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Grant Details

Grant Number: 5R01CA129769-04 Interpret this number
Primary Investigator: Mandelblatt, Jeanne
Organization: Georgetown University
Project Title: Older Breast Cancer Patients: Risk for Cognitive Decline
Fiscal Year: 2012
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Abstract

ABSTRACT Women 65 and older ("older women") account for nearly half of all new cases of breast cancer. With the "graying of America" the absolute number of older women diagnosed and undergoing breast cancer treatment will almost double by the year 2030. Treatment guidelines for these older patients include systemic therapy and older women are interested in chemotherapy for even small returns in survival extension. But systemic therapy is not without side effects, and numerous studies have documented cognitive decline after receipt of these agents. Imaging and animal studies confirm that cancer chemotherapy affects brain structure and function. However, very little is actually known about cognitive decline in older patients, because virtually all of the existing research has been conducted in younger patients. Since aging itself is associated with cognitive decline, older patients are likely to be particularly vulnerable to the adverse cognitive effects of systemic therapy. Our preliminary work suggests that this is the case, but this has never been empirically tested. This study will be the first large scale, prospective, controlled investigation to evaluate cognitive changes in older cancer patients. We use the vulnerability model of cancer survivorship to describe systemic therapy effects on cognition over a 12 month period, test associations between cognition and quality of life and to evaluate whether APOE polymorphisms moderate cognitive outcomes. We have assembled a team of oncologists, geriatricians, neurologists, neuro-, cognitive and behavioral psychologists and consumers from Lombardi Comprehensive Cancer Center, Memorial Sloan-Kettering Cancer Center, Boston University and Y- Me (a national consumer advocacy organization). We will enroll 325 newly diagnosed older breast cancer patients and an equal number of non-cancer friend controls. Participants will undergo baseline (pre-systemic therapy) neuropsychological testing and telephone interviews; clinical data will be abstracted from records. Participants will repeat cognitive testing and QOL measures 12 months after baseline. The primary outcome is change in the summary score on tests in the Attention, Working Memory, and Psychomotor Speed Domain. Four additional domains are included as secondary outcomes to assess broader cognitive function and examine differential impact: Language; Executive Functioning; Learning and Memory; Visuospatial. The results of this study will contribute to designing appropriate regimens for older women, developing preventive interventions, informing clinical decision-making about treatment, and guiding second generation studies. Overall, this topic has high research, clinical and public health importance, given the projected growth in the older population, rising incidence with advancing age, trends towards increasing use of systemic therapy in older patients, use of more aggressive dosing regimens, high survival rates, and increasing life expectancy.

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Publications

Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.
Authors: Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ, Corneveaux JJ, Hardy J, Vonsattel JP, Younkin SG, Bennett DA, De Jager PL, Larson EB, Crane PK, Kamboh MI, Kofler JK, Mash DC, Duque L, Gilbert JR, Gwirtsman H, Buxbaum JD, Kramer P, Dickson DW, Farrer LA, Frosch MP, Ghetti B, Haines JL, Hyman BT, Kukull WA, Mayeux RP, Pericak-Vance MA, Schneider JA, Trojanowski JQ, Reiman EM, Alzheimer's Disease Genetics Consortium (ADGC), Schellenberg GD, Montine TJ
Source: PLoS Genet, 2014 Sep;10(9), p. e1004606.
EPub date: 2014 Sep 4.
PMID: 25188341
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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 JS, Stern RA, Luta G, McGuckin M, Clapp JD, Hurria A, Jacobsen PB, Faul LA, Isaacs C, Denduluri N, Gavett B, Traina TA, Johnson P, Silliman RA, Turner RS, Howard D, Van Meter JW, Saykin A, Ahles T
Source: J Clin Oncol, 2014 Jun 20;32(18), p. 1909-18.
EPub date: 2014 May 19.
PMID: 24841981
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Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: the impact of APOE and smoking.
Authors: Ahles TA, Li Y, McDonald BC, Schwartz GN, Kaufman PA, Tsongalis GJ, Moore JH, Saykin AJ
Source: Psychooncology, 2014 Dec;23(12), p. 1382-90.
EPub date: 2014 Apr 30.
PMID: 24789331
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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 JS, Hurria A, McDonald BC, Saykin AJ, Stern RA, VanMeter JW, McGuckin M, Traina T, Denduluri N, Turner S, Howard D, Jacobsen PB, Ahles T, Thinking and Living With Cancer Study
Source: Semin Oncol, 2013 Dec;40(6), p. 709-25.
PMID: 24331192
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Alzheimer's disease: analyzing the missing heritability.
Authors: Ridge PG, Mukherjee S, Crane PK, Kauwe JS, Alzheimer?s Disease Genetics Consortium
Source: PLoS One, 2013;8(11), p. e79771.
