Lesson learned from high-dose chemotherapy for high-risk breast cancer (What you see is what you mean)

M. Colleoni*,1, N. Rotmensz2, G. Martinelli3, R. Gelber4, A. Coates5 and A. Goldhirsch6

1 Department of Medicine, 2 Department of Epidemiology and Biostatistics, and 3 Division of Hemato-oncology, Department of Medicine, European Institute of Oncology, Milan, Italy; 4 Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, USA; 5 The Cancer Council Australia, Sydney, NSW, Australia; 6 Oncology Institute of Southern Switzerland, Lugano, Switzerland, and Department of Medicine, European Institute of Oncology, Milan, Italy

*E-mail: marco.colleoni@ieo.it

Recognition of the importance of receptor expression is crucial for understanding treatment effects in the adjuvant treatment of breast cancer. The Netherlands Working Party on Autologous Transplantation in Solid Tumors recently presented the results of a randomized study comparing conventional dose chemotherapy with conventional dose chemotherapy followed by high-dose chemotherapy [1]. The authors should be complimented for providing data after a proper duration of follow-up and for having dissected them in a way that provides the readership with hypotheses-generating information [2]. The study was designed in an era when adjuvant therapies were prescribed according to risk factors: the higher the risk the more intensive the treatment. Recent developments include an increasing attention to predictive factors and to systemic therapies prescribed according to the higher chance of response [3]. As presented by the Dutch investigators, response to higher dose chemotherapy for patients who are at high risk for relapse is associated with some very interesting and unpredicted features: benefit was seen almost exclusively in patients with low grade breast cancer, in patients at young age (<40 years), and in those who had no overexpression of HER2/neu in their primary tumor. Furthermore, the patterns of response in this latter subpopulation are similar to those observed with endocrine treatments (i.e. delayed onset of the treatment difference).

The interpretation of these data might be facilitated by the following information:

In a series of 4565 consecutive patients, all operated on at the European Institute of Oncology from September 1999 to December 2002, 864 (18.9%) had HER2/neu overexpression classified as 3+, while 3701 patients (81.1%) had either 0 (58.3%), 1+ (11.0%) or 2+ (11.8%) classified tumors (Table 1). The table shows the correlation between the degree of expression of estrogen and progesterone receptors separately for pre- and postmenopausal women, clearly indicating the higher prevalence of endocrine responsive disease in the group of patients selected by the exclusion of HER2/neu overexpression. It is noteworthy that patients of premenopausal age with endocrine responsive disease are more likely to achieve a large endocrine effect with the high dose chemotherapy regimen through ovarian function suppression. Also women of postmenopausal age may obtain some additional endocrine effect from suppression of adrenals [4] due to cytotoxics and steroids, both given at higher doses to patients in the group allocated to high-dose chemotherapy.
The International Breast Cancer Study Group (IBCSG) Trial 15-95 of high-dose chemotherapy given up front for three courses compared with conventional dose regimen in 344 patients [5] also showed that high-dose chemotherapy was effective primarily in a subgroup of young women (<40 years of age). This was a retrospective analysis and therefore should be considered with caution. Endocrine effects of chemotherapy were recorded and in the high-dose group 85% of 95 patients with known menstrual activity had amenorrhea compared with only 48% of 98 patients in the conventional dose group.


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Table 1. Correlation between HER2/neu overexpression and degree of expression of ER and PgR
 
We therefore conclude that intensive chemotherapy should be studied in a population of patients with tumors that are not endocrine responsive to avoid the endocrine-related confounding effect.

REFERENCES

1. Rodenhuis S, Bontenbal M, Beex LV et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003; 349: 7–16.[Abstract/Free Full Text]

2. Coates AS, Gelber RD, Goldhirsch A. Subsets within the chemotherapy overview. International Breast Cancer Study Group. Lancet 1998; 352: 1783–1784.[CrossRef]

3. Goldhirsch A, Wood WC, Gelber RD et al. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 2003; 21: 3357–3365.[Abstract/Free Full Text]

4. Rose DP, Davis TE. Effects of adjuvant chemohormonal therapy on the ovarian and adrenal function of breast cancer patients. Cancer Res 1980; 40: 4043–4047.[Abstract]

5. Basser R, O’Neill A, Martinelli G et al. Randomized trial comparing up-front, multi-cycle dose-intensive chemotherapy (CT) versus standard dose CT in women with high-risk stage 2 or 3 breast cancer (BC): first results from IBCSG Trial 15-95. Proc Am Soc Clin Oncol 2003; 22: 6 (Abstr 20).





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