Older Breast Cancer Patients: Risk for Cognitive Decline. The Thinking and Living With Cancer (TLC) Study
Conditions: Cancer, Breast, Age-related Cognitive Decline, Cognitive Decline
Sponsor: Georgetown University

November, 2021 - Version  63  (Cognition Protocol- Version 63, H:\CPC\COGNITION )  1  
 
 
 
 
 
 
 
 
 
 
Title: OLDER BREAST CANCER PATIENTS: RISK FOR 
COGNITIVE DECLINE 
 
 
 
NCT03451383 
 
09 December 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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OLDER BREAST CANCER PATIENTS: RISK FOR COGNITIVE 
DECLINE 
 
 
Contact Principal Investigator 
• 
Jeanne Mandelblatt, MD, MPH  
Lombardi 
Comprehensive 
Cancer 
Center 
Georgetown University Medical Center 
3300 Whitehaven St, NW, Suite 4100 
Washington, DC 20007 
T: 202-687-0812 
F: 202-687-0305 
Email: mandelbj@georgetown.edu 
 
 
• 
Tim Ahles, PhD 
Memorial Sloan-Kettering 
Cancer Center 
1275 York Avenue 
New York, NY 10021 
T: 212-639-2000 
Email: ahlest@mskcc.org  
 
 
• 
Sunita Patel, PhD 
City of Hope Comprehensive  
Cancer Center 
1500 East Duarte Road 
Duarte, California 91010 
T: 626-218-6062 
             Email: spatel@coh.org 
 
• 
Brent Small, PhD 
University of South Florida  
4202 E. Fowler Ave., 
MHC1346  
Tampa, FL 33620  
T: 813-974-9746 Fax: 813-
974-9754  
E: bsmall@usf.edu 
 
• 
Kathleen Van Dyk, PhD 
University of California, Los 
Angeles 
502 Portola Plaza 
Los Angeles, CA 90095  
T: 310-825-2961  
kvandyk@mednet.ucla.edu 
 
Principal Investigators 
 
• 
Deena Mary Atieh Graham, MD 
John Theurer Cancer Center 
Hackensack University Medical Center 
92 Second St. 
Hackensack, NJ 07601 
T: (551) 996-5811 
E: deenagraham@hackensackumc.org 
 
• 
Heather Jim, PhD 
           Moffitt Cancer Center & Research Inst. 
          12902 Magnolia Dr. MRC-PSY 
          Tampa, FL 33612 
          T: (813) 745-6369 
E: heather.jim@moffitt.org 
 
• 
Traci Bethea, PhD 
Georgetown University Medical Center 
3300 Whitehaven St. NW 
Suite 4100 
Washington, DC 20007 
T: 202-687-0802 
Email: tb988@georgetown.edu 
 
 
• 
Paul Crane, MD 
University of Washington 
Memory and Brain Wellness Center 
325 Ninth Ave 
Seattle, WA 98104 
T: 206-520-5000 
Email: pcrane@uw.edu 
 
• 
Elizabeth Breen, PhD 
University of California, Los Angeles 
Department of Psychiatry and 
Biobehavioral Sciences 
300 Medical Plaza 
Los Angeles, CA 90095 
ebreen@mednet.ucla.edu 
 
 
 
• 
John Van Meter, PhD 
          Georgetown University Medical Center 
          4000 Reservoir Rd., NW 
           Building D, Suite 150 
          Washington, DC 20057 
          T: 202-687-8767 
          Email: jwv5@georgetown.edu 
 
• 
Judith Carroll, PhD 
UCLA Department of Psychiatry and 
Biobehavioral Sciences 
300 Medical Plaza, Suite 3330 
Mail Code 707624 
Los Angeles, CA 90095 
T:(310) 794-9678 
E: jcarroll@mednet.ucla.edu 
 
• 
Andrew J. Saykin, PsyD, ABCN 
                IU Health Neuroscience Center, Suite 4100 
               Indiana University School of Medicine 
               355 West 16th Street, Indianapolis, IN 46202 
               Email: asaykin@iupui.edu 
               Tel:  (317) 963-7501 
               Fax: (317) 963-7547 
 
• 
Brenna McDonald, PsyD 
Indiana University School of Medicine 
Department of Radiology and Imaging 
Sciences 
355 W. 16th St., GH Suite 4100   
Indianapolis, IN 46202 
mcdonalb@iupui.edu 
 
• 
Kelly Rentscher, PhD 
University of California, Los Angeles 
Semel Institute for Neuroscience & Human 
Behavior 
760 Westwood Plaza 
Los Angeles, CA 90024 
krentscher@ucla.edu 
 
 
 
 

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• 
Kimberly Davis, PhD 
Georgetown University 
Medical Center 
3300 Whitehaven St. NW 
Suite 4100 
Washington, DC 20007 
T: 202-687-6925 
Email: 
kmd54@georgetown.edu 
• 
Claudine Isaacs, MD 
Georgetown University 
Medical Center 
4000 Reservoir Road, N.W. 
Podium A Lombardi 
Washington, DC 20007 
T: 202-444-3677 
            E: isaacsc@georgetown.edu 
 
• 
Brandon Selvidio 
Georgetown University 
3900 Reservoir Road, NW 
SR107 
        Washington, DC 20007         
        Email: 
bs1178@georgetown.edu 
Collaborating Institutions: 
 
Georgetown University 
       
 
 
 
• 
Jaeil Ahn, PhD 
Georgetown University 
3900 Reservoir Rd, NW 
Basic Science Building 255 
Washington, DC 20057 
T: 202-687-0197 
Email: ja1030@georgetown.edu 
 
• 
Meghan Mihalache, MS 
Georgetown University Medical Center 
3300 Whitehaven St, NW 
Suite 4100 
Washington, DC 20007 
T: 202-687-8247 
 
           Email: mem323@georgetown.edu 
 
 
• 
Nora Holmes 
Georgetown University 
3900 Reservoir Road, NW SR107 
        Washington, DC 20007         
        T: 202-784-0087 
 
 Email: nh563@georgetown.edu  
 
• 
Samira Beheshtian 
Georgetown University 
3900 Reservoir Road, NW SR107 
        Washington, DC 20007         
        T: 202-687-2302 
 
 Email: sb1893@georgetown.edu 
 
 
 
 
 
 
 
• 
Marc Schwartz, PhD 
Georgetown University Medical Center 
3300 Whitehaven St, NW 
Suite 4100 
Washington, DC 20007 
T: 202-687-0185 
 
Email: schwartm@georgetown.edu 
 
• 
Michelle Tallarico, MPH, CCRA 
        Georgetown University Medical Center 
3300 Whitehaven St, NW 
Suite 4100 
Washington, DC 20007 
T: 202-687-0064 
 
Email: mdb33@georgetown.edu 
 
• 
R. Scott Turner, MD, PhD 
          Georgetown University Medical Center 
          4000 Reservoir Rd., NW 
           Building D, Suite 177 
          Washington, DC 20057 
          T: 202-784-6671 
          Email: rst36@georgetown.edu 
 
• 
Barry Hudson, PhD 
Georgetown University Medical Center 
4000 Reservoir Rd., NW 
Washington, DC 20057 
Email: bh705@georgetown.edu 
• 
Talia LeviTalia Levi 
Georgetown University Medical Center 
3300 Whitehaven St, NW 
Suite 4100 
Washington, DC 20007 
Email: tl838@georgetown.edu 
 
 
 
 
Dawn Leonard, MD  
    18109 Prince Philip Drive 
    Suite B-100 
    Olney, Maryland 20832            
    T: 301-260-3292 
    E: dawn.j.leonard@gunet.georgetown.edu 
 
