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Adjuvant Endocrine Therapy for Premenopausal Hormone Receptor–Positive Breast Cancer: Much Done, More to Do

Adjuvant Endocrine Therapy for Premenopausal Hormone Receptor–Positive Breast Cancer: Much Done, More to Do

Based on the 1995 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Overview, tamoxifen is now the standard of care for premenopausal women with hormone receptor–positive early breast cancers.[1] In this issue of ONCOLOGY, Dr. Kathy Pritchard provides a comprehensive review of the current role of ovarian suppression/ablation (OS/OA) in the management of these patients. Astonishingly, despite more than a century of research on the subject, many questions remain unanswered. Is there a benefit to be gained from the addition of a luteinizing hormone-releasing hormone (LHRH) agonist to tamoxifen for women who continue to menstruate after adjuvant chemotherapy? Is the optimal hormonal treatment of such patients a combination of tamoxifen and an LHRH agonist? Can OS/OA replace chemotherapy for select good-risk patients? As most patients with early breast cancer will survive their diagnosis,[2] is premature menopause resulting from permanent amenorrhea a required feature?

We hope that current ongoing studies will definitively answer how best to select not only the most effective combinations of adjuvant therapies, but also the subgroup of patients most likely to gain from these interventions. Any potential disease-free or overall survival advantage of combination treatments must be balanced against a possible increase in adverse effects and impairment of quality of life for these young patients.

EBCTCG Overview Update

The 2000 EBCTCG Overview included more than 7,000 women younger than 50 years who participated in randomized trials assessing the role of OA/OS.[3] This meta-analysis concluded that OA/OS significantly reduced breast cancer mortality but only in the absence of other treatments. Significantly, 47% of those studied had unknown hormone receptor status. Therefore, these results likely underestimate the impact of OA/OS.[3]

Dr. Pritchard discusses the unpublished 2006 EBCTCG Overview results, which similarly failed to show an advantage for OA plus chemomotherapy over chemotherapy alone, and subgroup analyses from this study are not yet available. However, the Early Breast Cancer Overview Group included 315 women aged 40 years or younger in their recent meta-analysis of 11,906 women.[4] In this subgroup the addition of an LHRH agonist to chemotherapy, with or without tamoxifen, significantly reduced rates of recurrence by 25.2% (P = .01) and all deaths by 27.4% (P = .01).

Major Studies

ant Breast Cancer Ovarian Ablation or Suppression randomized trial did not demonstrate an overall advantage for the addition of OS to adjuvant tamoxifen with or without chemotherapy,[5] its conclusions are limited by the fact that patients therein were treated with tamoxifen and OA/OS regardless of tumor estrogen receptor status. Moreover, 73% of the chemotherapy prescribed was CMF (cyclophosphamide, methotrexate, and fluorouracil), which is associated with a higher permanent amenorrhea rate than modern non–CMF-based chemotherapy regimens.[6] These factors may have masked the true impact of OS/OA, particularly in younger hormone receptor–positive breast cancer patients, who are most likely to have return of menses after chemotherapy.

Compared with those over 35, very young patients with endocrine-responsive and node-negative breast cancer have a worse outcome even if treated with tamoxifen and modern chemotherapy regimens,[7] which underscores the importance of optimizing tailored treatments for this group. The Zoladex In Premenopausal Patients (ZIPP) trial found that the addition of goserelin (Zoladex) to standard adjuvant therapy was more effective than standard therapy (tamoxifen for all, chemotherapy for 43%) in premenopausal women with early breast cancer.[8] These findings suggest that there is indeed a role for adjuvant combination therapy with tamoxifen and an LHRH agonist after chemotherapy especially among very young premenopausal women and that the most definitive benefit may be seen in women who do not experience permanent amenorrhea after chemotherapy. We look to the results of the ongoing Suppression of Ovarian Function Trial (SOFT) to clarify this issue.

Aromatase Inhibitors

Aromatase inhibitors (AIs) have become an alternative to tamoxifen for adjuvant hormonal therapy in postmenopausal women and, in combination with LHRH agonists, can produce profound estrogen depletion.[9] While contraindicated in premenopausal women due to increased ovarian stimulation, several large prospective randomized trials have been mounted to address whether an adjuvant combination of an LHRH agonist and an AI can improve clinical outcomes.

