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  • Review Article
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Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer

Nature Reviews Clinical Oncology volume 9, pages 223–229 (2012)Cite this article

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Abstract

Mature outcomes from adjuvant endocrine therapy trials in estrogen receptor-positive breast cancer have enabled comparisons with neoadjuvant clinical trials that have parallel randomizations of treatment in terms of the response of disseminated disease versus the local response within the breast. Imprecise end points, such as 'clinical response', have produced inconsistent results regarding the relationship between neoadjuvant and adjuvant endocrine therapy outcomes. However, the proliferation marker Ki-67, measured during neoadjuvant treatment, has predicted accurately and consistently the results of much larger studies in the adjuvant setting. In this Review, we summarize these trials and discuss the implications for the design of future adjuvant endocrine therapy trials. We conclude that there is sufficient evidence supporting the view that the degree of Ki-67 suppression is a reliable short-term surrogate for the adjuvant potential of endocrine drugs, at least in postmenopausal women. We propose that adjuvant endocrine therapy trials should only be conducted once adequately-powered neoadjuvant studies have indicated superior Ki-67 suppression in patients receiving experimental endocrine treatment versus the standard treatment.

Key Points

  • In postmenopausal women, on-treatment Ki-67 levels are more predictive of long-term outcome than baseline levels; studies validating the clinical value of this assessment as a prognostic tool are underway

  • Ki-67 values in three small neoadjuvant trials predicted outcomes of large adjuvant trials; future adjuvant designs should be based on a biological superiority hypothesis generated by a neoadjuvant study

  • The use of on-treatment Ki-67 and the preoperative endocrine prognostic index (PEPI) in premenopausal women with estrogen receptor-positive breast cancer requires further investigation

  • High Ki-67 values can identify endocrine therapy-resistant tumors as early as 2 weeks after neoadjuvant endocrine therapy; ongoing trials are investigating the utility of this observation

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Figure 1: Schematic representation for the ALTERNATE Trial.

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Acknowledgements

This work was supported by R01 CA095614 awarded to M. J. Ellis, a 2011 AVON Foundation research grant to support R. Goncalves and CALGB Clinical Scholar Award to C. Ma. The ACOSOG Z1031 trial was supported by grants by the National Cancer Institute to the American College of Physicians Oncology Group (U24 CA114736 and U10 076,001).

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Authors and Affiliations

  1. Breast Oncology Section, Washington University in St Louis, Campus Box 8056, 660 South Euclid Avenue, St Louis, 63110, MO, USA

    Rodrigo Goncalves, Cynthia Ma & Matthew James Ellis

  2. Siteman Cancer Center, Washington University in St Louis, Campus Box 8056, 660 South Euclid Avenue, St Louis, 63110, MO, USA

    Jingqin Luo

  3. Alliance for Clinical Trials in Oncology Statistical Office, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Vera Suman

Authors
  1. Rodrigo Goncalves
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Contributions

J. Luo researched the data for the article and reviewed the manuscript before submission. All the other authors researched the data for the manuscript, made a substantial contribution to discussion of the content, wrote, and edited and revised the manuscript before submission.

Corresponding author

Correspondence to Matthew James Ellis.

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Competing interests

M. J. Ellis declares he is consultant for Astra Zeneca, Novartis and Pfizer. He also receives research support from Astra Zeneca and he is stockholder of Bioclassifier LLC, which has licensed the PAM50 assay. The other authors declare no competing interests.

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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). https://doi.org/10.1038/nrclinonc.2012.21

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