                               Collaborating Institution: 
Montgomery General Hospital 
 
 
 
 
 
 
 
 
 
Collaborating Institution: 
Virginia Cancer Specialists, PC 
 
• 
Patricia Rodriguez, MD 
           1635 N. George Mason Drive  
           Suite 170, Arlington, VA 22205 
           T: 703-894-3800 
          E: patricia.rodriguez@usoncology.com 
 
 
 
 
 
• 
Shawn Tweedt, DO 
            18111 Prince Philip Drive 
            Suite T-12 
            Olney, MD 20832 
            T: 301-774-7874 
            E: montgomerysurgical@gmail.com 
 
 
 
 
 
 
 
 
 
 

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Denise Correa, PhD 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
T: 212-639-2000 
     Email: corread@mskcc.org 
 
 
Neelam Prashad 
Memorial Sloan-Kettering Cancer Center  
485 Lexington Ave  
New York, NY 10017  
    E: prashadn@mskcc.org 
 
Caraline Craig 
Memorial Sloan-Kettering Cancer Center  
485 Lexington Ave  
New York, NY 10017  
E: craigc@mskcc.org  
Maddie Fernbach 
Memorial Sloan-Kettering Cancer Center  
485 Lexington Ave  
New York, NY 10017  
E: fernbacm@mskcc.org  
Collaborating Institution: 
Washington Hospital Center 
 
• 
Asma Dilawari, MD 
Medstar Washington Hospital Center 
110 Irving St NW 
Washington, DC 20010 
T: 202-444-3677 
E: Asma.A.Dilawari@gunet.georgetown.edu 
 
 
Collaborating Institution: 
Reston Breast Care Specialists 
 
• 
Elizabeth Feldman, MD 
Reston Breast Care Specialists 
1860 Town Center Dr. #440 
Reston, VA 20190 
T: 703-435-4320 
E: Elizabeth.feldman@hcahealthcare.com 
 
 
Collaborating Institution: 
Memorial Sloan-Kettering 
Cancer Center- MSKCC 
 
• 
Anam Ahsan 
Memorial Sloan Kettering Cancer Center 
641 Lexington Ave, 7
th Floor 
New York, NY  10022 
                E: ahsana@mskcc.org 
 
• 
James Root, PhD                                         
        Memorial Sloan Kettering Cancer Center 
        641 Lexington Ave, 7
th Floor 
        New York, NY 10022 
        T: 646-888-0035 
        E: rootj@mskcc.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Amy Irwin, MD 
1830 Town Center Drive, Suite 303 
Reston, VA 20190 
T: 703-437-6535 
E: amy.irwin@usoncology.com 
 
 
 
 
     
 
 
• 
Tiffany Traina, MD 
1275 York Ave. 
New York, New York 10021 
T: 212-639-2000 
           Email: trainat@mskcc.org 
 
 
 
• 
Kate Flaherty 
Memorial Sloan Kettering Cancer Cente
641 Lexington Ave, 7
th Floor 
New York, NY  10022 
E:flaherk1@mskcc.org 
 
 
Crystal Bryant 
Moffitt Cancer Center & Research Institute 
12902 Magnolia Drive, MRC-PSY, 
Tampa, Florida 33612  
   E: crystal.bryant@moffitt.org 
 
                     Collaborating Institution: 
Moffitt Cancer Center & Research Institute 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Ashley Celis 
City of Hope Comprehensive Cancer Center 
1500 East Duarte Road 
Duarte, California 91010 
T:626-218-0678 
E: acelis@coh.org 
 
 
Trina McClendon 
   John Theurer Cancer Center  
   Hackensack University Medical Center 
92 Second St. 
Room G81 
Hackensack, NJ 07601 
  T: 551-996-4063 
   E: tmcclendon@hackensackUMC.org 
 
John West, MS 
Indiana University School of Medicine 
355 West 16th Street, Indianapolis, IN 46202 
jdwest@iupui.edu 
Collaborating Institution: 
City of Hope Comprehensive Cancer Center  
(discontinued study visits 11/2021) 
 
 
 
 
• 
Sunita Patel, PhD 
                 City of Hope Comprehensive Cancer Center 
1500 East Duarte Road 
Duarte, California 91010 
E: spatel@coh.org 
T:626-218-6062 
 
 
 
 
Collaborating Institution: 
Hackensack University Medical Center (HUMC) 
(discontinued study visits 1/2020) 
 
 
• 
Daniela Calderon 
John Theurer Cancer Center 
Hackensack University Medical Center 
92 Second St. 
Room G81 
Hackensack, NJ 07601 
        E: Daniela.calderon@hackensackmeridian.org 
 
 
 
 
Collaborating Institution: 
                      Indiana University 
 
• 
Jessica Bailey, BS 
        Indiana University School of Medicine 
        355 West 16th Street, Indianapolis, IN 46202 
        jnadkins@iupui.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Ty Lee 
City of Hope Comprehensive Cancer Ce
1500 East Duarte Road 
Duarte, California 91010  
T: 407-810-0810 
E: Tylee@coh.org 
 
 
 
 
 
• 
Aretha DiSalvo 
                 John Theurer Cancer Center at 
                 Hackensack University Medical Center 
                 T: 551-996-5098 
                 E: adisalvo@hackensackUMC.org 
 
 
 
 
 
 
 
 
 
 
• 
Kelly Nudelman, PhD 
Indiana University School of Medicine 
 950 W. Walnut St., R2 E124 
Indianapolis, IN 46202 
Kholohan@iu.edu 
 

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Lucille Adams-Campbell, PhD 
orgetown University 
mbardi Comprehensive Cancer Center 
01 Research Building 
202-687-3770 
lla9@georgetown.edu 
 
 
External Advisors 
 
• 
Harvey Cohen, MD 
Duke Cancer Institute 
3502 Blue Zone Duke Clinic 
Center for Aging 
Trent Drive, Durham NC 27710 
T: 919-660-7502 
E: Harvey.cohen@duke.edu 
 
 
• 
Clyde Schechter, MD 
               Albert Einstein College of Medicine  
               Jack and Pearl Resnick Campus  
              1300 Morris Park Avenue  
               Block, Room 406  
               Bronx, NY 10461 
         T: 718.430.2754  
         E:clyde.schechter@einstein.yu.edu 
 
 
 
 
 
Ex Officio 
• 
Paul Jacobsen, PhD 
                National Institutes of Health 
E: Jacobsen.phd@gmail.com 
 
 
 
• 
Hyman Muss, MD 
University of North Carolina 
Lineberger Comprehensive Cancer Cen
170 Manning Drive  
Chapel Hill, NC 27599 
T: 919-966-4431 
F: 919-843-3735 
Email: muss@med.unc.edu 
 
• 
Rebecca Silliman, MD, MPH, PhD 
Boston University Medical Center 
88 E. Newton Street, F428 
Boston, MA 02118 
T: 617-638-8383  
F: 617-638-8387 
Email: rsillima@bu.edu 
 
 
 

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OLDER BREAST CANCER PATIENTS: RISK FOR COGNITIVE DECLINE 
Schema for Patients: 
 
 
 
 
 
 
 
 
 
 
 
