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Grant Details

Grant Number: 5R01CA129769-09 Interpret this number
Primary Investigator: Mandelblatt, Jeanne
Organization: Georgetown University
Project Title: Older Breast Cancer Patients: Risk for Cognitive Decline
Fiscal Year: 2019
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Abstract

? DESCRIPTION (provided by applicant): There are compelling data indicating that cancer and its therapies are associated with cognitive decline ("chemo-brain") in certain survivors. Cognitive decline is an important public health issue facing our aging nation since it is a strong predictor f functional decline, hospital admission, mortality, and healthcare costs. For women 60 and older ("older"), who represent 71% of the three million US breast cancer survivors, cognitive decline is especially salient, since even small declines have negative effects on daily life. While there are multiple studies in younger survivors showing both persistent and late cognitive problems, there are insufficient data on long-term trajectories of and risks for cognitive decline in older survivos since past research has had small samples of older survivors; lacked pre-treatment data; was uncontrolled; and/or did not include follow-up. In recognition of this important evidence gap, the Institute of Medicine issued a recent call for collection of data about factors that influence the course of cancer survivorship in older survivors, stressing cognitive outcomes. In this revised continuation, our multi-disciplinary team will use a bio-behavioral cancer and aging framework to fill this gap by leveraging the Thinking and Living with Cancer (TLC) cohort. TLC is the only prospective cohort of older breast cancer survivors evaluated pre-treatment and 12 months later that includes matched controls. We have made excellent progress, meeting enrollment targets, publishing 19 papers, and presenting two abstracts. We also have provocative preliminary results showing divergent trajectories by treatment and genotype, with APOE ?4 positive chemotherapy-exposed survivors demonstrating dramatically steeper 12-month declines in several cognitive domains than other survivors and controls. Additionally, physical activity tended to decrease and multi-morbidity to increase the odds of 12-month decline. To understand longer-term trajectories of and risks for cognitive decline, we propose to conduct new assessments (24, 36, 48 months) of the TLC cohort, use banked DNA for COMT polymorphism testing, and add objective monitoring of physical activity and measurement of inflammatory markers. The aims are to: 1) ascertain trajectories of longitudinal cognitive function and test for differences in treatment exposure-control groups; 2) identify risk factors for cognitie decline in the 48 months post-enrollment and determine how effects are moderated by treatment exposure (chemotherapy>hormonal>control); and 3) assess how inflammatory products (CRP, IL6, and sTNFRII) co-vary with trajectories of cognition; and test if inflammation mediates effects of physical activity and multi-morbidity on cognitive decline. The results will have high impact by suggesting future mechanistic research and intervention trials, and supporting patient-physician discussions about treatment benefits and harms. Knowledge about whether trajectories of decline plateau, accelerate, or occur as late effects could improve survivorship care planning for older breast cancer survivors.

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Publications

Development of a Human APOE Knock-in Mouse Model for Study of Cognitive Function After Cancer Chemotherapy.
Authors: Speidell A.P. , Demby T. , Lee Y. , Rodriguez O. , Albanese C. , Mandelblatt J. , Rebeck G.W. .
Source: Neurotoxicity Research, 2018-10-04 00:00:00.0; , .
EPub date: 2018-10-04 00:00:00.0.
PMID: 30284204
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Cancer-Related Cognitive Outcomes Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study.
Authors: Mandelblatt J.S. , Small B.J. , Luta G. , Hurria A. , Jim H. , McDonald B.C. , Graham D. , Zhou X. , Clapp J. , Zhai W. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2018-10-03 00:00:00.0; , p. JCO1800140.
EPub date: 2018-10-03 00:00:00.0.
PMID: 30281396
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The Impact of Using Different Reference Populations on Measurement of Breast Cancer-Related Cognitive Impairment Rates.
Authors: Clapp J.D. , Luta G. , Small B.J. , Ahles T.A. , Root J.C. , Graham D. , Hurria A. , Jacobsen P.B. , Jim H. , McDonald B.C. , et al. .
Source: Archives Of Clinical Neuropsychology : The Official Journal Of The National Academy Of Neuropsychologists, 2018-02-17 00:00:00.0; , .
