Neoadjuvant Endocrine Therapy for Breast Cancer: An Overlooked Option?

Breast cancer mortality has declined in recent years due to advances in screening and adjuvant systemic therapy. Based on an overall estimated risk of relapse for an individual woman, her age, comorbidities, and tumor characteristics, she may be offered adjuvant hormone therapy, chemotherapy, or both. Adjuvant hormone therapy is recommended to almost every woman with estrogen-receptor- and/or progesterone(Drug information on progesterone)- receptor-positive breast cancer. Five years of adjuvant tamoxifen(Drug information on tamoxifen) therapy reduces the risk of breast cancer recurrence and death by 47% and 26%, respectively.[1] Third-generation aromatase inhibitors are now widely available and represent first-line therapy for postmenopausal women with metastatic breast cancer. Results from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial and, more recently, the National Cancer Institute of Canada MA.17 trial suggest that the administration of a 5-year course of an adjuvant aromatase inhibitor to hormone- receptor-positive postmenopausal women instead of or following 5 years of tamoxifen might be superior to tamoxifen alone.[2,3] Administration of tamoxifen for 2 to 3 years followed by exemestane(Drug information on exemestane) for a total of 5 years also appears to be superior to 5 years of tamoxifen.[4] Although adjuvant chemotherapy is also associated with a significant improvement in disease-free and overall survival, the proportional benefit of adjuvant chemotherapy is inversely correlated with age.[5] Multimodality therapy is recommended to almost every woman with a newly diagnosed primary breast cancer, but researchers continue to actively investigate questions regarding the sequence or timing of specific treatments. Lessons Learned From Clinical Trials of Neoadjuvant Chemotherapy
For women with early breast cancer, adjuvant chemotherapy and hormone therapy have been traditionally administered following definitive breast surgery. Until recently, neoadjuvant chemotherapy (also referred to as preoperative or primary chemotherapy) has been reserved for women with locally advanced breast cancer, to render them operable or to allow for breast preservation. Results from over a dozen randomized clinical trials have demonstrated that, compared to adjuvant chemotherapy, primary chemotherapy is associated with similar improvements in disease-free and/or overall survival, but that the latter approach might offer additional advantages.[6] Based on large randomized clinical trials such as the National Surgical Adjuvant Breast and Bowel Project B-18 trial and, more recently, B-27 trial, many clinicians offer primary chemotherapy to women with a moderate or large operable breast tumor to enhance breast conservation.[7,8] Primary chemotherapy might also allow in vivo observation of response to specific agents or combinations. Women with a pathologic complete response to primary chemotherapy in both the breast and the lymph nodes have an improved prognosis.[7,9] Clinicians may use primary systemic therapy as an in vivo chemosensitivity test to guide recommendations to individual women regarding changes or additions to treatment. The administration of primary chemotherapy might also allow for evaluation of baseline and changes in surrogate markers of response, such as breast imaging, tissue, and circulating markers. Serial biomarker evaluation might enhance our understanding of tumor biology and the mechanisms of action of standard and novel agents. A few disadvantages have been associated with the administration of primary chemotherapy to women with operable disease. Clinicians rely on disease stage to determine prognosis and make treatment recommendations. In women who are offered primary systemic therapy, it may not be possible to accurately determine baseline pathologic tumor and nodal stage prior to initiating treatment. However, residual disease in the breast and/or lymph nodes following primary chemotherapy might also provide prognostic information.[ 10] Although several experiences have suggested that sentinel node mapping following primary chemotherapy is accurate in experienced hands, there is no consensus regarding the proper timing of nodal evaluation in women with clinically negative axilla; the treating physician might recommend sentinel node mapping prior to primary systemic therapy.[11] Primary chemotherapy in women who are not candidates for breast-conserving surgery enhances breast preservation; however, investigators have not yet established whether breast preservation in this subgroup of patients may be associated with higher local recurrence rates.[6] Despite the possible disadvantages, many clinicians have accepted primary chemotherapy for select women with operable disease for the benefit of individual response assessment. Who Is a Candidate for Neoadjuvant Hormone Therapy?
