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American Journal of Epidemiology Advance Access originally published online on April 29, 2009
American Journal of Epidemiology 2009 169(12):1463-1470; doi:10.1093/aje/kwp077
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American Journal of Epidemiology © The Author 2009. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Time-Varying Effects of Prognostic Factors Associated With Disease-Free Survival in Breast Cancer

Loki Natarajan, Minya Pu, Barbara A. Parker, Cynthia A. Thomson, Bette J. Caan, Shirley W. Flatt, Lisa Madlensky, Richard A. Hajek, Wael K. Al-Delaimy, Nazmus Saquib, Ellen B. Gold and John P. Pierce

Correspondence to Dr. John P. Pierce, Cancer Prevention and Control Program, Rebecca and John Moores UCSD Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0901 (e-mail: jppierce{at}ucsd.edu).

Received for publication December 23, 2008. Accepted for publication March 11, 2009.

Early detection and effective treatments have dramatically improved breast cancer survivorship, yet the risk of relapse persists even 15 years after the initial diagnosis. It is important to identify prognostic factors for late breast cancer events. The authors investigated time-varying effects of tumor characteristics on breast-cancer-free survival using data on 3,088 breast cancer survivors from 4 US states who participated in a randomized dietary intervention trial in 1995–2006, with maximum follow-up through 15 years (median, 9 years). A piecewise constant penalized spline approach incorporating time-varying coefficients was adopted, allowing for deviations from the proportional hazards assumption. This method is more flexible than standard approaches, provides direct estimates of hazard ratios across time intervals, and is computationally tractable. Having a stage II or III tumor was associated with a 3-fold higher hazard of breast cancer than having a stage I tumor during the first 2.5 years after diagnosis; this hazard ratio decreased to 2.1 after 7.7 years, but higher tumor stage remained a significant risk factor. Similar diminishing effects were found for poorly differentiated tumors. Interestingly, having a positive estrogen receptor status was protective up to 4 years after diagnosis but detrimental after 7.7 years (hazard ratio = 1.5). These results emphasize the importance of careful statistical modeling allowing for possibly time-dependent effects in long-term survivorship studies.

breast neoplasms; proportional hazards models; survival

Abbreviations: ER, estrogen receptor; Her2, human epidermal growth factor receptor 2; PR, progesterone receptor; WHEL, Women's Healthy Eating and Living


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