© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 3, 240-241,
February 7, 2001
© 2001 Oxford University Press
CORRESPONDENCE |
Re: Randomized Trial of Fenretinide to Prevent Second Breast Malignancy in Women With Early Breast Cancer
Affiliation of authors: National Cancer Institute, European Institute of Oncology, Milan, Italy.
Correspondence to: Sylvie Ménard, M.D., National Cancer Institute, Milan, Italy (e-mail: menard{at}istitutotumori.mi.it).
The multicenter chemoprevention clinical trial (1) performed to evaluate the effect of the fenretinide treatment on the incidence of contralateral tumors in patients surgically treated for a previous breast cancer has shown a preventive effect of the synthetic retinoid only in premenopausal patients. The issue of a possible interaction between fenretinide and steroid hormones is still unclear. In breast carcinoma cell lines, fenretinide was shown to be active on tumors positive or negative for expression of both estrogen receptors (ERs) and progesterone receptors (PgRs), although it was slightly more effective on the receptor-positive tumor cells (2). To verify whether the sensitivity to fenretinide in vivo was dependent on the receptor status, we investigated a subset of 1329 women followed at the National Cancer Institute of Milan, with information on hormone receptor expression in primary tumor and in second ipsilateral (19 events) or contralateral (80 events) tumor recurrence. Expression of ER and PgR was assessed by immunohistochemistry. Cutoff limit for positivity for both receptors was set at staining of more than 10% of the cells in the immunohistochemical analysis after counting at least 200 cells and after independent evaluation by two investigators as described previously (3). The prevalence of ER-positive status and PgR-positive status in recurrent tumors according to the type of treatment and patient menopausal status at randomization was evaluated. The rationale is that more sensitive tumors, either receptor positive or receptor negative, should be less represented in the treated arm. The results in Table 1
indicate a decrease in frequency of hormone receptor positivity in the premenopausal fenretinide-treated group in comparison with the premenopausal-untreated group, a slightly more pronounced decrease for PgR positivity than for ER positivity. In both cases, however, the difference was not statistically significant at the conventional 5% significance level with the use of the Pearson chi-square test. On the contrary, in postmenopausal patients, where fenretinide did not produce a statistically significant difference in the appearance of contralateral tumors compared with those who did not receive the treatment, a tendency toward a slight increase in both receptor expressions was observed. The differences in both expressions again were not statistically significant.
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The Cox model was used to estimate the treatment effect according to menopausal status and hormone receptor expression in the primary tumor. The results, reported as a hazard ratio, indicated a protective fenretinide effect in premenopausal women and an opposite trend in postmenopausal women in general, with slight differences for receptor-positive and receptor-negative patients. Such differences were never statistically significant when tested with suitable interaction terms in the Cox models.
The above findings indicate that hormone receptor characteristics of the primary tumor do not seem to influence effects of fenretinide treatment, even though the hormone receptor-negative tumors in premenopausal women seem to benefit from fenretinide treatment to a lower extent than the receptor-positive tumors, in keeping with in vitro data. All of these data on hormone receptor expression do not shed much light on the reason why only premenopausal women benefit from the fenretinide treatment. A direct action of the retinoid on normal breast epithelial cells only when they are hormone stimulated can be hypothesized (4). Also, fenretinide was found to lower the circulating levels of insulin-like growth factor-I in early breast cancer (5), particularly in premenopausal patients. In conclusion, fenretinide seems to be active, regardless of the ER status and the PR status. This may further suggest a possible synergistic effect between fenretinide with tamoxifen that was observed in the preclinical model (6) and now under investigation in a clinical trial in premenopausal women.
NOTES
Supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro.
We thank Mrs. P. Aiello for technical assistance and Mrs. L. Mameli for manuscript preparation.
REFERENCES
1
Veronesi U, De Palo G, Marubini E, Costa A, Formelli F, Mariani L, et al. Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer. J Natl Cancer Inst 1999;91:1847–56.
2 Pellegrini R, Mariotti A, Tagliabue E, Bressan R, Bunone G, Coradini D, et al. Modulation of markers associated with tumor aggressiveness in human breast cancer cell lines by N-(4-hydroxyphenyl)retinamide. Cell Growth Differ 1995;6:863–9.[Abstract]cancerlit;96040186
3 Menard S, Casalini P, Tomasic G, Pilotti S, Cascinelli N, Bufalino R, et al. Pathobiologic identification of two distinct breast carcinoma subsets with diverging clinical behaviors. Breast Cancer Res Treat 1999;55:169–77.[Web of Science][Medline]cancerlit;99409670
4 Mehta RG, Moon RC, Hawthorne M, Formelli F, Costa A. Distribution of fenretinide in the mammary gland of breast cancer patients. Eur J Cancer 1991;27:138–41.cancerlit;91222619
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Torrisi R, Pensa F, Orengo MA, Catsafados E, Ponzani P, Boccardo F, et al. The synthetic retinoid fenretinide lowers plasma insulin-like growth factor I levels in breast cancer patients. Cancer Res 1993;53:4769–71.
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