Although primary chemotherapy is offered to a large group of women, primary hormone therapy, as thoroughly reviewed by Wong and Ellis, has been reserved for elderly women with locally advanced breast cancer or for those who are not candidates for surgery and/or chemotherapy.[12] When administered, primary hormone therapy clearly enhances breast preservation.[ 13] Wong and Ellis suggest that, like preoperative chemotherapy, primary hormone therapy may provide several advantages and should be considered for women with operable disease. However, at this time, primary hormone therapy may not be optimal for most women with operable breast cancer outside of a clinical trial. It might be difficult to fully assess whether hormone therapy alone is appropriate for most women with a newly diagnosed breast cancer prior to definitive staging. Hormone therapy alone is appropriate for women with a small hormone- receptor-positive node-negative tumor without poor prognostic characteristics. It might also be offered to a select group of women with stage II disease. Thus, women who are clinically node-negative may require sentinel node mapping prior to the administration of primary hormone therapy. Median time to response to hormone therapy is longer as compared with chemotherapy, which may explain, in part, why a 3- to 4-month course of primary hormone therapy rarely results in a pathologic complete response. Nevertheless, it is likely that an individual woman may benefit from primary hormone therapy as her response to a specific agent can be documented. If she achieves a suboptimal response, another hormone treatment or perhaps chemotherapy could be considered. Thus, clinical trials to address several questions that could help clinicians select appropriate patients for primary hormone therapy are acutely required. For example, what is the appropriate duration of preoperative treatment? If a woman does not respond to primary hormone therapy, should the clinician add or substitute another treatment? Should such a woman receive long-term adjuvant treatment with the same agent that initially fails to produce a response? What about women who are recommended both chemotherapy and hormone therapy? It is common to recommend the completion of all local therapy and adjuvant chemotherapy prior to prescribing hormone therapy. Although many physicians have combined tamoxifen with chemotherapy, it is now clear that outcomes are superior with sequential administration of the two modalities.[ 12] Whether aromatase inhibitors or newer hormone therapies can be combined with chemotherapy without detrimental effect is not known. If chemotherapy is recommended to a hormone-receptor-positive woman considering primary hormone therapy, what is the appropriate timing for chemotherapy administration? Studies, like those suggested by Wong and Ellis, that will randomize postmenopausal hormone-receptor-positive patients to neoadjuvant aromatase inhibitor or chemotherapy would indeed be useful. Clinical study designs that incorporate primary systemic therapy might require a small sample size and short follow-up to answer preliminary questions regarding sensitivity or resistance to specific agents, their mechanism of action, and the role of standard and novel breast imaging, tissue, and serum markers. Promising hypotheses can be tested in larger studies. For example, in a preliminary study, Ellis and colleagues reported a correlation between overexpression of HER1 and HER2 receptors and improved response to a 4-month course of neoadjuvant letrozole(Drug information on letrozole) (Femara) compared to tamoxifen.[13] Similar trend was observed in the recent report of the IMPACT (Immediate Preoperative Arimidex Compared to Tamoxifen) trial.[15] This hypothesis will be tested in a larger cohort of women who received tamoxifen or anastrozole(Drug information on anastrozole) (Arimidex) in the ATAC trial. Moreover, with the availability of robust technologies such as gene arrays and proteomics, trials of neoadjuvant hormone therapy will help determine patterns of sensitivity or resistance to specific agents. Administration of primary systemic therapy might also allow the study of pharmacogenetic effects on efficacy and safety of specific treatments. Finally, primary systemic therapy presents an excellent model for determination of efficacy of novel agents. It is not likely that hormone therapy will be withheld from women with hormone-receptor-positive tumors. Thus, studies such as the proposed American College of Surgeons Oncology Group Z0012 study to compare responses to the aromatase inhibitor exemestane (Aromasin) with or without the cyclooxygenase (COX)-2 inhibitor celecoxib(Drug information on celecoxib) (Celebrex) are needed. Conclusions
Primary hormone therapy is appropriate for postmenopausal women with locally advanced hormone-receptor- positive disease for whom the addition of chemotherapy is not likely to provide benefit. In addition, elderly women or those who have comorbidities and are not candidates for chemotherapy may benefit from this modality. Clinical trials are required to identify women with operable breast cancer who are most likely to benefit from primary hormone therapy. As Wong and Ellis emphasize, health-care professionals and women with newly diagnosed hormone-receptor- positive primary breast cancer should give strong consideration to participation in clinical trials that incorporate primary hormone therapy. Prospective clinical trials of primary systemic therapy may enhance our understanding of sensitivity or resistance to specific endocrine therapies and new agents utilizing fewer patients, shorter follow-up, and, as a result, fewer resources, thereby advancing current knowledge and leading to individualized treatment.