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Journal of Clinical Oncology, Vol 24, No 31 (November 1), 2006: pp. 4949-4951 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.9160
Still Waiting After 110 Years: The Optimal Use of Ovarian Ablation As Adjuvant Therapy for Breast CancerThe Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD Although Schinzinger1 first suggested that oophorectomy might be used to treat breast cancer in 1889, it is Sir George Beatson2 who is associated with its establishment as an effective therapeutic modality based on his seminal 1896 Lancet publication describing successful treatment of young women with advanced breast cancer with bilateral oophorectomy. Studies of surgical oophorectomy were followed by those assessing ovarian irradiation, leading ultimately to the 1948 launch at the Christie Hospital (Manchester, United Kingdom) of the first randomized trial of ovarian ablation (OA) using irradiation versus no OA for premenopausal women with operable breast cancer.3 By the 1960s, many considered OA to be an effective adjuvant modality in breast cancer, but interest subsided with the demonstration of the efficacy of adjuvant chemotherapy and the belief that OA failed to alter survival in premenopausal women. This view was challenged by the serial reports of the Early Breast Cancer Trialists' Collaborative Group showing that OA or ovarian suppression (OS) offered an unequivocal survival benefit compared with no therapy for women under 50 years of age.4-6 In addition, the ovarian suppressive or ablative effects of chemotherapy in young women were recognized,7 which raised the possibility that the benefits of chemotherapy might be mediated in part by indirect effects on the ovary leading to estrogen deprivation. These observations led to a generation of randomized trials assessing the efficacy of OA/OS by surgery, radiotherapy, or luteinizing hormone–releasing hormone agonists compared with chemotherapy8-12 or in addition to chemotherapy.11,13-15
In this issue, Ejlertsen et al12 report the long-term outcome of patients treated in such a trial, the Danish Breast Cancer Cooperative Group (DBCG) Trial 89B. This study randomly assigned 762 premenopausal women with steroid hormone receptor–positive early breast cancer deemed at high risk for recurrence (axillary nodal involvement or tumor size The unique strengths of this study include its maturity, exclusion of women with known steroid receptor–negative breast cancer who are unlikely to benefit from endocrine therapy, focus on an essentially node-positive population at high risk for recurrence, and uniform approach to therapy. Potential limitations include the use of a chemotherapy regimen (CMF) that some might consider substandard in the era of taxanes and anthracyclines, failure to incorporate tamoxifen, and elements of the statistical design and power.
The DBCG 89B investigators used a noninferiority statistical design to test the hypothesis that ovarian irradiation was not inferior to chemotherapy. Active-control noninferiority trials are often used when the choice of a placebo-controlled study is considered unethical. However, this type of trial design is challenging because of the need to define an acceptable margin of inferiority to reduce the risk of introducing a potentially suboptimal treatment into clinical practice while maintaining a reasonable sample size.16 The predefined sample size of 750 patients chosen for DBCG 89B permitted detection of a 25% relative decrease in disease-free survival with pelvic irradiation as clinically unacceptable using two-sided testing with Nonetheless, the conclusion of Ejlertsen et al12 that radiation-induced OA/OS and CMF have a similar effect on disease-free and overall survival for premenopausal women with receptor-positive breast cancer is likely to be correct. This study joins four other published studies comparing OA/OS by surgery,8 goserelin,9,11 or leuprolide10 with variations of CMF that have shown similar results for women with hormone-responsive disease. DBCG 89B is the only study that exclusively used irradiation to induce OA/OS and excluded women with known hormone receptor–negative disease (although 22% of the enrolled subjects had unknown receptor status), thereby limiting inclusion of patients expected to gain nothing from OA/OS and derive greater benefit from chemotherapy.17 A tragedy of all of these trials, as well as concurrent trials that tested chemotherapy followed by OA/OS, is that they failed to incorporate tamoxifen because of the prevailing belief at the time that it was not effective in premenopausal women with hormone-responsive disease.4 Still other trials tested OS plus tamoxifen versus chemotherapy, again without tamoxifen in the control chemotherapy arms,18-20 and not until the 1995 meeting of the Early Breast Cancer Trialists' Collaborative Group was the misconception about the lack of benefit from adjuvant tamoxifen in premenopausal women finally discredited.21 In the DBCG 89B trial, all but