Patient provides consent  
Eligible 
Ineligible; reasons 
for ineligibility noted 
PI and research staff introduces the study to surgeons and 
oncologists. Obtain permission to scan patient schedule, approach 
and screen patients. 
Research staff scans patient schedules to 
identify newly diagnosed women 60+ 
Research staff approaches potentially eligible patient, explains study 
and determines if patient is interested in study.  
Research staff screens medical records 
for potential eligibility (stage) 
Physician completes one-
time survey at time of 
registration of first patient 
Patient Refuses. No further 
contact; reasons for refusal 
noted 
Research staff determines eligibility 
based on self-report of medical history 
and ability to understand study 
Patient Registered (continue to baseline testing 
on page 5) 

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OLDER BREAST CANCER PATIENTS: RISK FOR COGNITIVE DECLINE 
Schema for Controls: 
 
 
 
 
 
 
 
 
 
Control provides consent  
Eligible 
Ineligible; reasons for 
ineligibility noted 
Control Registered. (Continue to baseline 
testing on page 5) 
Recruitment Method 1: (Friend Control) 
Research staff provided with contact 
information from patient of friend willing to be 
contacted as control 
Research staff approaches control, explains 
study, and screens for eligibility 
Research staff contacts control, explains 
study, screens for eligibility  
 
Recruitment Method 2: (Community Control) 
Recruitment from area retirement communities, 
senior centers and churches in the communities of 
the cases’ area of residence. 
Control Refuses. No further 
contact; reasons for refusal 
noted 
Eligibility Screen- (same as for 
cases)  

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Cognitive impairment on MMSE or BOMC or less than 3rd grade reading level on WRAT, 
she will be thanked and participation will end.    
Baseline Assessment 
Breast Cancer Patients (N=850) and Matched Non-Cancer Control Group (N = 850) 
• MMSE or BOMC and WRAT-4 screening to confirm ability to participate*  
• Blood collection for DNA testing of genetic polymorphisms 
• Blood collection for inflammatory markers, DAMPs and plasma AD-pathology markers and 
biobanking 
• Neurocognitive testing  
Timed Get Up and Go Test, grip strength, 4m Walk Gait Speed Test, sit to stand chair test 
•  (in-person visits only) 
• Sleep monitoring (Motionlogger) for one week 
• Height and weight (BMI) 
• Questionnaire  
• Optional neuroimaging (IU) 
• Chart Reviews-for clinical tumor related surgery (and reconstruction), RT and chemotherapy 
Follow-up Assessments 
12-, 24-, 36-, 48- and (up to approximately) 
60-months 
post baseline  
Neurocognitive testing, vital 
signs, BMI, timed up and 
go, grip strength, 4m speed 
test, sit to stand, 
questionnaire, sleep 
monitoring for one week, 
Blood collection, optional 
neuroimaging (IU), and 
medical chart review 
(cases) 
 
 
Lost to follow-up 
Refusal 
Deceased 
Registered Controls and Patients 

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Table of Contents 
      1.0 
PROTOCOL SUMMARY …………………….…………………………..… 9 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS……….………………………..….10 
3.0 
INTRODUCTION………………………………….……………………..…...11 
4.0 
ELIGILITY CRITERIA……………………………….………………………..15 
5.0 
STUDY DESIGN……………………………………..…………………...…..16 
6.0 
INFORMED CONSENT AND REGISTRATION………..…………….……21 
7.0 
DATA COLLECTION……………………………………..…………….……. 23 
8.0 
PRIMARY OUTCOMES…………………………………….………….….…34 
9.0 
STATISTICAL CONSIDERATIONS………………………….…….………. 34 
10.0 
DATA  MANAGEMENT, QUALITY ASSURANCE AND TRAINING..……46 
11.0  
PROTECTION OF HUMAN SUBJECTS……………………….………….. 49 
12.0 
REFERENCES…………………………………………………………….......54 
13.0  
APPENDICES (Please see attached)  
  
 
A.  CASE PROCEDURE CHECKLIST  
  
 
B.  CONTROL PROCEDURE CHECKLIST 
C.  STUDY BROCHURE  
D.  PHYSICIAN PERMISSION LETTER 
E.  CASE ELIGIBILITY SCREENING TOOL  
F.   CONTROL ELIGIBILITY SCREENING TOOL  
G.   SAMPLE CASE INFORMATION LETTER  
H.   SAMPLE CONTROL INFORMATION LETTER       
I.    CASE ASCERTAINMENT FORM 
J.   CONTROL ASCERTAINMENT FORM  
K.  CASE CONSENT FORM 
L.   CONTROL CONSENT FORM  
M.  HIPAA FORM 
N.   CASE REGISTRATION FORM 
O.  CONTROL REGISTRATION FORM 
P.   BASELINE NEUROPSYCHOLOGICAL BATTERY 
Q.  12- MONTH NEUROPSYCHOLOGICAL BATTERY 
R.  TIMED UP AND GO PROTOCOL 
S. BIOLOGICAL SAMPLE AND SHIPMENT NOTIFICATION FORM (IU) 
T. BMI FORM 
U. BASELINE QUESTIONNAIRE 
V. FOLLOW-UP QUESTIONNAIRE 
W. BLOOD COLLECTION PROTOCOL (WITH CPT) 
X. FRIEND NOMINATION FORM 

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Y. RECEIPT OF INCENTIVE 
Z. COVER LETTER FOR PHYSICIAN SURVEY 
AA. PHYSICIAN SURVEY 
BB. MEDICAL CHART AUDIT FORM 
CC. 
MEDICAL RECORD RELEASE REQUEST TEMPLATE 
DD. 
NEUROIMAGING BROCHURE INSERT 
EE.        ACTIGRAPH FORM (Discontinued 1/11/2021) 
FF.     BASELINE COGNITIVE SCREENER 
GG. 
FOLLOW-UP APPOINTMENT REMINDER 
HH. 
FOLLOW-UP APPOINTMENT LETTER 
II. FOLLOW-UP SCRIPT (CASES AND CONTROLS) 
JJ. FOLLOW-UP SCREENER (CASE) 
KK. FOLLOW-UP SCREENER (CONTROL) 
LL. RESEARCH PROXY FORM 
MM. 
ACTIGRAPH WEAR TIME FORM (Discontinued 1/11/2021) 
NN. 
BLOOD REQUISITION FORM 
OO. 
ACTIGRAPH COVER LETTER (Discontinued 1/11/2021) 
PP. ACTIGRAPH 
SCRIPT 
(PRIOR 
TO 
MAILING) 
(Discontinued 
1/11/2021) 
QQ. 
ACTIGRAPH PROTOCOL (Discontinued 1/11/2021) 
RR. 
ACTIGRAPH INSTRUCTIONS FOR SUBJECTS (Discontinued 
1/11/2021) 
SS. ACTIGRAPH INSTRUCTION SCRIPT (Discontinued 1/11/2021) 
TT. RECRUITMENT SCRIPT (CASE) 
UU. 
RECRUITMENT SCRIPT (CONTROL) 
VV. TCSR BOX FORM 
WW. 
24-, 48- MONTH NEUROPSYCHOLOGICAL BATTERY 
XX. 36-, 60- MONTH NEUROPSYCHOLOGICAL BATTERY 
YY. UCLA BOX FORM 
ZZ. ANNUAL MEDICAL REVIEW FORM 
AAA. COVID-19 SURVEY 
BBB. COVID-19 CONSENT ADDENDUM (ONLINE) 
CCC. COVID-19 CONSENT ADDENDUM (PHONE SCRIPT) 
DDD. COVID-19 SURVEY FAQS 
EEE. BLOOD COLLECTION PROTOCOL (WITHOUT CPT) 
FFF. 
REMOTE BATTERY MANUAL 
GGG. REMOTE BATTERY FORM 1 
HHH. REMOTE BATTERY FORM 2 
III. REMOTE BASELINE SCREENER 

