© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 8, 728,
April 21, 1999
© 1999 Oxford University Press
CORRESPONDENCE |
Re: erbB-2, p53, and Efficacy of Adjuvant Therapy in Lymph Node-Positive Breast Cancer
Affiliation of authors: Department of Oncology, Western General Hospital, Edinburgh, U.K.
Correspondence to: D. A. Cameron, M.D., F.R.C.P., Department of Oncology, Western General Hospital, Crewe Rd., S., Edinburgh, EH4 2XU, U.K.
One of the current emphases in biologic research in breast cancer is a shift toward factors that predict benefit from therapy, as opposed to those that relate to the prognosis for a patient. This is to be welcomed, but in the move, the ground rules already established for assessing the validity or otherwise of putative factors should not be ignored. It was therefore disappointing that the latest report on the CALGB 8541/8869 studies that assess the potential interaction between c-erbB-2 expression and dose intensity of adjuvant doxorubicin did not fully comply with the guidelines published by the late W. L. McGuire 7 years ago in this same journal (1). The confirmatory study by Thor et al. (2) clearly failed to confirm the earlier pilot study by Muss et al. (3), which had reported that benefit from the higher dose intensity of doxorubicin-based adjuvant therapy was only to be seen in patients whose tumors have high expression of c-erbB-2. Apart from a possible population bias in that the larger, confirmatory group was inevitably itself drawn from the patients in the original 8541 study, this negative conclusion concurred with Dr. McGuire's proposed guidelines.
The problem, however, lies in the attempt to explain this negative confirmatory report by developing a prognostic model for the disease-free survival of the patients studied. In so doing, the authors failed to comply with four of Dr. McGuire's seven guidelines. First, there was no clear biologic hypothesis for the negative term for estrogen receptor (ER) [quite apart from the problems that the presence or absence of ERs was not significant for disease-free survival in the univariate or multivariate analyses presented in the paper; and the fact that expression of ER has been reported to violate an essential assumption for inclusion in a Cox proportional hazards model, namely, that the hazard ratio should be independent of time (4)]. Second, there was no random allocation of the patients into an exploratory and confirmatory group for validation of this new prognostic model. Third, no sample-size calculation is presented to confirm that the population studied was of sufficient size to empower the prognostic model. Fourth, there is an inherent possible population bias in that the population on which the prognostic model was derived constituted the patients under scrutiny and represented less than two thirds of the entire cohort in CALGB 8541. Furthermore two of the three of the remaining McGuire guidelines are not really applicable to the proposed index.
It is clearly of importance to the Oncologic community, physician and patient alike, to know if there is a genuine interaction between the dose intensity of adjuvant anthracycline and outcome of women whose tumors have high expression of c-erbB-2, but this study, as presented, can only be interpreted as a negative confirmatory study. The application of an independently produced and validated prognostic model, such as that developed by the Nottingham group (5), is required before there is any conclusion other than that this study fails to confirm the earlier findings reported by Muss et al. (3).
REFERENCES
1
McGuire WL. Breast cancer prognostic factors: evaluation
guidelines [editorial]. J Natl Cancer Inst 1991;83:154-5.
2
Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson
IC, et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 1998;90:1346-60.
3
Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, et al.
c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast
cancer [published erratum appears in N Engl J Med 1994;331:211]. N Engl J
Med 1994;330: 1260-6.
4 Pichon MF, Broet P, Magdelenat H, Delarue JC, Spyratos F, Basuyau JP, et al. Prognostic value of steroid receptors after long-term follow-up of 2257 operable breast cancers. Br J Cancer 1996;73:1545-51.[ISI][Medline]cancerlit;96262138
5 Galea MH, Blamey RW, Elston CE, Ellis IO. The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 1992;22:207-19.[CrossRef][ISI][Medline]cancerlit;93004812
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||