© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 18, 1584-1585,
September 15, 1999
© 1999 Oxford University Press
CORRESPONDENCE |
Re: Prognostic Importance of Low c-erbB2 Expression in Breast Tumors
Affiliation of authors: Centre René Huguenin de Lutte Contre Le Cancer, Saint-Cloud, France.
Correspondence to: Frédérique Spyratos, Ph.D., Laboratoire d'Oncobiologie, Centre René Huguenin, 35 rue Dailly, 92211 Saint-Cloud, France (e-mail: spyratos{at}calva.net ).
Numerous studies involving thousands of patients have shown that c-erbB2 abnormalities (gene amplification and protein overexpression) are associated with a poor prognosis in patients with breast cancer [reviewed in (1)]. Recently, surprising data were published by Koscielny et al. in the Journal (2) and in the report of a prospective multicenter study (3) suggesting that low c-erbB2 protein expression is a strong negative prognostic factor for women with breast cancer. According to these reports, low c-erbB2 protein levels were statistically significantly more frequent in estrogen receptor (ER)-negative tumors. Moreover, median c-erbB2 protein levels were comparable in tumors and healthy breast tissue from nine patients.
To assess the implications of these results, we studied c-erbB2 protein expression in tumor
specimens, obtained from a retrospective series of 488 primary breast cancer patients, in which
c-erbB2 had been measured as it was by Koscielny et al. These patients' clinical
characteristics have been published elsewhere (4,5). The overall
distributions of c-erbB2 protein values was log-normal, with a geometric mean (201 arbitrary
units/mg protein; median, 170; interquartile range, 118-300) comparable to that in the multicenter
study (3) and particularly in the Villejuif series. With the use of
Koscielny's cutoff, low c-erbB2 protein levels were not statistically significantly more
numerous in ER-negative tumors than in ER-positive tumors (chi-square = 0.78; P = .37), while high c-erbB2 protein levels were statistically significantly more
numerous in ER-negative tumors (P<.001), as is found classically. When we examined
metastasis-free survival rates at 38 months (as had Koscielny) and 60 months according to
c-erbB2 protein expression (Table 1
), the lowest metastasis rate was
always observed in patients with low c-erbB2 protein expression. In contrast, the highest
metastasis rate was observed in patients with high c-erbB2 protein expression (P<.001).
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Thus, by use of the same methodology applied to a larger population, we obtained similar distributions and frequencies of low and high c-erbB2 protein levels as those reported by Koscielny et al., but we did not observe a negative prognostic impact of low levels of c-erbB2 protein or a high frequency of low protein levels in ER-negative tumors. Finally, mean c-erbB2 protein levels were generally 20 times higher in malignant tumors than in normal breast tissue obtained from patients who underwent reduction mammoplasty (n = 20; data not shown).
Several reasons can be proposed to explain these discrepancies: First, the overall number of patients in Koscielny's series was small (n = 117), particularly the number of patients with low (n = 10) and high (n = 17) c-erbB2 protein levels. The other series that showed a paradoxical detrimental effect of low c-erbB2 values included only 115 patients (5). Survival curves based on such small sample sizes can lead to statistical artifacts, especially when follow-up is short. Furthermore, in Koscielny's study only "healthy" tissues from the cancerous breast—rather than from a normal breast—were compared with adjacent tumor tissue. Finally, there may have been differences in the patient populations. Our 44 patients with low c-erbB2 protein levels did not have particularly adverse prognostic indicators: 89% of them had fewer than three positive axillary lymph nodes, and a small proportion had thymidine-kinase (7%), urokinase plasminogen activator (7%), and p53 values (9%) above their respective third quartiles (75th percentiles).
The link between low c-erbB2 protein expression and a poor outcome is not confirmed by our study of a larger number of patients with longer follow-up. Furthermore, c-erbB2 protein expression was not comparable in normal and malignant breast tissues.
REFERENCES
1 Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells 1998;16:413-28.[Web of Science][Medline]cancerlit;99048707
2
Koscielny S, Terrier P, Spielmann M, Delarue JC. Prognostic
importance of low c-erbB2 expression in breast tumors [letter]. J Natl Cancer
Inst 1998;90:712.
3 Koscielny S, Terrier P, Daver A, Wafflart J, Goussard J, Ricolleau G, et al. Quantitative determination of c-erbB-2 in human breast tumours: potential prognostic significance of low values. Eur J Cancer 1998;34: 476-81.cancerlit;98378918
4 Bouchet C, Spyratos F, Hacene K, Durcos L, Becette V, Oglobine J. Prognostic value of urokinase plasminogen activator in primary breast carcinoma; comparison of two immunoassay methods. Br J Cancer 1998;77:1495-501.[Web of Science][Medline]cancerlit;98314876
5 Dittadi R, Brazzale A, Pappagallo G, Salbe C, Nascimben O, Rosabian A, et al. ErbB2 assay in breast cancer: possibly improved clinical information using a quantitative method. Anticancer Res 1997;17:1245-7.[Medline]cancerlit;97283348
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