one of 375 patients stopped regular menses after pelvic irradiation, suggesting that irradiation as delivered in this study (15 Gy in 5 fractions over 1 week) effectively induces amenorrhea.12 This contrasts with the results of the Intergroup trial 0142 (E3193) that reported a 75% likelihood of achieving OA in 20 premenopausal women with steroid hormone receptor–positive disease as defined by postmenopausal levels of estradiol or follicle-stimulating hormone 6 months after treatment with tamoxifen and ovarian irradiation (20 Gy in 10 fractions over 2 weeks).22 Although differences in the radiotherapy prescription may account for this variation, these findings resemble the experience with chemotherapy-induced amenorrhea where some clinically amenorrheic women secrete premenopausal hormonal levels because of incomplete suppression of ovarian function.23 These results remind us that chemotherapy- or radiation-induced amenorrhea should not be viewed as synonymous with menopause. This is particularly important with the emergence of aromatase inhibitors as treatment for postmenopausal women and the resulting temptation to prescribe aromatase inhibitors to women with therapy-related amenorrhea. A recent report on the outcome of 45 young women who developed chemotherapy-induced amenorrhea at a median age of 47 years (range, 39 to 52 years) and were placed on an aromatase inhibitor showed that 12 women (27%) subsequently recovered ovarian function after a median total duration of amenorrhea of 12 months (range, 4 to 59 months) and after a median duration of aromatase inhibitor therapy of 6 months (range, 3 to 18 months), as manifested by resumption of menses, pregnancy without menses, or premenopausal hormonal levels in the absence of menses.24 This is a stark reminder that aromatase inhibitor modulation of negative feedback loops may lead to a paradoxical increase in gonadotropin secretion and ovarian stimulation. Indeed, the combination of follicle-stimulating hormone with aromatase inhibitor is an effective way to induce ovarian stimulation for embryo cryopreservation to preserve fertility before adjuvant chemotherapy.25 A logical extension of the DBCG 89B trial is to consider the role of OA/OS after chemotherapy. Four published randomized trials addressing this question have in aggregate shown little value for this sequence.11,13-15 The observations that chemotherapy without endocrine therapy may be ineffective in women less than age 35 years7 and that the benefit from using OS after chemotherapy may be limited to women younger than age 40 years11,14 suggest that OA/OS may benefit young premenopausal women with hormone receptor–positive disease who do not develop complete ovarian failure after chemotherapy. However, these trials were also fundamentally flawed by failure to incorporate tamoxifen optimally. Tamoxifen forms the backbone of adjuvant systemic endocrine therapy for all premenopausal women with steroid receptor–positive breast cancer at present, and the integration of these findings on OA/OS in the tamoxifen era has not been properly addressed. The DBCG 89B investigators had the foresight to limit participation to women with steroid receptor–positive breast cancer. The future testing and application of endocrine therapies like OA/OS will certainly take advantage of exploding knowledge about potential predictive markers of endocrine response like human epidermal growth factor receptor 2 or multigene expression profiles. Indeed, molecular profiling seems to define several different types of estrogen receptor–positive breast cancers with different natural history26 and likely different response to therapy.27,28 It is expected that advances in genomics, proteomics, and pharmacogenomics will refine our ability to use endocrine therapies effectively. In this context, several key international trials will belatedly address the historical accidents that have favored the use of chemotherapy and plagued the study of OA/OS in the premenopausal setting. The Suppression of Ovarian Function Trial is now comparing the role of 5 years of tamoxifen, OA/OS plus tamoxifen, and OA/OS plus exemestane for premenopausal women with steroid receptor–positive breast cancer who did not receive chemotherapy or who continue to have premenopausal estradiol levels after chemotherapy. The related Premenopausal Endocrine Responsive Chemotherapy Trial (PERCHE) trial is questioning whether premenopausal women benefit from chemotherapy through random assignment to optimal endocrine therapy alone or chemotherapy. Important considerations in this area in the future will revolve around optimal duration of OA/OS, balancing the potential breast cancer benefit with the related toxicity, especially bone loss. OS and CMF in the Zoladex Early Breast Cancer Research Association Study offered similar survival outcome in premenopausal women with receptor-positive breast cancer, but two thirds of the patients in the OS group resumed menses after 2 years of goserelin, whereas two thirds of patients