EPub date: 2018-02-17 00:00:00.0.
PMID: 29471454
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Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study.
Authors: Kinnunen K.M. , Cash D.M. , Poole T. , Frost C. , Benzinger T.L.S. , Ahsan R.L. , Leung K.K. , Cardoso M.J. , Modat M. , Malone I.B. , et al. .
Source: Alzheimer's & Dementia : The Journal Of The Alzheimer's Association, 2018 Jan; 14(1), p. 43-53.
EPub date: 2017-07-22 00:00:00.0.
PMID: 28738187
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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
Authors: Sims R. , van der Lee S.J. , Naj A.C. , Bellenguez C. , Badarinarayan N. , Jakobsdottir J. , Kunkle B.W. , Boland A. , Raybould R. , Bis J.C. , et al. .
Source: Nature Genetics, 2017-07-17 00:00:00.0; , .
EPub date: 2017-07-17 00:00:00.0.
PMID: 28714976
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Transethnic genome-wide scan identifies novel Alzheimer's disease loci.
Authors: Jun G.R. , Chung J. , Mez J. , Barber R. , Beecham G.W. , Bennett D.A. , Buxbaum J.D. , Byrd G.S. , Carrasquillo M.M. , Crane P.K. , et al. .
Source: Alzheimer's & Dementia : The Journal Of The Alzheimer's Association, 2017 Jul; 13(7), p. 727-738.
EPub date: 2017-02-07 00:00:00.0.
PMID: 28183528
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Frailty and long-term mortality of older breast cancer patients: CALGB 369901 (Alliance).
Authors: Mandelblatt J.S. , Cai L. , Luta G. , Kimmick G. , Clapp J. , Isaacs C. , Pitcher B. , Barry W. , Winer E. , Sugarman S. , et al. .
Source: Breast Cancer Research And Treatment, 2017 Jul; 164(1), p. 107-117.
EPub date: 2017-03-31 00:00:00.0.
PMID: 28364214
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Cognitive function and discontinuation of adjuvant hormonal therapy in older breast cancer survivors: CALGB 369901 (Alliance).
Authors: Bluethmann S.M. , Alfano C.M. , Clapp J.D. , Luta G. , Small B.J. , Hurria A. , Cohen H.J. , Sugarman S. , B Muss H. , Isaacs C. , et al. .
Source: Breast Cancer Research And Treatment, 2017-06-26 00:00:00.0; , .
EPub date: 2017-06-26 00:00:00.0.
PMID: 28653250
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Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2.
Authors: Katsumata Y. , Nelson P.T. , Ellingson S.R. , Fardo D.W. .
Source: Neurobiology Of Aging, 2017 May; 53, p. 193.e17-193.e25.
EPub date: 2017-01-09 00:00:00.0.
PMID: 28131462
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Using Eprognosis To Estimate 2-year All-cause Mortality In Older Women With Breast Cancer: Cancer And Leukemia Group B (calgb) 49907 And 369901 (alliance A151503)
Authors: Kimmick G.G. , Major B. , Clapp J. , Sloan J. , Pitcher B. , Ballman K. , Barginear M. , Freedman R.A. , Artz A. , Klepin H.D. , et al. .
Source: Breast Cancer Research And Treatment, 2017-03-10 00:00:00.0; , .
PMID: 28283904
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Personality, coping, and social support as predictors of long-term quality-of-life trajectories in older breast cancer survivors: CALGB protocol 369901 (Alliance).
Authors: Durá-Ferrandis E. , Mandelblatt J.S. , Clapp J. , Luta G. , Faul L. , Kimmick G. , Cohen H.J. , Yung R.L. , Hurria A. .
Source: Psycho-oncology, 2017-02-20 00:00:00.0; , .
EPub date: 2017-02-20 00:00:00.0.
PMID: 28219113
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Long-term trajectories of self-reported cognitive function in a cohort of older survivors of breast cancer: CALGB 369901 (Alliance).
