Presence of Estrogen Receptor Imparts a Poorer Prognosis for Young Women with Breast Cancer
ABSTRACT & COMMENTARY
Synopsis: It has long been recognized that breast cancer is particularly aggressive in young patients. Examining the results from four adjuvant chemotherapy trials from the International Breast Cancer Study Group involving 3700 pre- or perimenopausal patients, of whom 314 were younger than 35 years old at diagnosis, disease-free and overall survival was significantly worse for younger patients. Unexpectedly, for patients in this younger age group, the presence of estrogen receptor (ER) was associated with higher relapse rates and shorter survival. Perhaps endocrine ablative therapies are warranted in conjunction with chemotherapy for young women with ER-positive breast cancer.
Source: Aebi S, et al. Lancet 2000;355:1869-1874.
Breast cancer in young women has been associated with a poorer prognosis, and this is true even with aggressive adjuvant chemotherapy. In this report from the International Breast Cancer Study Group (IBCSG), the outcomes from several adjuvant chemotherapy trials were analyzed with particular reference to patient age and survival.
The IBCSG conducted four randomized controlled trials in which 3700 premenopausal breast cancer patients were treated with various timing and duration of adjuvant chemotherapy including cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without prednisone or oophorectomy. Of these, 314 were younger than 35 years of age. Relapse and death occurred earlier and more often in those younger than 35, compared with those older than 35 years. The 10- year disease-free survival was 35% for those younger than 35, compared to 47% for those older than 35 years, and overall survival was 49% vs. 62% for the same age groups, respectively (hazard ratio 1.5; 95% CI 1.28-1.77 [P < 0.001]).
Younger patients with ER-positive tumors had a significantly worse disease-free survival than those in the same age group with ER-negative tumors. This is in contrast to older (premenopausal) patients in whom the disease-free interval was similar irrespective of tumor ER status.
Aebi and colleagues conclude that young premenopausal patients treated with adjuvant CMF had a higher risk of relapse and death and they point out that the subset of patients in this group with ER positive tumors are at the greatest risk. Aebi et al suggest that the endocrine effects of CMF chemotherapy alone are inadequate and that these patients should be treated with more definitive endocrine ablation (e.g., oophorectomy or tamoxifen) in addition to chemotherapy if their tumors express estrogen receptors.
COMMENT BY WILLIAM B. ERSHLER, MD
The concept that breast cancer is more indolent in old age may be true, but data from a number of sources would also indicate that it is more aggressive in younger patients, particularly those in their twenties and thirties.1-3 This report from the IBCSG bears this out. The 314 women who were younger than 35 years at diagnosis fared considerably worse than the other 3386 who were 35 years of age or older and premenopausal, in terms of relapse and survival on their four adjuvant chemotherapy trials undertaken between 1978 and 1993. In these trials, tumor size, histopathological grade and axillary lymph node metastasis were significant prognostic factors. However, controlling for these factors, young age remained a significant predictor of poor outcome.
The unexpected and striking finding from this study, however, was that the presence of ER in tumors from these young patients had a remarkable adverse effect on outcome. Women younger than 35 with ER-positive tumors fared poorly with a 10-year disease-free survival of 25% and an overall survival of 39%—significantly worse than that for similarly aged patients with ER-positive tumors (disease-free survival of 46% and overall survival of 60% at 10 years).
What are the implications of this noteworthy finding? Of course, corroboration is necessary and should be sought without delay. (In this regard, similar data derived from other cooperative groups would be of value.) Nonetheless, the data presented are compelling. It is tempting to speculate that the more aggressive behavior of ER-positive tumors in this age group is indicative of a strongly positive signal produced by the higher estrogen levels present in these younger patients, and the failure of CMF chemotherapy to abrogate this effect. Perhaps more definitive endocrine ablative therapy is required for young patients with ER-positive tumors. Whether that alone would overcome the negative effect of young age remains to be seen. It is tempting to think that it might, and clinicians reading this report will no doubt have an inclination toward such an approach. However, for some young women with early- stage breast cancer, irreversible ovarian ablation might be considered extreme. Thus, future clinical investigation would seem warranted. It is possible that if examination of data from similar populations (e.g., NSABP) reveals similar findings (i.e., significantly worse prognosis for young women with ER-positive tumors), some might argue that it would be unethical to include an experimental arm that includes chemotherapy without hormonal ablation. However, it will be recalled that the IBCSG protocols included primarily CMF, and current regimens that include adriamycin or taxanes may more successfully reduce ovarian endocrine function and thereby result in more favorable clinical outcomes.
References
1. Kollias J, et al. Br J Cancer 1997;75:1318-1323.
2. Adami HO, et al. N Engl J Med 1986;315:559-563.
3. Chung M, et al. Cancer 1996;77:97-103.
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