treated with CMF did not.9 This suggests that permanent menopause may not be required for long-term benefit from OS, and temporary OS may be effective and minimize the long-term health effects of premature menopause. It is both exhilarating and sobering to compare the pace of clinical development of two different strategies of estrogen-deprivation therapy, OA/OS for premenopausal women and aromatase inhibitors for postmenopausal women. In the latter case, improvements in our understanding of breast cancer biology, use of more sophisticated trial design, and freedom from bias about the value of chemotherapy led to a rapid and ongoing evaluation of the rightful role for aromatase inhibitors. In the former case, our failure to capitalize optimally on Dr Beatson's observations was hampered by our inability to recognize OA/OS as the first targeted therapy, the use of primitive trial designs by modern standards, and fundamental misconceptions about the effectiveness of endocrine therapy in premenopausal women. With the advantage of hindsight, let us hope that it will not take another 100+ years to right these errors and that these lessons will inform our evaluation of biologically based therapy in the future. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions
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Early Breast Cancer Trialists' Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet 348:1189-1196, 1996[CrossRef][Medline] 7. Goldhirsch A, Gelber RD, Yothers G, et al: Adjuvant therapy for very young women with breast cancer: Need for tailored treatments. J Natl Cancer Inst Monogr 30:44-51, 2001 8. Thomson CS, Twelves CJ, Mallon EA, et al: Adjuvant ovarian ablation vs CMF chemotherapy in premenopausal breast cancer patients: Trial update and impact of immunohistochemical assessment of ER status. Breast 11:419-429, 2002[CrossRef][Medline] 9. Jonat W, Kaufmann M, Sauerbrei W, et al: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20:4628-4635, 2002 10. Schmid P, Untch M, Wallwiener D, et al: Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node-positive, premenopausal breast cancer patients: Preliminary results of the TABLE-study (Takeda Adjuvant Breast Cancer Study with Leuprorelin Acetate). Anticancer Res 22:2325-2332, 2002[Medline] 11. Castiglione-Gertsch M, O'Neill A, Price KN, et al: Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 95:1833-1846, 2003 12. Ejlertsen B, Mouridsen HT, Jensen M-B, et al: Ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: Similar efficacy from a randomized comparison in premenopausal patients with node-positive, hormone receptor–positive breast cancer. J Clin Oncol 24:4956-4962, 2006 13. Arriagada R, Le MG, Spielmann M, et al: Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy. Ann Oncol 16:389-396, 2005 14. Davidson NE, O'Neill AM, Vukov AM, et al: Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor–positive breast cancer: Results from INT 0101 (E5188). J Clin Oncol 23:5973-5982, 2005 15. Baum M, Hackshaw A, Houghton J, et al: Adjuvant goserelin in pre-menopausal patients with early breast cancer: Results from the ZIPP study. Eur J Cancer 42:895-904, 2006[CrossRef][Medline] 16. Kaul S, Diamond GA: Good enough: A primer on the analysis and interpretation of noninferiority trials. Ann Intern Med 145:62-69, 2006 17. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658-1667, 2006 18. 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Smith IE, Dowsett M, Yap Y-S, et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhea: Caution and suggested guidelines. J Clin Oncol 24:2444-2447, 2006 25. Oktay K, Buyuk E, Libertella N, et al: Fertility preservation in breast cancer patients: A prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol 23:4347-4353, 2005 26. Sorlie T, Tibshirani R, Parker J, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418-8423, 2003 27. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 28. Paik S, Tang G, Shak S, et al: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726-3734, 2006 This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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5 cm) to receive pelvic irradiation as a form of OA/OS or nine courses of cyclophosphamide, methotrexate, and fluorouracil (CMF) intravenously every 3 weeks. Both therapies were well tolerated, and there was no apparent difference in overall survival after a median follow-up time of 10.5 years and 358 first events (hazard ratio = 1.11; 95% CI, 0.88 to 1.42).
= 5% and ß = 20%. The observed unadjusted hazard ratio estimate for disease-free survival of 0.99 (95% CI, 0.81 to 1.22; P = .95) rejects the null hypothesis of inequality and supports the alternative hypothesis of equality. However, the upper boundaries of the CIs do not rule out a possible 22% greater disease-free survival or a 42% greater overall survival benefit with CMF, which raises the question of whether the DBCG 89B trial was adequately powered to address a noninferiority question in a clinically meaningful way. 
