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Originally published as JCO Early Release 10.1200/JCO.2004.07.961 on October 25 2004 © 2004 American Society of Clinical Oncology.
Adjuvant Chemotherapy for Elderly Women With Hormone Receptor-Positive Breast Cancer: An Old(er) ProblemThe Breast Oncology Program, Comprehensive Cancer Center, and the Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI Since the mid-1980s, mortality as a result of breast cancer has been declining in the Western world, due in part to the widespread application of adjuvant systemic therapy.1-3 However, for the most part, clinical trials have failed to address the benefit of adjuvant chemotherapy in elderly women.4 The few efforts to do so have involved what appear to be better tolerated, yet—one hopes—efficacious treatments. In this issue of the Journal of Clinical Oncology, Fargeot et al5 from the French Adjuvant Study Group (FASOG) report results of a prospective, randomized clinical trial of weekly adjuvant epirubicin compared to no postoperative chemotherapy for estrogen receptor (ER) -positive, node-positive patients over the age of 65 years, all of whom also received tamoxifen, either alone or concurrent with and following epirubicin. The investigators observed a modest but statistically significant improvement in disease-free survival, but no improvement in overall survival for the epirubicin-treated patients. Although this study represents a victory in accruing patients older than 65 years to a prospective chemotherapy trial, one must question whether these benefits are clinically meaningful. Retrospective subgroup analyses of early randomized trials of adjuvant chemotherapy compared to observation alone suggested that older women gain proportionally less benefit than younger women.6,7 Subsequently, the Oxford Worldwide Overview of adjuvant systemic therapy demonstrated a stepwise reduction in relative efficacy of adjuvant chemotherapy with advancing age by decade.3 Several hypotheses have been proposed to explain these observations, including shorter expected life span in general, differential reductions in delivered dose, and possible differences in tumor biology resulting in reduced sensitivity to chemotherapy in elderly patients.8,9 Examination of each of these possibilities provides little further insight. The significant survival benefit from adjuvant tamoxifen, even in older women, speaks against the argument that comorbidity and mortality from other causes prevent prolongation of survival due to suppression of breast cancer.2 Reductions in chemotherapy dose might play a role, since the elderly represent a special population of patients for whom concurrent morbidity could lead to decreased tolerance of toxic regimens.8,10,11 Some investigators have reported higher toxicities from chemotherapy in the elderly,12,13 but several studies have suggested that, with careful selection and with certain caveats, fit elderly women tolerate chemotherapy as well as their younger counterparts.14-16 Alternatively, the elderly may have tumors that are biologically less responsive to chemotherapy. Studies have demonstrated that untreated and treated prognoses differ by age, as do biologic factors that are known to be important in both prognosis and prediction for systemic therapy in general.17,18 Of these, increased expression of ER in older women is the most consistently observed difference. This observation would obviously lead to higher rates of benefit from endocrine therapy, but ER expression alone may also decrease chemosensitivity.19 Nonetheless, in addition to the present study by Fargeot et al,5 other large cooperative groups have also reported statistically significant improvement in outcomes in postmenopausal women with the use of chemotherapy plus tamoxifen compared to tamoxifen alone.13,20,21 Of interest, two of these studies—National Surgical Adjuvant Bowel and Breast Project B-16 and Southwest Oncology Group Intergroup 8814—employed doxorubicin-based regimens, raising the possibility that perhaps anthracycline therapy might be more effective in the elderly, hormone-responsive patient than nonanthracycline regimens. The results from the Fargeot study appear to provide even more support for this theory. Where does weekly epirubicin, as used in the Fargeot study,5 fit in the strategy for adjuvant treatment of the elderly? Using efficacy predictions based on the Oxford/Early Breast Cancer Clinical Trialists’ Group meta-analysis, and on relapse predictions based on Surveillance, Epidemiology, and End Results data, adjuvant regimens such as cyclophosphamide, methotrexate, and fluorouracil would be expected to reduce the absolute risk of recurrence over 10 years for a 70-year-old healthy woman with a T2, N1, ER-positive breast cancer by approximately 3%, when given in addition to tamoxifen.3,22 This estimate of benefit of