© 2004 by Oxford University Press
© 2004 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Effect of Epidermal Growth Factor Receptor Inhibitor on Development of Estrogen Receptor-Negative Mammary Tumors
Affiliations of authors: Departments of Medicine and Molecular and Cellular Biology, Breast Center, Baylor College of Medicine, Houston, TX (CL, SM, SH, PHB); AstraZeneca, Macclesfield, UK (AW).
Correspondence to: Powel Brown, MD, PhD, Baylor College of Medicine, One Baylor Plaza, MS: 600, Houston, TX 77030 (e-mail: pbrown{at}breastcenter.tmc.edu)
In their correspondence, Campiglio et al. comment that epidermal growth factor receptor (EGFR) blockade induced by the tyrosine kinase inhibitor ZD1839 (i.e., gefitinib) may offer new opportunities to fight breast cancer. We certainly agree and appreciate their comments pertaining to our recently reported results (1). They also raised very reasonable questions about the mechanism by which this agent suppresses mammary tumor development. We would like to respond to these important questions.
First, the authors asked whether the data from our recent experiments showing that ZD1839 suppresses estrogen receptor (ER)-negative mammary tumorigenesis in transgenic mice can be extrapolated to humans, clearly a critical question. We admit that the answer to this question awaits human clinical cancer prevention trials using EGFR inhibitors. However, until the results from these human studies are available, in our opinion the results in the MMTV-erbB2 mice offer the most relevant preclinical data supporting development of signal transduction inhibitors for the prevention of ER-negative human breast cancer.
Second, the authors raised the question whether EGFR blockade affects mammary gland development. ZD1839 had no effect on mammary gland development in these experiments (as can be seen in Fig.1A). In this experiment, we treated virgin mice only after the age of 3 months. By 3 months of age, the mouse mammary gland has developed fully to the state of an adult virgin mouse. We are now investigating whether EGFR inhibitors prevent ER-negative breast cancer in other mouse models that do not depend on the overexpression of erbB2. These results in other mouse models will provide additional information to determine whether the cancer preventive effect of EGFR blockade is generalizable.
Third, the authors asked whether our results occurred because of treatment of cryptic invasive tumors. This is an important question that was also raised after the publication of the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 breast cancer prevention trial (2–4). We have recently conducted experiments that directly address this question. In these experiments, MMTV-erbB2 mice were treated for 4 months from the age of 3 months to 7 months with ZD1839 (100 mg/kg) or vehicle, exactly as previously described (1). Normal appearing mammary glands were then removed from the mice. We then examined the frequency of hyperplasia, mammary intraepithelial neoplasia (MIN, which is similar to human ductal carcinoma in situ [DCIS] lesions) and cryptic invasive cancers in mammary glands of these mice. As shown in Fig. 1 B and C, ZD1839 treatment reduced the number of premalignant and non-invasive malignant lesions and cryptic invasive cancers. Specifically, we observed a statistically significant reduction in the number of mammary glands showing any premalignant or malignant lesion (P<.001 by a two-sided Fisher’s exact test), in mice treated with ZD1839 as compared with those treated with vehicle. In addition, the number of glands showing hyperplasia was statistically significantly reduced (P = .04) by ZD1839 treatment. The number of glands showing MIN lesions or cryptic invasive tumors was also reduced in mice treated with ZD1839, but this difference did not reach statistical significance (P = .10).
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These results could occur from an early block in the progression pathway (from normal to hyperplasia) or from a global effect at each step throughout tumor progression. However, in answer to the question asked, it is clear from these data that ZD1839 does not only treat cryptic invasive cancers. We favor the interpretation that ZD1839 suppresses ER-negative tumor progression at each stage. Indeed, this is similar to the conclusion drawn from studies of premalignant and non-invasive lesions in women treated with tamoxifen on the NSABP P-1 breast cancer prevention trial (2,5). As reported, tamoxifen was found to prevent the formation of premalignant lesions (5), as well as DCIS and invasive cancers (2).
Finally, we agree with the authors’ comment that additional preclinical and clinical studies will be needed before EGFR inhibitors are ready for wide spread use for the prevention of breast cancer.
NOTES
This work was supported by a National Institutes of Health Specialized Programs of Research Excellence (SPORE) grant (P50 CA58183), and by NCI CA101211.
Dr. Brown has a grant from Astra-Zeneca to conduct laboratory research on an unrelated project.
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.
2 Fisher B, Costantino JP, Wickerham L, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–88.
3 Radmacher MD, Simon R. Estimation of tamoxifen’s efficacy for preventing the formation and growth of breast tumors. J Natl Cancer Inst 2000;92:48–53.
4 Lippman SM, Brown PH. Tamoxifen prevention of breast cancer: an instance of the fingerpost. J Natl Cancer Inst 1999;91:1809–89.
5 Tan-Chiu E, Wang J, Costantino JP, Paik S, Butch C, Wickerham DL, et al. Effects of tamoxifen on benign breast disease in women at high risk for breast cancer. J Natl Cancer Inst 2003;95:302–7.
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J Natl Cancer Inst 2004 96: 715.
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