Grant Number:	4R01CA166293-04 Interpret this number
Primary Investigator:	Natarajan, Loki
Organization:	University Of California, San Diego
Project Title:	Genomic, Clinical and Behavioral Signature of Long-Term Breast Cancer Survival
Fiscal Year:	2016

DESCRIPTION (provided by applicant): Breast cancer is a heterogeneous disease with substantial variability in relapse rates across clinical and molecular features of the tumor. Clinicopathologic prognostic models (e.g.,Adjuvant!) are widely used to guide therapy. Prognostic gene expression signatures are then used to help clarify treatment options for clinically intermediate risk patients. PAM50 is a validated "open source" gene expression signature which has recently been endorsed for informing treatment decisions. However, for 40% of breast cancer patients estimated risk, and hence treatment, remains uncertain. Improvement in prognostic models is an active area of research. Models that integrate genomic and clinicopathologic factors show large improvements in prognostic ability. Newer statistical methods (non-linear and time-varying effects, competing risks for comorbid conditions) have improved risk estimates among subgroups and increased accuracy for late relapse (>5 or 10 years after diagnosis). Combination of orthogonal gene expression signatures with microRNA's (miRNA's) promises to increase the proportion of subjects assigned to low and high-risk groups. However, clinical utility of newer models is limited because additional validation in large cohorts with long-term follow-up is needed. Team: We have assembled unique resources to address these issues, including 1,723 well-annotated primary tumor samples from the WHEL cohort of community-dwelling early stage breast cancer survivors. WHEL participants have been actively followed for 15+ years, with regular assessment of comorbidities, body mass index, and physical activity. The team is comprised of leaders in breast cancer treatment and assay development, in genomics, in behavioral research, and in mathematical statistics and prognostic modeling. We aim to: 1. Assay PAM50, hypoxia gene signatures, and an 18 miRNA panel. Assays will be done at the Genome Institute, Washington Univ., St. Louis. We expect high-quality assays on ~1300 WHEL subjects. 2. Validate the PAM50/hypoxia clinco-genomic signatures, assess potential clinical benefit and identify weaknesses. We will compute risk estimates from published clinicopathologic models (Adjuvant), and genomic (PAM50, hypoxia, miRNA) signatures. We will validate models by comparing predicted and observed survival. Impact: The expected independent validation of the PAM50/hypoxia clinico-genomic signature will help translate its use into the clinic. Improvements for clinically intermediate-risk patientsare anticipated. 3, Develop a new prognostic model accounting for competing comorbidities, nonlinear and time- varying effects, and integrating novel genomic, and clinical factors. New models will integrate clinical and genomic features (i.e., PAM50, hypoxia signatures, miRNAs, comorbidities, obesity) and incorporate statistical refinements such as competing risk from non-cancer mortality and time-varying effects. Impact: We expect to further improve risk estimates for clinically intermediate risk and late relapse groups, and to quantify the expected clinical benefit which might result from these improved models.




Research-based PAM50 signature and long-term breast cancer survival.
Authors: Pu M. , Messer K. , Davies S.R. , Vickery T.L. , Pittman E. , Parker B.A. , Ellis M.J. , Flatt S.W. , Marinac C.R. , Nelson S.H. , et al. .
Source: Breast Cancer Research And Treatment, 2019-09-21 00:00:00.0; , .
EPub date: 2019-09-21 00:00:00.0.
PMID: 31542876
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MiRNAs and long-term breast cancer survival: Evidence from the WHEL Study.
Authors: Natarajan L. , Pu M. , Davies S.R. , Vickery T.L. , Nelson S.H. , Pittman E. , Parker B.A. , Ellis M.J. , Flatt S.W. , Mardis E.R. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2019-06-11 00:00:00.0; , .
EPub date: 2019-06-11 00:00:00.0.
PMID: 31186261
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A joint marginal-conditional model for multivariate longitudinal data.
Authors: Proudfoot J. , Faig W. , Natarajan L. , Xu R. .
Source: Statistics In Medicine, 2018-02-28 00:00:00.0; 37(5), p. 813-828.
EPub date: 2017-12-04 00:00:00.0.
PMID: 29205414
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Sedentary Behaviors and Biomarkers Among Breast Cancer Survivors.
Authors: Hartman S.J. , Marinac C.R. , Cadmus-Bertram L. , Kerr J. , Natarajan L. , Godbole S. , Patterson R.E. , Morey B. , Sears D.D. .
Source: Journal Of Physical Activity & Health, 2018-01-01 00:00:00.0; 15(1), p. 1-6.
EPub date: 2017-09-14 00:00:00.0.
PMID: 28682735
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Cognition, quality-of-life, and symptom clusters in breast cancer: Using Bayesian networks to elucidate complex relationships.
Authors: Xu S. , Thompson W. , Ancoli-Israel S. , Liu L. , Palmer B. , Natarajan L. .
Source: Psycho-oncology, 2017-10-20 00:00:00.0; , .
EPub date: 2017-10-20 00:00:00.0.
PMID: 29055062
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Objectively measured sedentary behavior and quality of life among survivors of early stage breast cancer.