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JJJ. 
GRIP STRENGTH FORM 
KKK. 4M WALK SPEED TEST FORM 
LLL. 
SIT TO STAND FORM 
MMM. SLEEP DIARY 
NNN. MOTIONLOGGER FORM 
OOO. MOTIONLOGGER INSTRUCTIONS FOR WEAR FORM 
 
1.0  
PROTOCOL SUMMARY  
We will use the vulnerability model of cancer survivorship to prospectively describe the magnitude 
of systemic therapy effects on cognition in older (age >60 years) breast cancer patients over up 
to approximately a 60 month period, test associations between cognition and quality of life (QOL) 
and evaluate whether APOE and COMT polymorphisms and inflammatory biomarkers, moderate 
cognitive outcomes. To achieve our objectives, we have assembled a multi-disciplinary team of 
oncologists, geriatricians, neurologists, neuro- and cognitive psychologists, behavioral scientists, 
and consumers from Lombardi Comprehensive Cancer Center (LCCC), Memorial Sloan-Kettering 
Cancer Center (MSKCC), Moffitt Cancer Center, City of Hope Cancer Center (COH) (discontinued 
study visits 11/2021), Hackensack University Medical Center (HUMC) (discontinued study visits 
1/2020), Indiana University School of Medicine (IU), University of California, Los Angeles (UCLA) 
and University of South Florida (USF). This team will work together to prospectively enroll 850 
newly diagnosed older breast cancer patients from LCCC, MSKCC, Moffitt, COH, HUMC and IU, 
all of which are tertiary referral centers with high volumes. A prospective referent group from the 
same source population as the patients who are not exposed to cancer or its treatments is critical 
for inference regarding the longitudinal trajectory of cognitive decline. Therefore, we will match an 
equal number of non-cancer friend controls. Friend controls reduce confounding by design, 
maximize internal validity, and enhance the efficiency of control recruitment (e.g., friends will be 
more motivated to participate than random community controls). If friends are not available, we 
will recruit controls from community settings who are frequency matched to patients on age, 
education, race and area.   
 
We will administer baseline neuropsychological testing prior to any systemic treatment (or at 
enrollment for controls), survey women about subjective cognitive function, psychosocial factors, 
QOL, physical measures and activities of daily living (IADLS). Women will always be tested prior 
to systemic treatment. We will avoid giving a baseline assessment on the same day that a woman 
will have chemo unless it is otherwise not possible. We will abstract cancer-related treatment data 
from medical records for cases. Since it is not feasible to obtain all medical records from cases 
and controls on general health issues that could affect cognition, cases and controls will provide 
self-reported medical history. At enrollment we will measure vital signs when possible, body mass 
index and obtain blood samples to test for APOE and COMT polymorphisms and examine 
inflammatory biomarkers; some DNA will be stored for future testing. If women are unable to 
provide blood, saliva samples will be used for DNA. APOE, COMT, future DNA testing and 
inflammatory biomarker analysis are for research purposes only; results will not be shared with 
participants. Participants will wear an actigraph to measure sleep for one week.  Eligible 
participants at GU and IU will have the option to participate in state-of-the-art imaging 
assessments to elucidate structural and functional brain changes associated with cognitive 
decline. We will conduct follow-up interviews, measure vital signs if possible, BMI and repeat the 
neuropsychological testing, surveys and physical measures every 12 months up to approximately 
60-months after baseline assessment. The 12-month time point corresponds to approximately 3-
6 months post-treatment among women who receive chemotherapy. Since work by our team and 

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others suggests that pre-frontal and frontal systems are the most affected by cancer therapy,1 our 
primary cognitive outcome will be change in summary score on tests included in the Executive 
Functioning, Working Memory, and Psychomotor Speed Domain (referred to as “EWP”). In 
secondary analyses, we will assess broader cognitive effects and consider questions of 
differential impact by examining changes in scores on four additional domains: Language, 
Attention, Learning and Memory, and Visuospatial. Neuroimaging will look at the corresponding 
gray matter atrophy, white matter diffusivity and brain functioning during the performance of 
selected tests of working and episodic memory, default mode activity during resting state and 
white matter hyper-intensities. 
 
Since cognition decreases with age, treatment effects could have a greater impact on older than 
on younger breast cancer patients. However, most prior studies have focused on younger 
patients, omitted baseline assessments, had small samples of older women, or depended on 
patient self-report of memory.2 This study will be the first to rigorously examine risks for targeted 
cognitive decline in older cancer patients, and the first to include genetic vulnerability, 
inflammatory markers, the role of physical activity and impact on QOL. The results of this research 
will contribute to designing appropriate regimens for older women, developing preventive 
interventions, informing clinical decision-making about treatment in this growing population, and 
guiding second generation studies.3-5 
 
2.0   
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 Conduct assessments every 12 months up to approximately 60-month to identify 
trajectories of longitudinal cognitive function (normal, phase shift, or accelerated 
aging).  
2.2 Identify risk factors for decline in cognitive function in the period up to approximately 
60 months post-enrollment.   
2.3 Assess inflammation as a potential mechanism for cognitive decline.  
2.4 To use neuroimaging to assess structural and functional effects of cancer treatment. 
2.5 Compare longitudinal biological aging in older breast cancer survivors vs. non-cancer 
controls and test the effects of exposure to more intensive cytotoxic cancer treatments 
(e.g., chemotherapy, repeated radiation) vs. endocrine therapy only or being a control on 
biological aging.  
2.6 Determine whether longitudinal physical and cognitive functional decline in older 
survivors is greater than in controls and test if differences are mediated by biological aging.  
2.7 Evaluate the impact of sleep on longitudinal function and biological aging in survivors 
vs. controls.  
 
 
3.0 
 INTRODUCTION 
 
Breast cancer is the leading cancer among women in the US.6 Half of the new cases each year 
occur among the population that is 60 years or older (hereinafter referred to as “older”).6-8 These 
numbers will double over the coming decades as the population ages and life expectancy 
lengthens9 so that by 2030 the number of new cases among older women will double. Thus, 
over the coming decades there will be a large increase in the absolute number of older women 
diagnosed with and seeking therapy for breast cancer.10,11 Systemic adjuvant chemotherapy 
(and hormonal regimens for estrogen receptor [ER] positive cases) is presently standard 
treatment to decrease the risk of relapse and mortality.12 Decisions about systemic therapy are 
based on patient and provider assessments of the balance between benefits and risks of 

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treatment. For several reasons, decisions about systemic therapy are more complex for older 
women than younger women, especially for chemotherapy. First, the benefits from 
chemotherapy may decrease with increasing age, although this conclusion is limited by the 
small number of older women in the original trials.13 Second, the risks of major chemotherapy 
toxicity increase with age. For example, Muss et. al. found that older breast cancer patients 
experienced a 1.5% rate of chemotherapy-related mortality compared to 0.2% for younger 
patients.14 Third, many older women have medical conditions that can impact the ability to 
tolerate chemotherapy. Despite the increased risk, data from our research shows that many 
older women would be willing to undergo chemotherapy for as little as a 12-month gain in life 
(C.1). Despite their large numbers, we know little about how systemic therapy affects cognition 
in older patients. Since cognitive side effects are among the most feared symptoms in older 
adults,15,16 these data will help inform decisions about treatment risks and benefits in this 
growing population. The addition of novel imaging data will be able to advance our 
understanding of how brain structural and functional changes translate into clinically relevant 
cognitive changes in the rapidly expanding population of aging cancer patients. The insights 
from this research are intended to inform future mechanistic research and contribute to informed 
systemic treatment decision making. 
 
