CORRESPONDENCE

Re: Effect of Epidermal Growth Factor Receptor Inhibitor on Development of Estrogen Receptor–Negative Mammary Tumors

Manuela Campiglio, Nicola Normanno, Sylvie Ménard

Affiliations of authors: Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy (MC, SM); Hematology Oncology, INT-Fondazione Pascale, Naples, Italy (NN).

Correspondence to: Sylvie Ménard, PhD, Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy (e-mail: sylvie.menard{at}istitutotumori.mi.it)

In the prevention of breast carcinoma, any new drug capable of inhibiting the onset of breast carcinoma will offer new opportunities to fight this disease. Data from Lu et al. (1) suggested that treatment with ZD1839 (an anti–epidermal growth factor [EGF]-receptor tyrosine-kinase inhibitor) to prevent hormone-independent breast carcinomas might be complementary to established antihormonal treatments. However, some considerations must be pointed out before conclusions can be extrapolated to the prevention of human tumors. In the MMTV-rat HER2/neu proto-oncogene transgenic mice model, any treatment that reduces mammary gland development, including vaccination against HER2/neu (2), has been shown to prevent or delay tumor onset by reducing the number of cells at risk of transformation. Accordingly, we found that even tamoxifen, in the same transgenic model, prevented the onset of mammary tumors, even though they were hormone receptor–negative tumors, by reducing the number of mammary alveoli (3). These results clearly contrast with observations obtained with tamoxifen in clinical trials that showed no effect on estrogen receptor–negative tumors, and thus indicate that the response of normal mammary tissue to drugs vary between transgenic mice and humans.

Similarly, in Ménard et al. (3), prevention might result from the inhibition of mammary gland development (true prevention) induced by ZD1839, as suggested by the observed decrease of normal breast epithelia proliferation. This result should be assessed by analyzing whole mounts of the mouse mammary gland tree (4,5). Prevention of tumor onset may, however, still be attributed to a therapeutic effect of the drug on small occult tumors. The lack of information concerning mammary gland morphology and the onset of preinvasive lesions in transgenic mice treated with ZD1839 hampers the discrimination between these two possibilities. Invasive carcinomas in transgenic mice are preceded by hyperplasia and in situ carcinomas, which may or may not be inhibited by ZD1839. The conclusion of Lu et al. suggesting that a mechanism by which ZD1839 prevented tumor onset in a transgenic mouse model cannot be faithfully extrapolated to humans. In fact, a direct effect on normal mammary cells of transgenic mice may have no clinical application to human breast pathology, because the effect of ZD1839 on human breast tissue that does not express the transgene might be completely different. If the observed delay in tumor onset is indeed attributable to a therapeutic effect of ZD1839 on occult tumors, clinical trials of ZD1839 in high-risk women could be planned, particularly in women carrying BRCA1 mutations, who often develop hormone-independent tumors. However, drug dosage might represent a problem because the prevention of mammary carcinogenesis in mice was obtained at doses associated with side effects (100 mg/kg). In humans, tumor responses and improvements in general symptoms were observed at a dose of less than 10 mg/kg (6,7). In conclusion, active doses of ZD1839 may vary greatly in mice and humans. The observations by Lu et al. should prompt further investigations of ZD1839 as a breast cancer prevention agent to clarify its action on normal breast tissue and gland development and to lead to the design of a clinical trial with ZD1839 as chemoprevention agent for breast cancer.

REFERENCES

1 Lu C, Speers C, Zhang Y, Xu X, Hill J, Steinbis E, et al. Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors. J Natl Cancer Inst 2003;95:1825–33.[Abstract/Free Full Text]

2 Nanni P, Nicoletti G, De Giovanni C, Landuzzi L, Di Carlo E, Cavallo F, et al. Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. J Exp Med 2001;194:1–12.[Abstract/Free Full Text]

3 Menard S, Aiello P, Tagliabue E, Rumio C, Lollini PL, Colnaghi MI, et al. Tamoxifen chemoprevention of a hormone-independent tumor in the proto-neu-transgenic mice model. Cancer Res 2000;60:273–5.[Abstract/Free Full Text]

4 Cappello P, Triebel F, Iezzi M, Caorsi C, Quaglino E, Lollini PL, et al. LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in HER-2/neu transgenic BALB/c mice. Cancer Res 2003;63:2518–25.[Abstract/Free Full Text]

5 Jones FE, Stern DF. Expression of dominant-negative ErbB2 in the mammary gland of transgenic mice reveals a role in lobuloalveolar development and lactation. Oncogene 1999;18:3481–90.[CrossRef][ISI][Medline]

6 Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:2237–46.[Abstract/Free Full Text]

7 Cohen EE, Rosen F, Stadler WM, Recant W, Stenson K, Huo D, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21:1980–7.[Abstract/Free Full Text]



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