adjuvant chemotherapy is consistent with that seen in the Fargeot study, after excluding the ER-negative patients who were erroneously included in the trial. Consistent with the theory that ER expression is a negative predictive factor for sensitivity to chemotherapy, the relative improvement in disease-free survival due to epirubicin (tamoxifen only, 20% compared to tamoxifen plus epirubicin, 50%) in this small subset was substantially larger than that observed in the remaining ER-positive patients. Taken together, do the results of the previously reported studies and from the current FASOG clinical trials provide conclusive evidence that all ER-positive, node-positive elderly women should receive adjuvant chemotherapy in addition to tamoxifen? If so, should the chemotherapy regimen include an anthracycline? We think not. First, the absence of a survival benefit in this study, and the dearth of data from other trials addressing this age group, speaks against widespread adoption of this approach. Although other studies have reported a modest survival benefit in all ER-positive, node-positive postmenopausal women, these studies have not been directly targeted towards the elderly, nor have retrospective subsets been presented from trials with women older than 65 years.13,20 One could argue that delay of recurrence is, by itself, an end point that justifies treatment, but this issue remains controversial.23,24 Second, these results must be placed in the context of ongoing progress in endocrine treatment of postmenopausal women in the modern era. Although still controversial, inhibition of aromatase activity has recently been shown in three published trials to significantly reduce the annual odds of recurrence by as much as 30% in ER-positive women.25-27 It seems intuitive that one can achieve greater benefit with less toxicity from the sequential use of hormonal treatments than by the addition of chemotherapy, although longer follow-up of these studies is needed.28 This randomized trial of chemotherapy compared to no chemotherapy in an elderly, ER-positive, node-positive patient population supports the hypothesis that breast cancer recurrences are reduced by adjuvant chemotherapy in the elderly. However, the absolute benefit is relatively low, and would be expected to be even lower when compared with improved endocrine therapies. Nonetheless, taken together, the results of this and other trials imply that there is a group of ER-positive postmenopausal women for whom endocrine therapy is not adequate, and for whom chemotherapy is most likely to be of benefit, if this group can be reliably identified. These observations call for two initiatives. First, more tolerable chemotherapeutic regimens with equal or better efficacy for this patient population must be identified. Such efforts are ongoing in Cancer and Leukemia Group B Intergroup 49907, in which women older than 65 years with node-positive and/or tumors larger than 3 cm are randomly assigned to a standard regimen (doxorubicin and cyclophosphamide or cyclophosphamide, methotrexate, and fluorouracil) or single-agent capecitabine. Second, we need better predictive markers to identify those patients with ER-positive breast cancers who might benefit from alternatives to tamoxifen alone. For example, in a preliminary report, which requires confirmation, investigators from the Southwestern Oncology Group have suggested that women who were most likely to benefit from addition of cyclophosphamide, doxorubicin, and fluorouracil to tamoxifen also overexpressed HER-2, while the HER-2–negative patients did just as well with tamoxifen alone.29 Recently reported studies also suggest that multigene expression analysis may provide a tool to more precisely define which patients will benefit less from tamoxifen or other endocrine therapies30 The field of pharmacogenetics is expanding rapidly, providing even more opportunity to individualize specific endocrine therapy and chemotherapies, including schedules and doses.31 With time, such approaches may identify patients most likely to benefit from chemotherapy in general, and to specific regimens, such as those that contain anthracyclines. With these tools, patients and physicians will be better able to choose therapies that are tailored to an individual patient’s inherent genetics and tumor biology, making application of these treatments safer and more effective. Until then, it remains difficult to know how best to treat elderly women who have hormone receptor positive breast cancer. Authors’ Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Honoraria: Daniel F. Hayes, Genomics Health, Pfizer. Research Funding: Daniel F. Hayes, AstraZeneca. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue. Acknowledgment Supported by a grant from the National Institutes of Health RO1 CA092461 (D.F.H.) and by Fashion Footwear Foundation/QVC Presents Shoes on Sale (D.F.H.). REFERENCES 1. Peto R, Boreham J, Clarke M, et al: UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 355:1822, 2000[Medline] 2. Early Breast Cancer Trialist’s Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998[CrossRef][Medline] 3. Early Breast Cancer Trialist’s Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 352:930-942, 1998[CrossRef][Medline] 4. Muss HB: Factors used to select adjuvant therapy of breast cancer in the United States: An overview of age, race, and socioeconomic status. J Natl Cancer Inst Monogr No. 30:52-55, 2001