3.1 Conceptual Framework 
 
Our depiction of how systemic therapy produces cognitive decline (and decrements in QOL) in 
older breast cancer patients builds on our prior work.17,18 and the vulnerability model of 
survivorship.19 We define cognitive decline as failure to show practice effects on 
neuropsychological testing over time and/or decreases in scores.20 We postulate that systemic 
treatments lead to poor cognitive outcomes through several pathways, including direct toxic 
effects on the brain and indirect side effects, such as fatigue.21-23 Other outcomes (e.g., 
satisfaction and mortality), may also be affected by treatment, but are not the focus of this study. 
Our model highlights the fact that the impact of systemic treatment on cognition in older women 
takes place against the backdrop of aging, one of the strongest predictors of cognitive decline. 
We include a friend-matched control group to capture this trajectory. Since there is credible 
evidence that APOE genotype affects the risk of cognitive decline after systemic therapy, we 
include this gene in our model.20,24-26 The model acknowledges that other factors, such as 
cognitive reserve, frailty, activity and vascular status, may also be independent risks for cognitive 
impairment, and must be considered as potential confounders if not equally distributed among 
patients and controls. Cognitive “reserve” is based on factors such as intelligence, education, 
literacy and occupation. Reserve has been shown to protect against decline.2,27-32 Like cognitive 
reserve, “frailty” reflects a loss of physiological reserve and regulation. Frailty may affect treatment 
received and increase risk of cognitive decline.33-38 Factors that impair the vascular integrity of the 
brain and increase in prevalence with age are also potential causes of cognitive decline, including 
hypertension, elevated cholesterol, and cardiac disease. Treatment side effects such as 
persistent fatigue and inactivity may also affect cognitive (and QOL) outcomes.39,40 We focus on 
the variables shown in Figure 1 since they can be easily measured, are modifiable and/or can be 
targeted by interventions.41 

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Physician, patient and 
clinical 
factors 
also 
affect 
treatment 
and 
outcomes that follow 
from therapy.4,42-52 Of 
these, comorbidity is 
likely to be particularly 
important, since half of 
older individuals have 3 
or more conditions, and 
many are increasingly 
frail.34,53-55 
Other 
individual factors, such 
has mood, are related 
to 
self-reported 
cognition,56-58 and can also be part of QOL outcomes. Obesity is another factor that can affect 
QOL and cognition via its impact on comorbidities, hormonal levels and as an indirect marker of 
activity. In addition, there is a circular relationship, or endogeneity, between some covariates in 
our model. For instance, as noted above, comorbidity and frailty will influence the selection of 
chemotherapy, so that women who receive chemotherapy may be healthier than average.59 
Healthier women are less likely to develop cognitive (and QOL) declines than women with 
comorbidities and frailty.60 Therefore, it might appear that women who undergo chemotherapy 
have better cognitive (and QOL) outcomes than women who are not treated with chemotherapy, 
if one does not consider these selection factors. We will conduct propensity score approach to 
“correct” for this selection bias when estimating the impact of systemic treatment on cognitive and 
QOL outcomes. 
 
3.2 Systemic Therapy and Cognition 
 
Breast cancer systemic therapy has been associated with self-reported and objectively measured 
cognitive declines in 17% to 75% of younger cancer patients,3,47,61,62,62-72 even after controlling for 
depression, anxiety and fatigue.73 Declines have also been seen in 27% of younger women 
undergoing neo-adjuvant therapy.58  However, not all researchers have demonstrated 
impairment.74-79 Many of these studies have been criticized for failing to consider practice effects; 
when such effects are considered deficits are usually more consistent.80 Overall, the fact that a 
subgroup of cancer patients experience persistent post-treatment cognitive changes is near 
universally accepted.5,81  
 
The results of virtually all prior studies have focused on younger women. However, there is strong 
evidence to support the concept that older women will experience cognitive decline after systemic 
treatment. Analysis of our data shows that older patients have worse cognitive performance after 
chemotherapy than older controls and younger patients, especially on tests of working memory 
and spatial ability. While the number of older women in this analysis was small (n=30), these 
results support the premise of the current study - that older women will have cognitive declines 
after chemotherapy and that these declines will be of greater magnitude than reported for younger 
women. Second, aging is associated with a progressive loss of cognitive function.82 Such deficits 
are enhanced by vascular disease and other chronic conditions that are prevalent in older 
populations.27-29,83-85 Third, our group and others have used structural MRI to show that 
chemotherapy is associated with reductions in gray and white matter in younger patients that 
mimic those seen with aging.86,87 Finally, the one pilot study with older patients (n=50) did show 

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cognitive decrements after systemic treatment.2 Since the rates of exposure to chemotherapy and 
hormonal treatment are increasing in the growing older patient population, risk for poor cognitive 
outcomes is likely to increase in the coming decades.  
 
3.3 Chemotherapy and Cognition 
 
A causal relationship between chemotherapy and cognitive decline is supported by several lines 
of evidence. First, the relationship is consistently observed.61,62,64,65,73,88-97 Second, effects show a 
dose-response relationship. For instance, van Dam noted that patients on high-dose 
chemotherapy had a risk of cognitive impairment 8.2 times higher than controls and 3.5 times 
greater than patients on standard chemotherapy, after considering other factors.89 Our group has 
also shown dose-like effects.91 Third, a causal relationship between chemotherapy and cognition 
is biologically plausible.98-101  
 
3.4 Potential Mechanisms 
 
Animal studies have demonstrated that even small amounts of chemotherapy can cause cell 
death and decreased cell division in areas important for normal cognitive functioning; 
consequently, systemic agents do not have to cross the blood-brain barrier in high doses to impact 
brain function.102 In addition, in animal models, drugs such as methotrexate decrease 
hippocampal and striatal concentrations of neurotransmitters involved in the maintenance and 
regulation of memory and attention.98,103,104 Human imaging studies also support the idea that 
chemotherapy is directly neurotoxic. For instance, our group and others have shown that there is 
a reduction in volume of frontal brain structures and changes in the integrity of white matter tracks 
after chemotherapy.86,105-107 One of our studies evaluating young breast cancer patients with 
functional MRI showed a pattern of reduced frontal cortex activation during a working memory 
task compared to patients not treated with chemotherapy and healthy controls.108 Similar results 
have been observed using functional positron emission tomography (PET) and electro-
physiological studies.109 Taken as a whole, these data suggest that chemotherapy has direct 
adverse effects on cognition.   
 
