Neoadjuvant Studies of Endocrine Approaches in Breast Cancer Mandated Before Embarking on Large Adjuvant Studies


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Largely based on studies demonstrating that letrozole can suppress plasma estradiol levels to a greater extent than anastrozole,1 the adjuvant activity of these endocrine agents were compared in 4,136 patients with node-positive breast cancer in the FACE trial. As reviewed in this issue of The ASCO Post, Smith et al2 now report equivalent efficacy and toxicity in the two arms of the trial. Although the trial was terminated prematurely without the requisite number of patients experiencing an event, the size of the trial and the similarity of the event rate with other comparable trials indicate that it is unlikely a difference will emerge with longer follow-up and more events.

The FACE trial can therefore be considered an unrealized investment for the company involved and disappointing news for physicians and patients, who would have appreciated a simple choice of an aromatase inhibitor based on superior efficacy. Since the degree of estradiol suppression was misleading with regard to significant efficacy differences between aromatase inhibitors, one can consider whether alternative pharmacodynamic biomarkers used for aromatase inhibitor comparisons might have predicted the negative result FACE trial with more accuracy.

One promising option is to study the tumor proliferation marker Ki67 before and after the initiation of neoadjuvant or presurgical endocrine therapy. Once neoadjuvant endocrine therapy has been started, the degree of Ki67 positivity has reproducible prognostic and predictive value, both in terms of individual outcomes3 as well as in identifying the relative efficacy of different adjuvant endocrine approaches.4

Ki67 Suppression in Clinical Trials

Before the results of the FACE trial, three adjuvant endocrine therapy trials—BIG 1-98, ATAC, and MA.27—could be matched to three neoadjuvant studies with the same treatment randomization (P024, IMPACT, and ACOSOG Z1031).4 In each case, the degree of Ki67 suppression in the neoadjuvant study paralleled the result of the adjuvant study. In the case of the P024 and IMPACT studies, Ki67 suppression was greater for letrozole vs tamoxifen or anastrozole vs tamoxifen, accurately predicting that the BIG 1-98 and ATAC trials would both be positive in favor of the aromatase inhibitor. Ki67 data from the IMPACT trial also indicated that the combination of tamoxifen and anastrozole would not be more effective than tamoxifen alone, suggesting that the neoadjuvant endocrine therapy model could also provide valuable negative predictive information, which could prevent futile comparisons between endocrine approaches in the adjuvant setting.5


We strongly recommend there be an absolute requirement for positive Ki67 data from the neoadjuvant endocrine setting before embarking on a decades-long effort to complete an adjuvant investigation in estrogen receptor–positive breast cancer.
— Matthew J. Ellis, MB, BChir, BSc, PhD, FRCP

This proposition was further supported when the ACOSOG Z1031 Ki67 analysis predicted that exemestane would be equivalent to anastrozole,6 the final result in the MA.27 study.7 The new clinical data from the FACE trial again demonstrate that Ki67 suppression data can reliably identify futile comparisons between endocrine agents, since there were no differences between letrozole and anastrozole in the Z1031 comparison.

Although the POETIC trial, a presurgical Ki67 suppression study comparing anastrozole and letrozole in 3,913 patients, preliminarily reported a difference in favor of Ki67 suppression for letrozole (in a nonrandomized comparison), the Ki67 suppression difference detected in this very large study did not translate into a clinically relevant difference in the FACE trial.8 The POETIC trial result is very useful, however, in that it indicates the power produced by smaller neoadjuvant or presurgical trials with less than 5% of the size of an adjuvant trial produces sufficient Ki67 data to reject an adjuvant design.

Neoadjuvant Data Required First

We strongly recommend there be an absolute requirement for positive Ki67 data from the neoadjuvant endocrine setting before embarking on a decades-long effort to complete an adjuvant investigation in estrogen receptor–positive breast cancer. In this regard, the marked antiproliferative effects of a cyclin-dependent kinase (CDK) 4/6 inhibitor when added to anastrozole in the NeoPalAna study suggest adjuvant CDK4/6 studies will likely produce a positive outcome.

Dr. Ellis is Professor/Director, Lester and Sue Smith Breast Center – Administrative Oncology/Medicine and MCB, Baylor College of Medicine, Houston, Texas.

Disclosure: Dr. Ellis has consulted for AstraZeneca, Pfizer, Novartis, and Celgene.

References

1. Geisler J, Helle H, Ekse D, et al: Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels. Clin Cancer Res 14:6330-6335, 2008.

2. Smith I, Yardley D, Burris H, et al: Comparative efficacy and safety of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor-positive, node-positive early breast cancer: Final results of the randomized phase III Femara versus Anastrozole Clinical Evaluation (FACE) trial. J Clin Oncol 35:1041-1048, 2017.

3. Ellis MJ, Suman VJ, Hoog J, et al: Ki67 proliferation index as a tool for chemotherapy decisions during and after neoadjuvant aromatase inhibitor treatment of breast cancer: Results from the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol. January 3, 2017 (early release online).

4. Goncalves R, Ma C, Luo J, et al: Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer. Nat Rev Clin Oncol 9:223-229, 2012.

5. Dowsett M, Ebbs SR, Dixon JM, et al: Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: Influence of hormonal status and HER-2 in breast cancer—A study from the IMPACT trialists. J Clin Oncol 23:2477-2492, 2005.

6. Ellis MJ, Suman VJ, Hoog J, et al: Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: Clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype—ACOSOG Z1031. J Clin Oncol 29:2342-2349, 2011.

7. Goss PE, Ingle JN, Pritchard KI, et al: Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27—A randomized controlled phase III trial. J Clin Oncol 31:1398-1404, 2013.

8. Bliss JM, Morden J, Evans A, et al: Clinico-pathological relationships with Ki67 in POETIC (CRUK/07/015)—Critical lessons for assessing Ki67 for prognosis and as a pharmacodynamic marker. 2016 San Antonio Breast Cancer Symposium Abstract P2-05-01.

9. Ma CX, Gao F, Luo J, et al: NeoPalAna: Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor positive breast cancer. Clin Cancer Res. March 7, 2017 (early release online).


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