Authors: Mandelblatt J.S. , Clapp J.D. , Luta G. , Faul L.A. , Tallarico M.D. , McClendon T.D. , Whitley J.A. , Cai L. , Ahles T.A. , Stern R.A. , et al. .
Source: Cancer, 2016-07-22 00:00:00.0; , .
EPub date: 2016-07-22 00:00:00.0.
PMID: 27447359
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Assessment Of The Genetic Variance Of Late-onset Alzheimer's Disease
Authors: Ridge P.G. , Hoyt K.B. , Boehme K. , Mukherjee S. , Crane P.K. , Haines J.L. , Mayeux R. , Farrer L.A. , Pericak-Vance M.A. , Schellenberg G.D. , et al. .
Source: Neurobiology Of Aging, 2016 May; 41, p. 200.e13-20.
PMID: 27036079
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The Executive Prominent/memory Prominent Spectrum In Alzheimer's Disease Is Highly Heritable
Authors: Mez J. , Mukherjee S. , Thornton T. , Fardo D.W. , Trittschuh E. , Sutti S. , Sherva R. , Kauwe J.S. , Naj A.C. , Beecham G.W. , et al. .
Source: Neurobiology Of Aging, 2016 May; 41, p. 115-21.
PMID: 27103524
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Global And Local Ancestry In African-americans: Implications For Alzheimer's Disease Risk
Authors: Hohman T.J. , Cooke-Bailey J.N. , Reitz C. , Jun G. , Naj A. , Beecham G.W. , Liu Z. , Carney R.M. , Vance J.M. , Cuccaro M.L. , et al. .
Source: Alzheimer's & Dementia : The Journal Of The Alzheimer's Association, 2016 Mar; 12(3), p. 233-43.
PMID: 26092349
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Interaction Between Variants In Clu And Ms4a4e Modulates Alzheimer's Disease Risk
Authors: Ebbert M.T. , Boehme K.L. , Wadsworth M.E. , Staley L.A. , Alzheimer's Disease Neuroimaging Initiative , Alzheimer's Disease Genetics Consortium , Mukherjee S. , Crane P.K. , Ridge P.G. , Kauwe J.S. .
Source: Alzheimer's & Dementia : The Journal Of The Alzheimer's Association, 2016 Feb; 12(2), p. 121-9.
PMID: 26449541
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Discovery Of Gene-gene Interactions Across Multiple Independent Data Sets Of Late Onset Alzheimer Disease From The Alzheimer Disease Genetics Consortium
Authors: Hohman T.J. , Bush W.S. , Jiang L. , Brown-Gentry K.D. , Torstenson E.S. , Dudek S.M. , Mukherjee S. , Naj A. , Kunkle B.W. , Ritchie M.D. , et al. .
Source: Neurobiology Of Aging, 2016 Feb; 38, p. 141-50.
PMID: 26827652
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A Novel Alzheimer Disease Locus Located Near The Gene Encoding Tau Protein
Authors: Jun G. , Ibrahim-Verbaas C.A. , Vronskaya M. , Lambert J.C. , Chung J. , Naj A.C. , Kunkle B.W. , Wang L.S. , Bis J.C. , Bellenguez C. , et al. .
Source: Molecular Psychiatry, 2016 Jan; 21(1), p. 108-17.
PMID: 25778476
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Reliable change in neuropsychological assessment of breast cancer survivors.
Authors: Andreotti C. , Root J.C. , Schagen S.B. , McDonald B.C. , Saykin A.J. , Atkinson T.M. , Li Y. , Ahles T.A. .
Source: Psycho-oncology, 2016 Jan; 25(1), p. 43-50.
PMID: 25808921
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Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression In The Zcwpw1 And The Celf1 Loci
Authors: Karch C.M. , Ezerskiy L.A. , Bertelsen S. , Alzheimer¿s Disease Genetics Consortium (ADGC) , Goate A.M. .
Source: Plos One, 2016; 11(2), p. e0148717.
PMID: 26919393
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Genetically Predicted Body Mass Index And Alzheimer's Disease-related Phenotypes In Three Large Samples: Mendelian Randomization Analyses
Authors: Mukherjee S. , Walter S. , Kauwe J.S. , Saykin A.J. , Bennett D.A. , Larson E.B. , Crane P.K. , Glymour M.M. , Adult Changes in Thought Study Investigators , Religious Orders Study/Memory and Aging Project Investigators , et al. .