3.5 Hormonal Therapy and Cognition 
 
Recent studies have found evidence for negative cognitive outcomes in breast cancer patients 
receiving hormonal therapies.110,111 Castellon et al. found a dose-response like pattern of deficits 
among breast cancer survivors, where patients treated with chemotherapy and tamoxifen had 
lower cognitive performance than those treated with chemotherapy.90 Cognitive effects of 
hormonal therapies are also biologically plausible since estrogen receptors are found in many 
parts of the central nervous system.47,112,113 In non-cancer populations, hormone replacement 
therapy (HRT) seems to improve cognition in post-menopausal women114 and appears in some 
studies to decrease the risk of AD by up to 29%,115-1178 In Turner’s syndrome, our team has shown 
that absent estrogen and androgen production leads to cognitive deficits that can be ameliorated 
by replacement therapy.118-121 Other possible mechanisms by which hormonal treatment could 
affect cognition include decreases in cholinergic activity,122,123 reduced induction of serotonin 
receptors,124 direct toxic effects on dendrites and synaptic connectivity,114,125 and changes in 
lipids.126 Interestingly, polymorphisms of estrogen receptors influence APOE synthesis127,128 and 
interact with APOE in risk for AD.129 In addition, HRT only appears to be protective of cognitive 
decline among women without an APOE ε4 allele.130 Thus, there are several plausible 
mechanisms of action of hormonal therapy on cognition.131  
 
3.6 Aging 

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Aging is associated with a gradual loss of cognitive function, especially in domains that rely on 
frontal systems (e.g., processing speed and working memory).82 The precise biological basis of 
cognitive aging is unknown,28 but several processes have been implicated, including declines in 
IGF-1 and growth hormone, changes in the pre-frontal cortex and hippocampus, declines in 
dopamine, increases in cytokines and decreased ability to remodel synapses.27,28,132-135These 
processes may be mediated by physical activity,27,136 lifelong learning and education and 
occupation level;46 these factors contribute to “cognitive reserve”.75,27-29 As noted above, there is 
also evidence to suggest that systemic therapy effects may accelerate or mimic the aging 
process.86,137 Several groups have also shown that age (at least up to age 60, the oldest age 
included) is associated with cognitive declines in breast cancer patients.56,80,138,139 Frailty is 
another age-related process that appears to accelerate cognitive decline. In addition, cognitive 
aging appears to vary as a function of gene-environment interactions.140 This will be the first large 
study of cognition in older cancer patients. Inclusion of APOE testing will allow us to examine 
gene-treatment exposure interactions.  
 
3.7 Genes 
 
Polymorphisms of repair/plasticity genes and genes that influence neurotransmitters can increase 
the risk for negative cognitive outcomes associated with aging and injury.141,141-143 In this study we 
focus on APOE and COMT for several reasons. First, APOE and COMT are the most important 
genetic risk factor for Alzheimer’s,20,24-26 and its polymorphisms are associated with pre-clinical 
memory declines.144,145 Second, there is strong evidence linking APOE genotype to cognitive 
outcomes in younger cancer patients.20,24-26 For instance, we have demonstrated that younger 
survivors treated with chemotherapy who had at least one ε4 allele scored significantly lower in 
visual memory and spatial ability than survivors without an ε4 allele,89 although it is not clear if 
this result can be extrapolated to older patients. Third, APOE 4 and COMT val+ occur in about 
25% and 75% of the population, respectively, so have a large potential public health impact.146 
Moreover, moderation of effects by APOE status has been used in pharmacogenetic studies to 
successfully identify patients who do and do not respond to new therapies for AD;147,148 our results 
could extend this paradigm to evaluating systemic therapy for breast cancer patients. Finally, 
there is an increasing background risk of AD and cognitive impairment with age, so there is every 
reason to believe that APOE and COMT polymorphisms will be important markers of older women 
who have a high risk for cognitive decline from breast cancer systemic therapy. Both APOE and 
COMT have been associated with cancer-related cognitive decline, have readily available tests, 
are frequent and are of interest to survivors. Results for other polymorphisms (e.g., DRD2, MDR) 
are interesting, but have not yet been sufficiently detailed. Therefore, we will obtain blood to store 
DNA to test emerging genes in future research under separate funding as they become clinically 
validated. 149-154 If the subject is unable to give a blood sample the day of their visit, saliva will be 
collected. Overall, the inclusion of APOE and COMT will yield important new information in a very 
relevant, but unstudied population at minimal marginal cost; this information will lay the foundation 
for new therapeutic and mechanistic research targeted to older patients.     
 
3.8 Biomarkers 
 
3.8.1 Inflammatory Biomarkers 
 
Aging-related processes such as inflammation,220-224 altered DNA repair,225, 226 cell senescence, 
227, 228 telomere shortening, and lipid metabolism may increase risk for cognitive decline.226, 229, 
230, 231  We focus on inflammation because it is associated with cognitive decline in older non-
cancer populations 223, 232, 233 and younger cancer survivors.234, 235 The markers most commonly 

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reported in cancer-related cognitive decline and other cancer symptoms are CRP, IL6, and 
sTNFRII.236-250 Inflammation is also increased in multi-morbidity251-255and can be reduced by 
physical activity256 and other lifestyle factors. 
 
3.8.2 Alzheimer’s Disease Biomarkers 
 
Cognitive aging is a heterogeneous process, ranging from mild memory problems without 
dementia to frank dementia seen in diseases like AD. The framework used to guide testing 
hypotheses that cognitive aging seen in CRCD and AD, especially early AD, share risk factors 
and clinical-pathological features (i.e., pathology, cognitive profiles, and brain alterations), and 
that inflammation is central to these relationships.16,21,48,49 With aging, cellular stress and 
damage accumulation result in apoptotic, necrotic, and senescent cells that release danger-
associated molecular patterns (DAMPs). DAMPS activate secondary immune responses and 
the release of cytokines, amplifying the signaling cascade.50 This cycle is thought to be a critical 
element in “inflammaging” (rising inflammation with increasing age), further driving age-related 
progression of neurodegeneration.51 Well-characterized DAMPS with links to AD include soluble 
amyloid β (Aβ), S100 proteins, and HMBG1.52 AD is further known to have bidirectional effects 
on inflammation.53 54-59  
 
3.8.3 Receptor for Advanced Glycation End Product (RAGE) 
A major mechanism associated with cognition and brain aging is chronic inflammation. Our 
team has shown that the Receptor for Advanced Glycation End-products (RAGE) is a major 
driver of inflammation. Recently, we have shown that blocking RAGE can prevent cognitive 
problems in mice pre-treated before chemotherapy. TLC samples will test the relationships 
between RAGE biomarkers and cognitive decline. The results will have high impact by 
informing future clinical trials of RAGE inhibitors to prevent older women from having 
cognitive problems after their cancer therapy. 
 
3.9 Vascular Disease 
 
Vascular disease increases with age and is associated with dementia and mild cognitive 
deficits.155 Factors that affect vascular function also are associated with cognitive performance, 
including obesity, smoking, and low levels of high density lipoproteins (HDL), independent of 
stroke.84,85 Interestingly, statin medications are protective of cognitive decline after considering 
lipid levels.155 Since these studies generally used the Mini-mental State Exam (MMSE) as the 
measure of cognition, the results must be interpreted with caution. However, in the Cardiovascular 
Health Study, where cognition was measured using neuropsychological tests, the presence of 
cerebrovascular disease or diabetes and the APOE ε4 allele was associated with memory 
impairments.156,157 Similar results were seen in the Netherlands.158 Given the high prevalence of 
these illnesses in older breast cancer patients, patients with the ε4 allele might be especially 
vulnerable to cognitive decline after systemic therapy.  
 
4.0 
Eligibility Criteria  
 
 
We have selected eligibility criteria to ensure that cases and controls are comparable in all aspects 
(except cancer status) and that participants are able to complete the neuropsychological tests as 
specified in this protocol.  Since the neuropsychological assessments were designed and 
validated in English, and are not currently available in other languages, we have limited eligibility 

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to English speaking women. Eligibility will be determined based on medical records and/or self-
report.  
 
