Originally published as JCO Early Release 10.1200/JCO.2008.17.2544 on July 28 2008

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Effect of Molecular Disease Subsets on Disease-Free Survival in Randomized Adjuvant Chemotherapy Trials for Estrogen Receptor–Positive Breast Cancer

Lajos Pusztai, Kristine Broglio, Fabrice Andre, W. Fraser Symmans, Kenneth R. Hess, Gabriel N. Hortobagyi

From the Departments of Breast Medical Oncology and Pathology and Division of Quantitative Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and the Translational Research Unit, Institut Gustave Roussy, Villejuif, France

Corresponding author: Lajos Pusztai, MD, DPhil, Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439; e-mail: lpusztai{at}mdanderson.org

Purpose The majority of estrogen receptor (ER)–positive cancers are sensitive to endocrine therapy and may not derive much further benefit from chemotherapy, but a subset are potentially chemotherapy sensitive. Molecular diagnostic tests allow the identification of these various subsets with some accuracy. The goal of the current analysis was to examine how the proportion of cases in the various risk (recurrence score [RS]) categories of a commercially available multigene assay influences the power of randomized trials to show benefit from adjuvant chemotherapy.

Methods We modeled 10-year disease-free survival (DFS) for hypothetical, two-arm clinical trials that randomly assigned patients with ER-positive breast cancer to endocrine therapy alone or endocrine therapy plus chemotherapy. We varied the proportion of patients in low, intermediate, and high RS categories and used DFS estimates for each risk group based on results from the Southwest Oncology Group 8814 study.

Results The probability of observing significant improvement in DFS as a result of chemotherapy decreases as the proportion of patients in the low RS category increases. For example, if a trial is designed with 80% power and the actual proportion of low RS patients accrued to the study increases from 40% to 60%, the power drops to 63%.

Conclusion Variable accrual of low RS patients into different randomized adjuvant chemotherapy trials may partly explain contradictory results in the literature. Studies can be underpowered to detect improvement with chemotherapy as a result of inclusion of too many patients with low RS. Future adjuvant studies for ER-positive breast cancer will need to consider stratifying patients by molecular subtype.

published online ahead of print at www.jco.org on July 28, 2008.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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