Authors: Hartman S.J. , Marinac C.R. , Bellettiere J. , Godbole S. , Natarajan L. , Patterson R.E. , Kerr J. .
Source: Supportive Care In Cancer : Official Journal Of The Multinational Association Of Supportive Care In Cancer, 2017 Aug; 25(8), p. 2495-2503.
EPub date: 2017-03-22 00:00:00.0.
PMID: 28326507
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Sleep duration and breast cancer prognosis: perspectives from the Women's Healthy Eating and Living Study.
Authors: Marinac C.R. , Nelson S.H. , Flatt S.W. , Natarajan L. , Pierce J.P. , Patterson R.E. .
Source: Breast Cancer Research And Treatment, 2017 04; 162(3), p. 581-589.
EPub date: 2017-02-11 00:00:00.0.
PMID: 28190251
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Kernel Density Estimation As A Measure Of Environmental Exposure Related To Insulin Resistance In Breast Cancer Survivors
Authors: Jankowska M.M. , Natarajan L. , Godbole S. , Meseck K. , Sears D.D. , Patterson R.E. , Kerr J. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2017-03-03 00:00:00.0; , .
PMID: 28258052
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An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome.
Authors: de Vries Schultink A.H. , Alexi X. , van Werkhoven E. , Madlensky L. , Natarajan L. , Flatt S.W. , Zwart W. , Linn S.C. , Parker B.A. , Wu A.H. , et al. .
Source: Breast Cancer Research And Treatment, 2017 02; 161(3), p. 567-574.
EPub date: 2016-12-22 00:00:00.0.
PMID: 28005246
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A prognostic model for advanced colorectal neoplasia recurrence.
Authors: Liu L. , Messer K. , Baron J.A. , Lieberman D.A. , Jacobs E.T. , Cross A.J. , Murphy G. , Martinez M.E. , Gupta S. .
Source: Cancer Causes & Control : Ccc, 2016 Oct; 27(10), p. 1175-85.
EPub date: 2016-08-12 00:00:00.0.
PMID: 27517467
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Prolonged Nightly Fasting and Breast Cancer Prognosis.
Authors: Marinac C.R. , Nelson S.H. , Breen C.I. , Hartman S.J. , Natarajan L. , Pierce J.P. , Flatt S.W. , Sears D.D. , Patterson R.E. .
Source: Jama Oncology, 2016-08-01 00:00:00.0; 2(8), p. 1049-55.
PMID: 27032109
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Prognostic Impact of Modulators of G proteins in Circulating Tumor Cells from Patients with Metastatic Colorectal Cancer.
Authors: Barbazan J. , Dunkel Y. , Li H. , Nitsche U. , Janssen K.P. , Messer K. , Ghosh P. .
Source: Scientific Reports, 2016-02-26 00:00:00.0; 6, p. 22112.
EPub date: 2016-02-26 00:00:00.0.
PMID: 26916336
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Baseline Depressive Symptoms, Completion of Study Assessments, and Behavior Change in a Long-Term Dietary Intervention Among Breast Cancer Survivors.
Authors: Wang J.B. , Pierce J.P. , Ayala G.X. , Cadmus-Bertram L.A. , Flatt S.W. , Madanat H. , Newman V.A. , Nichols J.F. , Natarajan L. .
Source: Annals Of Behavioral Medicine : A Publication Of The Society Of Behavioral Medicine, 2015 Dec; 49(6), p. 819-27.
PMID: 26091977
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Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors.
Authors: Bao L. , Messer K. , Schwab R. , Harismendy O. , Pu M. , Crain B. , Yost S. , Frazer K.A. , Rana B. , Hasteh F. , et al. .
Source: Plos One, 2015; 10(11), p. e0142487.
PMID: 26554380
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Risk of breast cancer recurrence associated with carbohydrate intake and tissue expression of IGFI receptor.
Authors: Emond J.A. , Pierce J.P. , Natarajan L. , Gapuz L.R. , Nguyen J. , Parker B.A. , Varki N.M. , Patterson R.E. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2014 Jul; 23(7), p. 1273-9.
PMID: 24755714
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AbsCN-seq: a statistical method to estimate tumor purity, ploidy and absolute copy numbers from next-generation sequencing data.
Authors: Bao L. , Pu M. , Messer K. .
Source: Bioinformatics (oxford, England), 2014-04-15 00:00:00.0; 30(8), p. 1056-1063.
EPub date: 2014-04-15 00:00:00.0.
PMID: 24389661
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Postdiagnosis C-reactive protein and breast cancer survivorship: findings from the WHEL study.
Authors: Villaseñor A. , Flatt S.W. , Marinac C. , Natarajan L. , Pierce J.P. , Patterson R.E. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2014 Jan; 23(1), p. 189-99.
PMID: 24220913
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Lifetime cigarette smoking and breast cancer prognosis in the After Breast Cancer Pooling Project.
Authors: Pierce J.P. , Patterson R.E. , Senger C.M. , Flatt S.W. , Caan B.J. , Natarajan L. , Nechuta S.J. , Poole E.M. , Shu X.O. , Chen W.Y. .
Source: Journal Of The National Cancer Institute, 2014 Jan; 106(1), p. djt359.
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