4.1  
Subject Inclusion Criteria 
 
      For cancer patients, eligibility includes:  
• being female 
• Age 60+ at diagnosis of a new primary histological confirmed adenocarcinoma 
breast cancer  
• AJCC stages 0-3 or planning on undergoing neoadjuvant therapy 
• In the judgment of the consenting professional, able to communicate well enough 
in English through verbal and written communication to complete the study 
assessments and provide informed consent 
• If currently taking psychoactive medications (including, but not limited to 
anticonvulsants, antidepressants, and anxiolytics), dose must have been stable at 
least two months prior to enrollment. 
• 
Participant report of no previous or current chemotherapy or hormonal treatment 
use (anastrazole, exemestane, etc.) 
§ 
This does not include hormonal replacement therapy, synthetic 
thyroid hormones, etc.  
 
 
      For controls, eligibility includes: 
• being female 
• Age 60+ 
• In the judgment of the consenting professional, able to communicate well enough 
in English through verbal and written communication to complete the study 
assessments and provide informed consent 
• If currently taking psychoactive medications (including, but not limited to 
anticonvulsants, antidepressants, and anxiolytics), dose must have been stable at 
least two months prior to enrollment. 
 
4.2 
Subject Exclusion Criteria 
     We apply the same exclusion criteria for patients and controls.  
• 
Participant report of a history of formal diagnosis of neurological problems (i.e. 
Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis, Dementia, Seizure 
Disorders, brain tumors, etc.) 
• 
Participant report of surgery on the brain for any reason (cancerous or non-
cancerous tumors, subdural hematomas, AV malformations, increased intracranial 
pressure, etc.) 
• 
Participant report of a history of stroke (with the exception of TIA if ≥1 year ago) 
• 
Participant report of HIV/AIDS 
• 
Participant report of moderate to severe head trauma (loss of consciousness > 60 
min or with evidence of structural brain changes on imaging) 
• 
History of major psychiatric disorder (DSM-IV Axis 1) (i.e. major depressive 
disorder (untreated or poorly treated), bipolar disorders, schizophrenia, or 
substance abuse disorders (self-reported and/or stated in medical record). 

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• 
Participant report of a history of prior breast or other cancer with the exception of 
non-melanoma skin cancer.  
§ 
An exception for cases only: women who completed treatment for a 
previous cancer at least 5 years ago and have not undergone any 
chemotherapy or hormonal therapy. This previous cancer cannot be breast 
cancer.  
 
• 
Participant report of previous or current chemotherapy or hormonal therapy use 
• 
Participant use of methotrexate (Amethopterin, Rhematrex, Trexall) or rituximab 
(Rituxin) 
for 
rheumatoid 
arthritis, 
psoriasis 
or 
Crohn’s 
disease, 
or 
cyclophosphamide (Cytoxan, Neosar) for Lupus. 
• 
Visual or hearing impairment that would preclude ability to complete interviews or 
neuropsychological testing, such as significant macular degeneration or being 
unable to correct hearing with hearing aides 
• 
Non-English speaking 
• 
To participate in the optional neuroimaging portion of the study:  
§ 
Participant cannot be claustrophobic  
§ 
Participant cannot have a pacemaker, aneurysm clip or other implants that 
are not MRI safe 
§ 
Participant cannot have any type of implanted electrical device   
 
5.0     STUDY DESIGN 
The overarching objective of this study is to use the vulnerability model of cancer survivorship to 
define the impact of systemic treatment on cognition in a cohort of older breast cancer patients 
and controls. We will also examine whether cognition is associated with QOL and whether APOE 
and COMT polymorphisms and physical activity moderate cognitive decline.  
 
To accomplish these goals, we will prospectively enroll 850 newly diagnosed older breast cancer 
patients from five tertiary care cancer centers, and an equal number of matched non-cancer friend 
controls. When friends cannot be recruited we will frequency match cases to local controls from 
similar source populations based on age, education, race and area (i.e., NY, DC, FL, CA, NJ, IN).  
 
All women will undergo study visits at baseline (pre-systemic therapy) and every 12 months up to 
approximately 60-months post-baseline. The study timepoints include interviews, vitals when 
possible, BMI measurement, neurocognitive testing, actigraph monitoring , blood collection and 
optional neuroimaging (IU). The preference is to interview patients before radiation (if planned), 
but patients who receive intensity modulated radiation therapy (IMRT) or other RT before seeing 
an oncologist for adjuvant therapy will still be eligible. We will control for timing of radiation in 
analysis. We expect this situation to be uncommon since current rates of IMRT are very low and 
RT is generally given after any planned chemotherapy. The 12-month follow up corresponds to 
3-6 months post-chemotherapy completion, provides a standardized anchor point for all subjects, 
and is consistent with the design of comparable prospective research in the field.58 We 
acknowledge that that early effects could diminish over time. A total of up to 27ml of blood will be 
collected at each time point to examine genetic polymorphisms (Indiana University) and 
inflammatory biomarkers (UCLA). Up to 15ml of blood will be stored at Georgetown University’s 
Tissue Culture Shared Resource from each study visit. If women refuse to give blood or saliva, 
they are still eligible to participate. If women are unable to provide a blood sample at their study 
visit, 2ml of saliva will be collected and blood will be attempted at the next visit. Blood samples 
will be collected at least 2 weeks after any vaccinations if possible. 
 

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We will review medical and pathology records of the cases once for tumor factors and cancer 
treatment. Patients and controls will provide self-reported information on general health and 
comorbidities. We will compare patients on any systemic therapy to controls as our primary 
comparison. We will also compare patients who receive systemic therapy to patients who receive 
no systemic therapy as another “control” group to capture any non-specific effects of a cancer 
diagnosis on cognition.58,87 We will explore if there are differences in cognitive effects by type of 
therapy (chemotherapy and hormonal vs. hormonal alone). Results for imaging cases will be 
compared to their own prior pre-treatment baseline studies (if available) and matched controls at 
yoked time points.  
 
Our primary cognitive outcome is change in score on tests in the Executive Functioning, Working 
Memory, and Psychomotor Speed Domain (EWP); in secondary analysis we also examine 
changes in scores on 4 additional domains: Language; Attention; Learning and Memory; 
Visuospatial. The primary imaging outcomes are changes in 1) gray matter atrophy, 2) white 
matter diffusivity, and 3) functional brain activation during working memory. Secondary outcomes 
include: 1) functional brain activation during episodic memory, 2) default mode activity during 
resting state, and 3) white matter hyper-intensities. 
 
5.1 Recruitment Plan  
 
5.1.1 Expected cancer Patient Sample 
 
We expect 539 women with non-metastatic cancer annually. We estimate that 30-40% will not be 
eligible (see below), leaving an average of 350 women per year. In our past studies we have 
obtained physician consent to approach 80-90% of older women. Since this study involves 
interviews and cognitive testing, we estimate that physicians will provide consent to approach 
75% (262 per year). In our work on similar protocols with younger women, 75-80% of women 
have consented.20 We assume consent rates for older women will be lower. Therefore, we 
conservatively estimate that 60% will consent, yielding 158 potential women/year. Since we must 
identify and test women prior to initiation of any systemic therapy, we may lose some women 
(non-systemic losses due to staffing limits and administrative delays), so we conservatively 
estimated that we could enroll ~170 women each year  from MSKCC, LCCC (and satellites), 
Moffitt, COH (discontinued study visits 11/2021), HUMC (discontinued study visits 1/2020) and 
IU. Since the required sample is 850, we have enough women for our goals, even under 
conservative assumptions. If there are fewer subjects than anticipated at our six sites, we will use 
other area hospitals as additional recruitment sites; these sites will follow the same procedures 
as outlined herein. A greater number of controls will be enrolled to ensure that we are able to 
match them to cases. A subset of the women recruited from Indiana University and satellites will 
have the option to participate in neuroimaging. We estimate that we can enroll ~75 cases and 
~75 controls during the accrual period that will be matched by age, race and area.  
 