Source: Alzheimer's & Dementia : The Journal Of The Alzheimer's Association, 2015 Dec; 11(12), p. 1439-51.
PMID: 26079416
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Association Of Long Runs Of Homozygosity With Alzheimer Disease Among African American Individuals
Authors: Ghani M. , Reitz C. , Cheng R. , Vardarajan B.N. , Jun G. , Sato C. , Naj A. , Rajbhandary R. , Wang L.S. , Valladares O. , et al. .
Source: Jama Neurology, 2015 Nov; 72(11), p. 1313-23.
PMID: 26366463
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Convergent Genetic And Expression Data Implicate Immunity In Alzheimer's Disease
Authors: International Genomics of Alzheimer's Disease Consortium (IGAP) .
Source: Alzheimer's & Dementia : The Journal Of The Alzheimer's Association, 2015 Jun; 11(6), p. 658-71.
PMID: 25533204
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Associations Between Potentially Modifiable Risk Factors And Alzheimer Disease: A Mendelian Randomization Study
Authors: Østergaard S.D. , Mukherjee S. , Sharp S.J. , Proitsi P. , Lotta L.A. , Day F. , Perry J.R. , Boehme K.L. , Walter S. , Kauwe J.S. , et al. .
Source: Plos Medicine, 2015 Jun; 12(6), p. e1001841; discussion e1001841.
PMID: 26079503
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Park10 Is A Major Locus For Sporadic Neuropathologically Confirmed Parkinson Disease
Authors: Beecham G.W. , Dickson D.W. , Scott W.K. , Martin E.R. , Schellenberg G. , Nuytemans K. , Larson E.B. , Buxbaum J.D. , Trojanowski J.Q. , Van Deerlin V.M. , et al. .
Source: Neurology, 2015-03-10 00:00:00.0; 84(10), p. 972-80.
PMID: 25663231
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Rarity Of The Alzheimer Disease-protective App A673t Variant In The United States
Authors: Wang L.S. , Naj A.C. , Graham R.R. , Crane P.K. , Kunkle B.W. , Cruchaga C. , Murcia J.D. , Cannon-Albright L. , Baldwin C.T. , Zetterberg H. , et al. .
Source: Jama Neurology, 2015 Feb; 72(2), p. 209-16.
PMID: 25531812
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Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: the impact of APOE and smoking.
Authors: Ahles T.A. , Li Y. , McDonald B.C. , Schwartz G.N. , Kaufman P.A. , Tsongalis G.J. , Moore J.H. , Saykin A.J. .
Source: Psycho-oncology, 2014 Dec; 23(12), p. 1382-90.
PMID: 24789331
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Effects Of Multiple Genetic Loci On Age At Onset In Late-onset Alzheimer Disease: A Genome-wide Association Study
Authors: Naj A.C. , Jun G. , Reitz C. , Kunkle B.W. , Perry W. , Park Y.S. , Beecham G.W. , Rajbhandary R.A. , Hamilton-Nelson K.L. , Wang L.S. , et al. .
Source: Jama Neurology, 2014 Nov; 71(11), p. 1394-404.
PMID: 25199842
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Genome-wide Association Meta-analysis Of Neuropathologic Features Of Alzheimer's Disease And Related Dementias
Authors: Beecham G.W. , Hamilton K. , Naj A.C. , Martin E.R. , Huentelman M. , Myers A.J. , Corneveaux J.J. , Hardy J. , Vonsattel J.P. , Younkin S.G. , et al. .
Source: Plos Genetics, 2014 Sep; 10(9), p. e1004606.
PMID: 25188341
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Chemobrain: Is It Time To Initiate Guidelines For Assessment And Management?
Authors: Patel S.K. , Hurria A. , Mandelblatt J.S. .
Source: Oncology (williston Park, N.y.), 2014 Sep; 28(9), p. 809-10.
