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Neoadjuvant Endocrine Therapy for Breast Cancer: An Overlooked Option?

Neoadjuvant Endocrine Therapy for Breast Cancer: An Overlooked Option?

Locally advanced breast cancer accounts for up to 70% of breast cancer cases worldwide.[ 1] In the past decade, neoadjuvant systemic therapy has emerged as a therapeutic option for early breast cancer. The main goal of neoadjuvant treatment is to downstage breast tumors, rendering them operable or permitting breast-conserving surgery. The therapy has been used increasingly in patients who have large breast tumors and are candidates for mastectomy, but in whom tumor shrinkage allows for less extensive surgery and better cosmetic results.[2] The degree of the tumor's responsiveness to preoperative therapy could serve as a surrogate for the response of micrometastasis to therapy and the consequent outcome.[3] Most neoadjuvant studies have evaluated chemotherapy, with response rates ranging from 60% to 90%. The National Surgical Adjuvant Breast and Bowel Project B-18 trial demonstrated that preoperative chemotherapy with doxorubicin and cyclophosphamide (Cytoxan, Neosar) was as effective as postoperative chemotherapy and permitted more lumpectomies.[3] Similarly, the Oxford overview analysis showed that patients with estrogen-receptor (ER)- positive tumors achieved a survival benefit from adjuvant endocrine therapy, justifying the use of neoadjuvant endocrine therapy in ER-positive tumors. The role of neoadjuvant endocrine therapy in elderly patients and patients with severe comorbid conditions is well established.[4] Aromatase inhibitors in the neoadjuvant setting provide an excellent alternative to chemotherapy as they are not associated with many of the side effects seen with cytotoxic therapy. What data do we have, however, to help us decide which form of therapy is appropriate based on patient characteristics? Neoadjuvant Endocrine Therapy
Few controlled studies of neoadjuvant endocrine therapy have been conducted. Earlier studies of tamoxifen as primary treatment alone compared to surgery followed by tamoxifen demonstrated good initial responses, but long-term recurrence rates were high. These findings led to decreasing enthusiasm for this drug as primary treatment. Several additional studies concluded, however, that tamoxifen was a reasonable alternative for elderly patients with operable breast cancer. The development of aromatase inhibitors and their efficacy in postmenopausal women with metastatic breast cancer led to numerous studies of these drugs in both the neoadjuvant and adjuvant settings. An important phase III, double-blind randomized, multicenter study conducted by Ellis et al compared 4 months of letrozole (Femara) with tamoxifen in postmenopausal women who had hormone-receptor- positive breast cancer and were ineligible for surgery.[5] In the letrozole group, 60% of patients responded vs 41% in the tamoxifen groups; 48% underwent successful breast-conserving surgery in the letrozole group vs 36% in the tamoxifen group. Another objective of this study was to examine the relationship between HER2/neu expression and tumor response. The authors concluded that ER-, ErbB-1-, and ErbB-2-positive primary breast cancer responded well to letrozole, but responses to tamoxifen were few. Patients with low positive levels of ER expression were responsive to letrozole, leading to the concern that this subset of patients could be unnecessarily excluded from the benefits of endocrine therapy. These observations brought us one step closer to an understanding of the biology of breast cancer. Small studies have also evaluated exemestane (Aromasin) in the neoadjuvant setting. The Immediate Preoperative Arimidex Compared to Tamoxifen (IMPACT) trial cited by Wong and Ellis compared the efficacy of anastrozole (Arimidex) and tamoxifen alone and in combination as neoadjuvant therapy. Preliminary data presented at the 2003 San Antonio Breast Cancer symposium showed comparable efficacy for anastrozole and tamoxifen in postmenopausal women with ER-positive operable breast cancer, although it should be noted that twice as many patients were eligible for breast-conserving surgery in the anastrozole group compared with the tamoxifen group. No studies have directly compared neoadjuvant aromatase inhibitor therapy to neoadjuvant chemotherapy in postmenopausal women. Wong and Ellis have made indirect comparisons that are difficult at best, given the different patient characteristics with respect to age, ER status, menopausal status, and size of the tumor. Nevertheless, aromatase inhibitors appear to have better toxicity profiles than chemotherapy, which has both longterm and short-term adverse effects in the elderly population. The most common adverse effects seen with aromatase inhibitors include hot flashes, fatigue, and osteoporosis; their adverse effect on blood lipids is being investigated further. The extent of breast-conserving surgery among patients who receive an aromatase inhibitor compared with those who receive anthracycline-based therapy is about the same when T2 and larger tumors are included. Overall response rates in phase II and III trials of neoadjuvant chemotherapy range from 48% to 95%, but most of these trials did not report response rates based on ER status.[6] Survival
No randomized studies have compared survival of patients treated with neoadjuvant endocrine therapy followed by surgery with those undergoing surgery followed by adjuvant endocrine therapy. Current evidence suggests that no survival advantage is associated with neoadjuvant systemic therapy, but there is also no obvious downside to this therapy. In lieu of long-term randomized or observational studies, the only means by which to assess improved survival would be the development of valid biomarkers as surrogates of long-term outcome. Conclusions
Neoadjuvant endocrine therapy has a probable role in elderly postmenopausal patients with significant comorbidities. Well-designed randomized trials comparing neoadjuvant aromatase inhibitor therapy with neoadjuvant chemotherapy would assist clinicians in their treatment decisions. Development of validated biomarkers that could predict response would aid in tailoring medical therapy to individual patients, as demonstrated in the responsiveness of ER-positive, HER1- positive, and HER2-positive patients to letrozole. This strategy should be studied further. Additional studies of the molecular mechanisms of estrogendependent breast cancer should also be conducted. Microarray gene analysis studies are ongoing in an attempt to determine which tumors will respond to neoadjuvant endocrine therapy.


Dr. Vogel receives grant or research support from NIH/NCI/ NSABP, Pfizer, and Novartis; is a paid consultant for Cytyc Health Corp; and is a member of the speaker’s bureau for AstraZeneca, Pfizer, Eli Lilly, and Novartis.


1. Bear HD: Indications for neoadjuvant chemotherapy for breast cancer. Semin Oncol 25(2 suppl 3):3-12, 1998.
2. Bonadonna G, Veronesi U, Brambilla C, et al: Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. J Natl Cancer Inst 82:1539- 1545, 1990.
3. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998.
4. Hoff PM, Valero V, Buzdar AU, et al: Combined modality treatment of locally advanced breast carcinoma in elderly patients or patients with severe comorbid conditions using tamoxifen as the primary therapy. Cancer 88:2054-2060, 2000.
5. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 19:3808-3816, 2001.
6. Shannon C, Smith I: Is there still a role for neoadjuvant therapy in breast cancer? Crit Rev Oncol Hematol 45:77-90, 2003.

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