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Cited by 237Breast Cancer Treatment StudiesBreast Lesions and CarcinomasStatistical Methods in Epidemiology

Time-dependence of hazard ratios for prognostic factors in primary breast cancer

Hilsenbeck, Susan G., Ravdin, Peter M., de Moor, Carl A., Chamness, Gary C., Osborne, C. Kent, Clark, Gary M.·1998·Breast Cancer Research and Treatment
DOI 10.1023/a:1006133418245
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Abstract

Some prognostic factors, such as steroid receptors, appear strongly related to outcome in early studies with short follow-up, but as follow-up matures the relationships appear to weaken. We investigated this phenomenon for several factors (tumor size, axillary lymph nodes, S-phase fraction, estrogen receptor (ER) status, and adjuvant therapy) in a large sample of breast cancer cases (N=2,873) with up to 17 years of follow-up for disease-free survival (DFS). Subjects in the study were identified from patients who had hormone receptor assays performed in our laboratory. Analysis of DFS included fitting a multivariate Cox proportional hazards model, testing for nonproportionality, and examining diagnostic plots. The assumption of proportional hazards was violated for several factors including ER, tumor size, and S-phase fraction. For ER, the hazard ratio was initially less than 1.0, indicating a good effect on prognosis, but increased at later times to values greater than 1.0, indicating a bad effect on prognosis. In contrast, the hazard ratios for tumor size and S-phase were initially high and decreased asymptotically toward 1.0 over time. Analysis of p53 expression in a subset of cases yielded qualitatively similar results. We conclude that several standard prognostic factors (ER, tumor size, S-phase fraction) and possibly other investigational factors have important but nonproportional effects on hazard. It is likely that violation of proportional hazards is common and not limited to breast cancer. Failure to recognize violations of proportional hazards can lead to both over- and under-estimation of the effects of important prognostic factors.

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Crossref · 10.1023/a:1006133418245

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  • Expression of estrogen receptor (ER)-α is a favorable prognostic factor.

    “Elevated serum levels of estradiol are weakly associated with increased breast cancer risk (62), while expression of estrogen receptor (ER)-α is a favorable prognostic factor (63).”

    From Diabetes and Cancer (2010) · cites this paper as [63]

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Authors
Hilsenbeck, S. G., Ravdin, P. M., de Moor, C. A., Chamness, G. C., Osborne, C. K., & Clark, G. M.
Affiliations
The University of Texas at San Antonio Health Science Center (US)
ORCID
Venue
Breast Cancer Research and Treatment
Publisher
Springer Science and Business Media LLC
Published
1998-11
Volume
52
Issue
1-3
Pages
227-237
ISSN
  • 0167-6806 (ISSN-L)
  • 1573-7217
DOI
10.1023/a:1006133418245
OpenAlex
W2019665138
Cited by
237
References
24
Citations by year
2026: 1 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 2 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 10 · 2015: 10 · 2014: 14 · 2013: 10 · 2012: 10
FWCI
2.38
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Breast Cancer Research and Treatment (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (P30CA 54174, P30CA054174, P01CA030195, P01_CA30195)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
Keywords
primary breast cancer, prognostic factors, proportional hazards assumption violation, estrogen receptor status, tumor size, S-phase fraction, p53 expression, adjuvant therapy, axillary lymph nodes, disease-free survival, hormone receptor assays
MeSH terms
Adult, Aged, Breast Neoplasms, Female, Humans, Middle Aged, Prognosis, Receptors, Estrogen, Time Factors, Proportional Hazards Models, Tumor Suppressor Protein p53, S Phase, Disease-Free Survival

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