PMID: 25224483
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Cognitive effects of cancer systemic therapy: implications for the care of older patients and survivors.
Authors: Mandelblatt J.S. , Jacobsen P.B. , Ahles T. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2014-08-20 00:00:00.0; 32(24), p. 2617-26.
EPub date: 2014-08-20 00:00:00.0.
PMID: 25071135
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Cognitive Impairment In Older Patients With Breast Cancer Before Systemic Therapy: Is There An Interaction Between Cancer And Comorbidity?
Authors: Mandelblatt J.S. , Stern R.A. , Luta G. , McGuckin M. , Clapp J.D. , Hurria A. , Jacobsen P.B. , Faul L.A. , Isaacs C. , Denduluri N. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2014-06-20 00:00:00.0; 32(18), p. 1909-18.
PMID: 24841981
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Cognitive effects of cancer and its treatments at the intersection of aging: what do we know; what do we need to know?
Authors: Mandelblatt J.S. , Hurria A. , McDonald B.C. , Saykin A.J. , Stern R.A. , VanMeter J.W. , McGuckin M. , Traina T. , Denduluri N. , Turner S. , et al. .
Source: Seminars In Oncology, 2013 Dec; 40(6), p. 709-25.
PMID: 24331192
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Clinical Presentation Of Chronic Traumatic Encephalopathy
Authors: Stern R.A. , Daneshvar D.H. , Baugh C.M. , Seichepine D.R. , Montenigro P.H. , Riley D.O. , Fritts N.G. , Stamm J.M. , Robbins C.A. , McHale L. , et al. .
Source: Neurology, 2013-09-24 00:00:00.0; 81(13), p. 1122-9.
PMID: 23966253
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Cognitive Function In Older Women With Breast Cancer Treated With Standard Chemotherapy And Capecitabine On Cancer And Leukemia Group B 49907
Authors: Freedman R.A. , Pitcher B. , Keating N.L. , Ballman K.V. , Mandelblatt J. , Kornblith A.B. , Kimmick G.G. , Hurria A. , Winer E.P. , Hudis C.A. , et al. .
Source: Breast Cancer Research And Treatment, 2013 Jun; 139(2), p. 607-16.
PMID: 23681403
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Variants In The Atp-binding Cassette Transporter (abca7), Apolipoprotein E ¿4,and The Risk Of Late-onset Alzheimer Disease In African Americans
Authors: Reitz C. , Jun G. , Naj A. , Rajbhandary R. , Vardarajan B.N. , Wang L.S. , Valladares O. , Lin C.F. , Larson E.B. , Graff-Radford N.R. , et al. .
Source: Jama, 2013-04-10 00:00:00.0; 309(14), p. 1483-92.
PMID: 23571587
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Initial Assessment Of The Pathogenic Mechanisms Of The Recently Identified Alzheimer Risk Loci
Authors: Holton P. , Ryten M. , Nalls M. , Trabzuni D. , Weale M.E. , Hernandez D. , Crehan H. , Gibbs J.R. , Mayeux R. , Haines J.L. , et al. .
Source: Annals Of Human Genetics, 2013 Mar; 77(2), p. 85-105.
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Sorl1 Is Genetically Associated With Late-onset Alzheimer's Disease In Japanese, Koreans And Caucasians
Authors: Miyashita A. , Koike A. , Jun G. , Wang L.S. , Takahashi S. , Matsubara E. , Kawarabayashi T. , Shoji M. , Tomita N. , Arai H. , et al. .
Source: Plos One, 2013; 8(4), p. e58618.
PMID: 23565137
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Independent And Epistatic Effects Of Variants In Vps10-d Receptors On Alzheimer Disease Risk And Processing Of The Amyloid Precursor Protein (app)
Authors: Reitz C. , Tosto G. , Vardarajan B. , Rogaeva E. , Ghani M. , Rogers R.S. , Conrad C. , Haines J.L. , Pericak-Vance M.A. , Fallin M.D. , et al. .
Source: Translational Psychiatry, 2013; 3, p. e256.
