesis of Menard et al. (Table 1Go).

We continue to obtain a better understanding of the impact of tamoxifen in the chemoprevention setting and are starting to have a better indication of where to search for potential mechanisms. Of course, the great challenge in breast cancer prevention remains the ER-negative form of the disease, where alternatives to the hormonal approach are needed, and with some urgency.

NOTES

It is a pleasure to acknowledge the participation of the Italian women who took part in this study and all the members of the Italian Tamoxifen Study Group. The study was funded in part by grants from the CNR, the Italian Association for Research on Cancer, the American–Italian Cancer Foundation, and from the Italian League Against Cancer.

REFERENCES

1 Veronesi U, Maisonneuve P, Rotmensz N, Costa A, Sacchini V, Travaglini R, et al. Italian randomized trial among women with hysterectomy: Tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst 2003;95:160–5.[Abstract/Free Full Text]

2 Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, et al. Overview of main outcomes in breast cancer prevention trials. Lancet 2003;361:296–300.[CrossRef][ISI][Medline]



             
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