EPub date: 2013 Nov 7.
PMID: 24244562
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Clinical presentation of chronic traumatic encephalopathy.
Authors: Stern RA, Daneshvar DH, Baugh CM, Seichepine DR, Montenigro PH, Riley DO, Fritts NG, Stamm JM, Robbins CA, McHale L, Simkin I, Stein TD, Alvarez VE, Goldstein LE, Budson AE, Kowall NW, Nowinski CJ, Cantu RC, McKee AC
Source: Neurology, 2013 Sep 24;81(13), p. 1122-9.
EPub date: 2013 Aug 21.
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 RA, Pitcher B, Keating NL, Ballman KV, Mandelblatt J, Kornblith AB, Kimmick GG, Hurria A, Winer EP, Hudis CA, Cohen HJ, Muss HB, Alliance for Clinical Trials in Oncology
Source: Breast Cancer Res Treat, 2013 Jun;139(2), p. 607-16.
EPub date: 2013 May 17.
PMID: 23681403
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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 RS, Conrad C, Haines JL, Pericak-Vance MA, Fallin MD, Foroud T, Farrer LA, Schellenberg GD, George-Hyslop PS, Mayeux R, Alzheimer's Disease Genetics Consortium (ADGC)
Source: Transl Psychiatry, 2013 May 14;3, p. e256.
EPub date: 2013 May 14.
PMID: 23673467
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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 BN, Wang LS, Valladares O, Lin CF, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue M, Baldwin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RC, Griffith P, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, Bennett DA, Hendrie H, Hall KS, Goate AM, Byrd GS, Kukull WA, Foroud TM, Haines JL, Farrer LA, Pericak-Vance MA, Schellenberg GD, Mayeux R, Alzheimer Disease Genetics Consortium
Source: JAMA, 2013 Apr 10;309(14), p. 1483-92.
PMID: 23571587
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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 LS, Takahashi S, Matsubara E, Kawarabayashi T, Shoji M, Tomita N, Arai H, Asada T, Harigaya Y, Ikeda M, Amari M, Hanyu H, Higuchi S, Ikeuchi T, Nishizawa M, Suga M, Kawase Y, Akatsu H, Kosaka K, Yamamoto T, Imagawa M, Hamaguchi T, Yamada M, Morihara T, Takeda M, Takao T, Nakata K, Fujisawa Y, Sasaki K, Watanabe K, Nakashima K, Urakami K, Ooya T, Takahashi M, Yuzuriha T, Serikawa K, Yoshimoto S, Nakagawa R, Kim JW, Ki CS, Won HH, Na DL, Seo SW, Mook-Jung I, Alzheimer Disease Genetics Consortium, St George-Hyslop P, Mayeux R, Haines JL, Pericak-Vance MA, Yoshida M, Nishida N, Tokunaga K, Yamamoto K, Tsuji S, Kanazawa I, Ihara Y, Schellenberg GD, Farrer LA, Kuwano R
Source: PLoS One, 2013;8(4), p. e58618.
EPub date: 2013 Apr 2.
PMID: 23565137
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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 ME, Hernandez D, Crehan H, Gibbs JR, Mayeux R, Haines JL, Farrer LA, Pericak-Vance MA, Schellenberg GD, Alzheimer's Disease Genetics Consortium, Ramirez-Restrepo M, Engel A, Myers AJ, Corneveaux JJ, Huentelman MJ, Dillman A, Cookson MR, Reiman EM, Singleton A, Hardy J, Guerreiro R
Source: Ann Hum Genet, 2013 Mar;77(2), p. 85-105.
EPub date: 2013 Jan 30.
PMID: 23360175
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Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis.
Authors: Whitcomb DC, LaRusch J, Krasinskas AM, Klei L, Smith JP, Brand RE, Neoptolemos JP, Lerch MM, Tector M, Sandhu BS, Guda NM, Orlichenko L, Alzheimer's Disease Genetics Consortium, Alkaade S, Amann ST, Anderson MA, Baillie J, Banks PA, Conwell D, Coté GA, Cotton PB, DiSario J, Farrer LA, Forsmark CE, Johnstone M, Gardner TB, Gelrud A, Greenhalf W, Haines JL, Hartman DJ, Hawes RA, Lawrence C, Lewis M, Mayerle J, Mayeux R, Melhem NM, Money ME, Muniraj T, Papachristou GI, Pericak-Vance MA, Romagnuolo J, Schellenberg GD, Sherman S, Simon P, Singh VP, Slivka A, Stolz D, Sutton R, Weiss FU, Wilcox CM, Zarnescu NO, Wisniewski SR, O'Connell MR, Kienholz ML, Roeder K, Barmada MM, Yadav D, Devlin B
Source: Nat Genet, 2012 Dec;44(12), p. 1349-54.