Preliminary results of the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 study, in which 1,801 premenopausal women with endocrine-responsive breast cancer were randomly assigned to goserelin and tamoxifen or goserelin and anastrozole (Arimidex), were presented in mid-2008. A second randomized question was the role of zoledronic acid (Zometa).[10] At a median follow-up of 60 months, no significant difference was seen in disease-free survival between patients who received goserelin plus tamoxifen and those who received goserelin plus anastrozole, but this trial may have been underpowered to detect small differences between these two groups. SOFT is randomly assigning such women to receive tamoxifen alone, OS plus tamoxifen, or OS plus exemestane (Aromasin), while the Tamoxifen and Exemestane Trial (TEXT) has randomly assigned premenopausal patients to the LHRH agonist triptorelin (Trelstar) with tamoxifen or with exemestane (with or without chemotherapy). In the meantime, single-agent AI therapy may promote recovery of ovarian function in some women with chemotherapy-induced amenorrhea and should be used with caution and regular biochemical monitoring of ovarian function using highly sensitive estradiol assays.[11]

Other Trials

Prospective trials randomizing premenopausal women with early-stage hormone receptor–positive breast cancer to adjuvant combination hormonal therapy or to chemotherapy and hormonal therapy are lacking. The Premenopausal Endocrine Responsive Chemotherapy (PERCHE) and Premenopausal Optimal Management Is Endocrine Therapy (PROMISE) trials closed early due to poor patient accrual. Provocatively, a small study that also closed prematurely randomly assigned 174 patients with node-positive, hormone receptor–positive disease to receive four cycles of adjuvant chemotherapy added to OS and 5 years of tamoxifen or to OS and tamoxifen without chemotherapy. At 10 years of follow-up, the investigators found no difference in disease-free or overall survival between the two groups.[12]

Conclusions

In keeping with current expert guidelines,[13,14] we support the use of either tamoxifen alone or tamoxifen plus OS as adjuvant endocrine therapy for premenopausal women with hormone receptor–positive breast cancer. The most apparent benefit of combination treatment has been observed in retrospective subgroup analyses of women younger than 40 years enrolled in large trials. The use of AIs together with LHRH agonists at this time remains investigational. We look forward to the successful completion of the ongoing adequately powered studies that are characterizing optimal therapies for this challenging patient group.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

1. Tamoxifen for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:1451-1467, 1998.
2. Giordano SH, Hortobagyi GN: Time to remove the subspecialty blinders: Breast cancer does not exist in isolation. J Natl Cancer Inst 100:230-231, 2008.
3. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005.
4. LHRH-agonists in Early Breast Cancer Overview Group: Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: A meta-analysis of individual patient data from randomised adjuvant trials. Lancet 369:1711-1723, 2007.
5. Ovarian ablation or suppression in premenopausal early breast cancer: Results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst 99:516-525, 2007.
6. Petrek JA, Naughton MJ, Case LD, et al: Incidence, time course, and determinants of menstrual bleeding after breast cancer treatment: A prospective study. J Clin Oncol 24:1045-1051, 2006.
7. Colleoni M, Rotmensz N, Peruzzotti G, et al: Role of endocrine responsiveness and adjuvant therapy in very young women (below 35 years) with operable breast cancer and node negative disease. Ann Oncol 17:1497-1503, 2006.
8. 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.
9. Jannuzzo MG, Di Salle E, Spinelli R, et al: Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone. Breast Cancer Res Treat. March 11, 2008 (epub ahead of print).
10. Gnant MB, Mlineritsch B, Schippinger W, et al: Adjuvant ovarian suppression combined with tamoxifen or anastrazole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive, stage I and II breast cancer: First efficacy results from ABCSG-12 (abstract LBA4). J Clin Oncol 26(15S):6s, 2008.
11. Smith IE, Dowsett M, Yap YS, et al: Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: Caution and suggested guidelines. J Clin Oncol 24:2444-2447, 2006.
12. Thürlimann B, Price KN, Gelber RD, et al: Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93. Breast Cancer Res Treat. Feb 8, 2008 (epub ahead of print).
13. Goldhirsch A, Wood WC, Gelber RD, et al: Progress and promise: Highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 18:1133-1144, 2007.
14. NCCN practice guidelines in oncology, v.2.2008. Available at www.nccn.org. Accessed Dec 16, 2008.
 
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