Although the age-adjusted survival of cancer patients has improved over the last decade, with US population aging, there will be a sharp rise in total numbers of new cancer diagnoses and cancer morbidity through 2050. The vast majority of these new cases will be in patients over the age of 65. Treatment of cancer in the elderly is complicated by the increased risk of treatment-related toxicities, which are currently difficult to predict due to the lack of reliable, clinical use models and chronological age is not an accurate predictor of toxicity risks. Development of a molecular marker of aging would help clinicians to predict a patients' risk of treatment- related toxicity with higher certainty. Work in the Sharples lab has revealed that the cellular senescent factor, p16INK4a, can be used as a faithful biomarker of molecular age and physiologic reserve in humans. Importantly, data from our recent clinical trial demonstrate that p16INK4a expression correlates with the occurrence of life- threatening grade 3/4 toxicities and hospital admission in patients' ?50 years of age with early stage breast cancer receiving combination docetaxel and cyclophosphamide therapy (TC). Therefore, we propose to develop and validate the use of p16INK4a biomarker as a predictor of TC-induced toxicities and related hospitalizations to guide choice of chemotherapy regimen (drugs and dosage) and to alert clinicians to consider appropriate prevention strategies. Accurate prediction of patients at risk (or lack of risk) of adverse events such as neutropenic fever could result in substantial healthcare cost savings by targeting growth factor treatment to those at highest risk of myelosuppression. Additionally, we believe that our p16INK4a assay could be incorporated into existing oncological practice without the need for extensive clinical trial validation and physician education, immediately impacting patient care. Completion of the work proposed here, will allow us to develop analytical performance data necessary for CLIA approval and solidify evidence of clinical utility for toxicity risk assessment in breast cancer patients necessary for commercialization and market adoption.

Public Health Relevance

Chemotherapy treatments cure cancer and increase lifespan of patients, but can have severe side effects that compromise effectiveness of treatment. In this proposal, we will determine if biomarker of aging, p16 can predict patients at high risk for developing treatment-associated toxicities

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Sorg, Brian S
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University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
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He, Shenghui; Sharpless, Norman E (2017) Senescence in Health and Disease. Cell 169:1000-1011
Demaria, Marco; O'Leary, Monique N; Chang, Jianhui et al. (2017) Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov 7:165-176
Wood, William A; Krishnamurthy, Janakiraman; Mitin, Natalia et al. (2016) Chemotherapy and Stem Cell Transplantation Increase p16INK4a Expression, a Biomarker of T-cell Aging. EBioMedicine 11:227-238
Dumond, Julie B; Francis, Owen; Cottrell, Mackenzie et al. (2016) Tenofovir/emtricitabine metabolites and endogenous nucleotide exposures are associated with p16(INK4a) expression in subjects on combination therapy. Antivir Ther 21:441-5