PMID: 23673467
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Alzheimer's Disease: Analyzing The Missing Heritability
Authors: Ridge P.G. , Mukherjee S. , Crane P.K. , Kauwe J.S. , Alzheimer¿s Disease Genetics Consortium .
Source: Plos One, 2013; 8(11), p. e79771.
PMID: 24244562
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Common Genetic Variants In The Cldn2 And Prss1-prss2 Loci Alter Risk For Alcohol-related And Sporadic Pancreatitis
Authors: Whitcomb D.C. , LaRusch J. , Krasinskas A.M. , Klei L. , Smith J.P. , Brand R.E. , Neoptolemos J.P. , Lerch M.M. , Tector M. , Sandhu B.S. , et al. .
Source: Nature Genetics, 2012 Dec; 44(12), p. 1349-54.
PMID: 23143602
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Brain vulnerability to chemotherapy toxicities.
Authors: Ahles T.A. .
Source: Psycho-oncology, 2012 Nov; 21(11), p. 1141-8.
PMID: 23023994
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Cancer- and cancer treatment-associated cognitive change: an update on the state of the science.
Authors: Ahles T.A. , Root J.C. , Ryan E.L. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2012-10-20 00:00:00.0; 30(30), p. 3675-86.
EPub date: 2012-10-20 00:00:00.0.
PMID: 23008308
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Comprehensive Search For Alzheimer Disease Susceptibility Loci In The Apoe Region
Authors: Jun G. , Vardarajan B.N. , Buros J. , Yu C.E. , Hawk M.V. , Dombroski B.A. , Crane P.K. , Larson E.B. , Alzheimer's Disease Genetics Consortium , Mayeux R. , et al. .
Source: Archives Of Neurology, 2012 Oct; 69(10), p. 1270-9.
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Brain Expression Genome-wide Association Study (egwas) Identifies Human Disease-associated Variants
Authors: Zou,F. , Chai,H.S. , Younkin,C.S. , Allen,M. , Crook,J. , Pankratz,V.S. , Carrasquillo,M.M. , Rowley,C.N. , Nair,A.A. , Middha,S. , et al. .
Source: Plos Genetics, 2012; 8(6), p. e1002707.
PMID: 22685416
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The Structure And Validity Of Self-reported Affect In Mild Cognitive Impairment And Mild Alzheimer's Disease
Authors: Ready R.E. , Carvalho J.O. , Green R.C. , Gavett B.E. , Stern R.A. .
Source: International Psychogeriatrics / Ipa, 2011 Aug; 23(6), p. 887-98.
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Common Variants At Ms4a4/ms4a6e, Cd2ap, Cd33 And Epha1 Are Associated With Late-onset Alzheimer's Disease
Authors: Naj,A.C. , Jun,G. , Beecham,G.W. , Wang,L.S. , Vardarajan,B.N. , Buros,J. , Gallins,P.J. , Buxbaum,J.D. , Jarvik,G.P. , Crane,P.K. , et al. .
Source: Nature Genetics, 2011 May; 43(5), p. 436-41.
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Meta-analysis Confirms Cr1, Clu, And Picalm As Alzheimer Disease Risk Loci And Reveals Interactions With Apoe Genotypes
Authors: Jun,G. , Naj,A.C. , Beecham,G.W. , Wang,L.S. , Buros,J. , Gallins,P.J. , Buxbaum,J.D. , Ertekin-Taner,N. , Fallin,M.D. , Friedland,R. , et al. .
Source: Archives Of Neurology, 2010 Dec; 67(12), p. 1473-84.
PMID: 20697030
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Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve.
Authors: Ahles T.A. , Saykin A.J. , McDonald B.C. , Li Y. , Furstenberg C.T. , Hanscom B.S. , Mulrooney T.J. , Schwartz G.N. , Kaufman P.A. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2010-10-10 00:00:00.0; 28(29), p. 4434-40.
EPub date: 2010-10-10 00:00:00.0.
PMID: 20837957
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New Challenges in Psycho-Oncology Research IV: Cognition and cancer: Conceptual and methodological issues and future directions.
Authors: Ahles T.A. , Hurria A. .
Source: Psycho-oncology, 2018 01; 27(1), p. 3-9.
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