EPub date: 2012 Nov 11.
PMID: 23143602
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Brain vulnerability to chemotherapy toxicities.
Authors: Ahles TA
Source: Psychooncology, 2012 Nov;21(11), p. 1141-8.
EPub date: 2012 Oct 1.
PMID: 23023994
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Cancer- and cancer treatment-associated cognitive change: an update on the state of the science.
Authors: Ahles TA, Root JC, Ryan EL
Source: J Clin Oncol, 2012 Oct 20;30(30), p. 3675-86.
EPub date: 2012 Sep 24.
PMID: 23008308
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Comprehensive search for Alzheimer disease susceptibility loci in the APOE region.
Authors: Jun G, Vardarajan BN, Buros J, Yu CE, Hawk MV, Dombroski BA, Crane PK, Larson EB, Alzheimer's Disease Genetics Consortium, Mayeux R, Haines JL, Lunetta KL, Pericak-Vance MA, Schellenberg GD, Farrer LA
Source: Arch Neurol, 2012 Oct;69(10), p. 1270-9.
PMID: 22869155
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Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants.
Authors: Zou F, Chai HS, Younkin CS, Allen M, Crook J, Pankratz VS, Carrasquillo MM, Rowley CN, Nair AA, Middha S, Maharjan S, Nguyen T, Ma L, Malphrus KG, Palusak R, Lincoln S, Bisceglio G, Georgescu C, Kouri N, Kolbert CP, Jen J, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, Alzheimer's Disease Genetics Consortium, Petersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N
Source: PLoS Genet, 2012;8(6), p. e1002707.
EPub date: 2012 Jun 7.
PMID: 22685416
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Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.
Authors: Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, Larson EB, Bird TD, Boeve BF, Graff-Radford NR, De Jager PL, Evans D, Schneider JA, Carrasquillo MM, Ertekin-Taner N, Younkin SG, Cruchaga C, Kauwe JS, Nowotny P, Kramer P, Hardy J, Huentelman MJ, Myers AJ, Barmada MM, Demirci FY, Baldwin CT, Green RC, Rogaeva E, St George-Hyslop P, Arnold SE, Barber R, Beach T, Bigio EH, Bowen JD, Boxer A, Burke JR, Cairns NJ, Carlson CS, Carney RM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cotman CW, Cummings JL, DeCarli C, DeKosky ST, Diaz-Arrastia R, Dick M, Dickson DW, Ellis WG, Faber KM, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Gilman S, Giordani B, Glass JD, Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jicha GA, Jin LW, Johnson N, Karlawish J, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Lah JJ, Levey AI, Lieberman AP, Lopez OL, Mack WJ, Marson DC, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Parisi JE, Perl DP, Peskind E, Petersen RC, Poon WW, Quinn JF, Rajbhandary RA, Raskind M, Reisberg B, Ringman JM, Roberson ED, Rosenberg RN, Sano M, Schneider LS, Seeley W, Shelanski ML, Slifer MA, Smith CD, Sonnen JA, Spina S, Stern RA, Tanzi RE, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Woltjer RL, Cantwell LB, Dombroski BA, Beekly D, Lunetta KL, Martin ER, Kamboh MI, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Montine TJ, Goate AM, Blacker D, Tsuang DW, Hakonarson H, Kukull WA, Foroud TM, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD
Source: Nat Genet, 2011 May;43(5), p. 436-41.
EPub date: 2011 Apr 3.
PMID: 21460841
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The structure and validity of self-reported affect in mild cognitive impairment and mild Alzheimer's disease.
Authors: Ready RE, Carvalho JO, Green RC, Gavett BE, Stern RA
Source: Int Psychogeriatr, 2011 Aug;23(6), p. 887-98.
EPub date: 2011 Mar 24.
PMID: 21429280
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Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve.
Authors: Ahles TA, Saykin AJ, McDonald BC, Li Y, Furstenberg CT, Hanscom BS, Mulrooney TJ, Schwartz GN, Kaufman PA
Source: J Clin Oncol, 2010 Oct 10;28(29), p. 4434-40.
EPub date: 2010 Sep 13.
PMID: 20837957
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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 AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner N, Fallin MD, Friedland R, Inzelberg R, Kramer P, Rogaeva E, St George-Hyslop P, Alzheimer's Disease Genetics Consortium, Cantwell LB, Dombroski BA, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Lunetta KL, Martin ER, Montine TJ, Goate AM, Blacker D, Tsuang DW, Beekly D, Cupples LA, Hakonarson H, Kukull W, Foroud TM, Haines J, Mayeux R, Farrer LA, Pericak-Vance MA, Schellenberg GD
Source: Arch Neurol, 2010 Dec;67(12), p. 1473-84.
EPub date: 2010 Aug 9.
PMID: 20697030
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