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Originally published as JCO Early Release 10.1200/JCO.2005.92.003 on July 5 2005 © 2005 American Society of Clinical Oncology.
Neoadjuvant Endocrine Therapy for Breast Cancer: More Questions Than AnswersDivision of Oncology, Siteman Comprehensive Cancer Center, Washington University, St Louis, MO Neoadjuvant endocrine therapy studies for breast cancer are a great opportunity to develop insights into the biologic basis for the efficacy of estrogen receptor–targeting agents. Neoadjuvant endocrine treatment is also appealing from the drug development perspective. Theoretically, a promising new adjuvant endocrine strategy could be first tested as a short-term neoadjuvant treatment against a standard medication. Improvements in tumor response rate, surgical outcomes, and evidence for enhanced efficacy at the cellular level, for example in terms of the effect on proliferation, would provide a sound basis for taking the new approach forward into the resource-demanding setting of a phase III adjuvant trial.1 The potential of randomized phase III neoadjuvant endocrine treatment trials was first emphasized by the results of a double-blind study by Eiermann et al (Letrozole P024)2 that compared 4 months of the aromatase inhibitor letrozole with tamoxifen as neoadjuvant treatment for women with hormone-receptor–positive tumors who were ineligible for breast-conserving surgery. Letrozole outperformed tamoxifen in terms of clinical and radiologic response rates as well as in the incidence of subsequent breast-conserving surgery. Interestingly, the advantage of letrozole appeared to be particularly evident in a subpopulation of tumors with estrogen-receptor–positive (ER+) and human epidermal growth factor receptor (HER) 1 and/or HER2-positive tumors, indicating that the comparison of endocrine agents in the neoadjuvant setting could provide insights into the molecular basis for differences in efficacy between endocrine agents.3 The enhanced efficacy of letrozole was also apparent at the level of the cell cycle, since letrozole suppressed tumor Ki67 immunohistochemical staining to a greater extent than tamoxifen.4 These results were consistent with the advantages of third generation aromatase inhibitors over tamoxifen in other disease settings.5 The Immediate Preoperative Anastrozole, tamoxifen or Combined with Tamoxifen study (IMPACT) is only the second phase III neoadjuvant endocrine trial to be reported in the peer-reviewed literature.6 The primary hypothesis focused on a drug development question: would the results of the neoadjuvant endocrine trial (IMPACT) mirror those of a much larger adjuvant study (the Arimidex, Tamoxifen, Alone or in Combination trial; ATAC)? In particular, the investigators wanted to prove that negative preliminary data for enhanced efficacy of anastrozole and tamoxifen in combination compared with tamoxifen alone in the preoperative setting would theoretically have prevented ATAC investigators from randomly assigning 3,000 women to the combination arm. With these primary aims in mind, 330 patients with ER+ breast cancer were randomly assigned to 3 months of treatment with either anastrozole, tamoxifen, or the combination of the two in a multicenter trial in the United Kingdom and Germany. Response was monitored by caliper measurements ("clinical response") and by ultrasound. Final surgical outcomes were compared with the surgical approach that would have been initially chosen for the patient if she had not received primary systemic therapy. Unfortunately, none of these clinical end points showed any difference among the three arms and the efficacy of anastrozole was lower than postulated in the statistical design. Given these negative results, this editorial was solicited to consider whether the hypothesis regarding the neoadjuvant-adjuvant link is in jeopardy for neoadjuvant endocrine trials, or whether the IMPACT study was a valiant but flawed test of the postulate. A comparison of the conduct of the IMPACT trial versus the Letrozole P024 trial reveals some straightforward issues that support the latter conclusion. First is the question of sample size. Whereas the IMPACT and Letrozole P024 trial sizes were similar, the IMPACT study involved a three-way randomization. With fewer patients in each treatment group than the Letrozole P024 study, the risk of a false-negative result (type II error) in the IMPACT study was greater. The second question concerns baseline tumor size. In the Letrozole P024 study, the minimum tumor size for eligibility was 3 cm and all patients enrolled were considered ineligible for breast-conserving surgery. In the IMPACT study, the median tumor size was in the 3 to 4 cm range, so that a substantial number of tumors must have been less than 2 cm to start with, and one can reasonably question the accuracy of caliper-based response measurements with palpable breast masses smaller than 2 cm. Third is the question of the degree of estrogen-receptor expression used for eligibility criteria. The Letrozole P024 study required the ER to be expressed in at least 10% of the malignant infiltrating component of the tumor, but in the IMPACT study, only 1% of the cells were required to express ER. It is very clear that neoadjuvant endocrine therapy response rates are closely related to estrogen-receptor expression.4 In a preplanned analysis of the Letrozole P024 study, response rates began to reliably exceed 50% only in extremely ER-rich tumors (Allred scores of 7 and 8). It would be worthwhile to conduct a blinded rescoring of the ER results in the IMPACT study using the Allred score rather than the H score used by Smith et al6 to allow some cross trial comparisons on this issue. Fourth, the IMPACT study was not restricted to women who required presurgical downstaging to achieve breast-conserving surgery or to improve operability. About half of the patients had small tumors at baseline that could have been adequately excised without sacrificing the breast. The population of patients with small cancers markedly reduced the chance the study would detect improvements in surgical