5. Fargeot P, Bonneterre J, Roché H, et al: Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of French Adjuvant Study Group 08 Trial. J Clin Oncol 22:4674-4682, 2004 6. Fisher B, Slack N, Katrych D, et al: Ten year follow-up results of patients with carcinoma of the breast in a cooperative clinical trial evaluating surgical adjuvant chemotherapy. Surg Gynecol Obstet 140:528-534, 1975[Medline] 7. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-410, 1976[Abstract] 8. Bonadonna G, Valagussa P: Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 304:10-15, 1981[Abstract] 9. Goldhirsch A, Gelman RS, Gelber RD, et al: Treatment of breast cancer in elderly patients. Lancet 336:564, 1990[CrossRef][Medline]
10. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in Stage II breast cancer. J Clin Oncol 4:1162-1170, 1986 11. Gelman RS, Taylor SG 4th: Cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: The elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 2:1404-1413, 1984[Abstract]
12. Crivellari D, Bonetti M, Castiglione-Gertsch M, et al: Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: The International Breast Cancer Study Group Trial VII. J Clin Oncol 18:1412-1422, 2000 13. Fisher B, Redmond C, Legault-Poisson S, et al: Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: Results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol 8:1005-1018, 1990[Abstract] 14. Gelman RS, Taylor SG 4th: Cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: The elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 2:1404-1413, 1984 15. Begg CB, Carbone PP: Clinical trials and drug toxicity in the elderly: The experience of the Eastern Cooperative Oncology Group. Cancer 52:1986-1992, 1983[CrossRef][Medline]
16. Ibrahim N, Frye D, Buzdar A, et al: Doxorubicin-based chemotherapy in elderly patients with metastatic breast cancer: Tolerance and outcome. Arch Intern Med 156:882-888, 1996 17. Adami H-O, Malker B, Meirik O, et al: Age as a prognostic factor in breast cancer. Cancer 56:898-902, 1985[CrossRef][Medline] 18. Eppenberger-Castori S, Moore DH Jr, Thor AD, et al: Age-associated biomarker profiles of human breast cancer. Int J Biochem Cell Biol 34:1318-1330, 2002[CrossRef][Medline] 19. Lippman ME, Allegra JC, Thompson EB, et al: The relation between estrogen receptors and response rate to cytotoxic chemotherapy in metastatic breast cancer. N Engl J Med 298:1223-1228, 1978[Abstract] 20. Albain KS, Green S, Ravdin P, et al: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from intergroup trial 0100. Proc Am Soc Clin Oncol 21:37a, 2002 (abstr 143) 21. Colleoni M, Litman HJ, Castiglione-Gertsch M, et al: Duration of adjuvant chemotherapy for breast cancer: A joint analysis of two randomised trials investigating three versus six courses of CMF. Br J Cancer 86:1705-1714, 2002[CrossRef][Medline]
22. Ravdin PM, Siminoff LA, Davis GJ, et al: Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 19:980-991, 2001 23. Gelber R, Goldhirsch A: A new endpoint for the assessment of adjuvant therapy in postmenopausal women with operable breast cancer. J Clin Oncol 4:1772-1779, 1986[Abstract] 24. Gelber RD, Goldhirsch A, Cavalli F: Quality-of-life-adjusted evaluation of adjuvant therapies for operable breast cancer. Ann Intern Med 114:621-628, 1991 25. ATAC Trialists’ Group T: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline]
26. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003
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28. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment working group update: Use of aromatase inhibitors in the adjuvant setting. J Clin Oncol 21:2597-2599, 2003 29. Ravdin P, Green S, Albain K, et al: Initial report of the SWOG biological correlative study of c-erbB-2 expression as a predictor of outcome in a trial comparing adjuvant CAF T with tamoxifen alone. Proc Am Soc Clin Oncol 17:97a, 1998 (abstr 324) 30. Paik S, Shak S, Tang G, et al: Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients-NSABP B-20 and B-14. Breast Cancer Research and Treatment 82:S11, 2003 (abstr 16) 31. Stearns V, Davidson NE, Flockhart DA: Pharmacogenetics in the treatment of breast cancer. Pharmacogenomics J 4:143-153, 2004[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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