Neoadjuvant endocrine therapy for breast cancer: more questions than answers.

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. 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) 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. 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. These results were consistent with the advantages of third generation aromatase inhibitors over tamoxifen in other disease settings. 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. 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 22 AUGUST 1 2005