outcomes. A final issue was the question of treatment duration. The Letrozole P024 study gave preoperative medication for an extra month, which may have produced more responses. There are some clear take-home lessons for future neoadjuvant endocrine studies. If tumor response is the primary end point, baseline tumor size must exceed 2 to 3 cm. An investigation into more reliable approaches to response measurement in neoadjuvant endocrine therapy trials would be most welcome, since caliper measurements are hardly a robust measurement tool, even in the best of hands, and ultrasound measurements are also quite problematic in the multicenter setting. Second, baseline tumor ER expression should be present in at least 10% of infiltrating cancer cells and preferably should score in the 7 to 8 range by the Allred scoring method. Interestingly, both the IMPACT and the Letrozole P024 study concur with the conclusion that HER2 overexpression is not a reason to avoid neoadjuvant aromatase inhibitor in the setting of an ER-rich tumor, though the efficacy of tamoxifen appears to be compromised in these dual-positive tumors. Third, if there is a major interest in surgical outcomes in the protocol design, the patients enrolled should require a mastectomy at baseline or at least be at risk for a poor cosmetic result from breast-conserving surgery. In terms of treatment duration, my personal preference is to treat for 4 months and even longer in the occasional patient with inoperable disease who is experiencing an ongoing response but whose disease is not yet fully operable. The IMPACT Ki67 data are not reported in this initial paper so one cannot comment on this important information at this stage. Considering the problems with the measurement of tumor response, however, it may well be that the change in Ki67 in a central blinded laboratory analysis is the most robust test with which to judge the IMPACT trial's contribution the viability of the primary hypothesis regarding the neoadjuvant-adjuvant relationship. The routine application of neoadjuvant endocrine therapy is acceptable in the setting of an ER-rich tumor that is large but operable, or locally advanced in an older patient who is clearly not a candidate for chemotherapy. There is no question that being older or medically frail does not equate with indifference to breast-conserving surgery. The use of neoadjuvant endocrine therapy in younger and healthier patients should, however, be subjected to a randomized trial. A key unresolved question is that we still do not have adequate data to link any of the short-term surrogate outcomes we have measured in the neoadjuvant endocrine setting with the subsequent risk of relapse and death from breast cancer. The median follow-up for the Letrozole P024 trial is now about 4 years, and so some of these outcome data should be available soon. It is worth mentioning that both the IMPACT trial and the Letrozole P024 study, as well as all other studies I am aware of, are individually underpowered in this regard, requiring a meta-analysis. A decision regarding neoadjuvant chemotherapy compared with neoadjuvant endocrine therapy would be made easier if there were predictive tests that could select a subpopulation of tumors whose response to the neoadjuvant aromatase inhibitor is in a range of 80% to 90%. If such a test also identified a tumor subtype for which chemotherapy did not improve outcomes, then we would have made real progress toward making neoadjuvant endocrine therapy a new standard of care. The recent findings7 by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and Genomic Health Inc are therefore of great interest. A 21-gene expression assay was established using quantitative reverse transcription polymerase chain reaction (q RT-PCR) from RNA extracted from archived formalin-fixed paraffin-embedded tissue (Oncotype DX; Genomic Health Inc, Redwood City, CA). This assay was used to demonstrate that approximately half of the population of women with node-negative hormone-receptor–positive breast cancer who were treated with adequate local therapy and tamoxifen have an excellent prognosis and are unlikely to benefit from chemotherapy.5 It therefore seems quite hopeful that an RNA profiling test could eventually put decisions regarding the use of neoadjuvant endocrine treatment on a sound medical footing. This possibility is the aim of an ongoing phase II neoadjuvant letrozole trial funded by the National Cancer Institute that is focused on developing an RNA-based test for prospective validation. The American College of Surgeons Oncology Group is also in the final stages of activating a neoadjuvant endocrine therapy study (Z1031) that is specifically designed to be a prelude to a comparison between neoadjuvant chemotherapy and neoadjuvant endocrine therapy by defining both the aromatase inhibitor and the patient population that will be studied. When the Z1031 study begins to enroll patients, neoadjuvant aromatase therapy will be widely available as a research option for appropriately selected patients throughout the United States. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members has 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Ellis MJ: Neoadjuvant endocrine therapy as a drug development strategy. Clin Cancer Res 10: 391S-395S, 2004 (suppl 1, part 2)
2. Eiermann W, Paepke S, Appfelstaedt J, et al: Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12: 1527-1532, 2001
3. 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
4. Ellis MJ, Coop A, Singh B, et al: Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res 63: 6523-6531, 2003 5. Wong ZW, Ellis MJ: First-line endocrine treatment of breast cancer: Aromatase inhibitor or antioestrogen? Br J Cancer 90: 20-25, 2004[CrossRef][Medline] 6. Smith IE, Dowsett M, Ebbs SR, et al: Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen or both in combination: The IMPACT multicenter double blind randomized trial. J Clin Oncol 5108-5117, 2005
7. 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
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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