5.1.2. Cancer Participant Recruitment-LCCC, MSKCC, Moffitt, COH, HUMC, IU and their 
satellites  
 
At LCCC, we will recruit from the breast cancer clinics in the LCCC/MedStar network. The network 
includes the main academic hospital and several local community referral hospitals in the metro-
DC area. The network sees a population with diverse economic status and race/ethnicity and 20-
25% of older breast cancer patients are from minority groups. At MSKCC, patients will be 
identified through the Breast Cancer Medicine Service clinic schedule.  At MSKCC, we will recruit 
from the main hospital and its affiliated community hospitals and practices in Manhattan, Long 
Island, Westchester and New Jersey. At LCCC, MSKCC, Moffitt, COH (discontinued study visits 

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11/2021), HUMC (discontinued study visits 1/2020) and IU patient recruitment will be facilitated 
by our co-investigators who care for older patients and/or are the directors of our breast clinics. 
At LCCC we will also work with existing shared resources (e.g., SRBSR) to use their established 
mechanisms for ascertaining newly diagnosed breast cancer patients that meet our eligibility 
criteria.  
 
We will follow the same procedures at all study recruitment sites. We will identify women in the 
period between initial diagnosis and the start of any planned systemic therapy, generally 1-2 to 
10-12 weeks after diagnosis. Physicians will be contacted to obtain blanket permission for 
research staff to screen patient schedules and charts for potentially eligible patients. (See 
Appendix D). Research staff will use doctor referrals and clinic schedules to approach patients in 
person, by phone, by mail, or by email. Research staff will make every effort to approach all 
possible participants to avoid any selection bias. If individual physicians prefer, they will first 
describe the study to patients and get their permission to be contacted by the study team.  
 
To ensure compliance at all satellite sites, research staff from LCCC, MSKCC, Moffitt, COH 
(discontinued study visits 11/2021) , HUMC (discontinued study visits 1/2020) and IU will 
conduct all research at all sites in order to adhere to the approved IRB procedures for the study. 
Site investigators or recruitment personnel will identify eligible patients and research staff from 
LCCC, MSKCC, Moffitt, COH (discontinued study visits 11/2021), HUMC (discontinued study 
visits 1/2020) and IU will contact the patients and coordinate their participation in order to 
ensure that sites do not exceed enrollment and to eliminate the potential for numerous minor 
and major protocol deviations. The LCCC research coordinator will be responsible for managing 
the regulatory submissions for LCCC and their satellites (Montgomery General Hospital, Virginia 
Cancer Specialists, PC, Washington Hospital Center, Reston Breast Care Specialists) and will 
ensure that these sites receive updated regulatory communication and documents in a timely 
manner. 
 
Women who are interested in the study will be contacted to review medical history for eligibility 
screening (Appendix E). Some participants may be unavailable to answer questions for the 
eligibility screen during the initial conversation with the research staff because of time 
constraints. If the patient has expressed interest in the study, and is unable to complete the 
eligibility screen in person, they will be contacted over the phone to complete the screen. We 
will use mail contact as a backup procedure if necessary. 
 
If women are eligible, they will be given the study materials and consent to read (Appendices C, 
G and K), or verbally consented (if allowable by site IRBs). All procedures will be explained by 
the research staff and all questions will be answered. If eligibility is confirmed, patients will be 
asked to sign the written consent form or give verbal consent (if allowable by site IRBs). (See 
Appendix K) The patients will also be asked to sign a HIPAA waiver for permission to review 
medical records for cancer and cancer treatment related data. (See Appendix M)  If the patient 
refuses the blood draw or is unable to provide a sample, she will be given a saliva kit for the 
purpose of collecting DNA. If she refuses either of these options for DNA collection, she is still 
eligible to participate. Patients are asked to wear an actigraph for one week to measure sleep. If 
the patient refuses to wear the actigraph, she is still eligible to participate. Subjects at Indiana 
University are also given the option of participating in neuroimaging. If a subject refuses the 
neuroimaging, she is still eligible to participate. 
 
If the patient is ineligible for the research study, the research staff will destroy all information 
collected during the initial eligibility determination, except for any minimal information maintained 
for screening log purposes (e.g., patient initials, date and outcome of approach, age and race). 

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The recruitment process outlined presents no more than minimal risk to the privacy of the patients 
who are screened and minimal PHI will be maintained as part of a screening log.  For these 
reasons, we seek a (partial) limited waiver of authorization for the purposes of (1) reviewing 
medical records to identify potential research subjects and obtain information relevant to the 
enrollment process; (2) conversing with patients regarding possible enrollment; (3) handling of 
PHI contained within those records and provided by the potential subjects; and (4) maintaining 
limited information in a screening log of patients approached (if applicable). 
 
5.1.3. Research Proxy  
Cognitive declines could limit ability to continue participation and/or decisional capacity and lead 
to informative missing data. This would under-estimate the true effects of treatment on cognition 
or lead to spurious conclusions if data are missing differentially by case-control group. To 
mitigate the impact of this issue, we will obtain contact information for a family member or friend 
and ask participants to designate a “research proxy” for this project. This is standard in 
Alzheimer’s and other aging research. The proxy can make decisions related to research 
participation based on the best interests of the participant but participants do not relinquish 
rights to refuse participation in any or all research activities. A proxy consent form (Appendix LL) 
will be filled out primarily at baseline, but can be filled out at any time point in addition to the 
standard informed consent and HIPAA form. Subjects who refuse to assign a proxy can still 
participate in the study. Proxies are only contacted if research staff believe the participant lacks 
the decisional capacity to continue independently. 
 
5.1.4 Control Recruitment at LCCC, MSKCC, Moffitt, COH, HUMC and IU 
 
 
5.1.4a Friend Control Recruitment  
 
To recruit friend controls, each enrolled cancer patient will be asked to list the names, 
addresses and telephone numbers of 5-7 female friends aged 60 years and older who they think 
might be interested in study participation. We will give each breast cancer patient a letter, 
stamped envelope, study brochure and a pre-paid response card and envelope that she can 
give or mail to her friends. (See Appendix H) Or, with their permission, we will contact their 
friends directly. If the case gives permission or the friend indicates by response card that she is 
willing to be contacted, the study team will call the friend to explain procedures. If more than one 
friend per case consents to contact, we will enroll the friend who is most closely matched to the 
case on age. Potential friend controls will be asked to confirm eligibility by answering routine 
medical questions (See Appendix F). If the control is eligible, she will be asked to provide 
consent (See Appendix L). If the control refuses the blood draw or is unable to provide a 
sample, she will be given a saliva kit for the purpose of collecting DNA. If she refuses either of 
these options for DNA collection, she is still eligible to participate. Controls are asked to wear an 
actigraph for one week to measure sleep. If the control refuses to wear the actigraph, she is still 
eligible to participate.  The control is also given the option of participating in neuroimaging. If 
she refuses the neuroimaging, she is still eligible to participate. 
 
 
5.1.3b Community Control Recruitment 
 
When necessary, friend recruitment will be supplemented with local recruitment methods to 
generate frequency matched controls. We will use this approach if patients: a) chose to not identify 
friends, b) have friends who live out of local vicinity, c) do not have a consenting friend, or d) none 
of the friends is eligible. We will use area retirement communities and frequency match to cases 
in the area on age (within 5 years), education (< high school, HS to < college, college graduate) 
and race. We will monitor control accrual on a monthly basis, and if we are not finding friends or 

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well matched controls using the above strategies, we will supplement recruitment with outreach 
using flyers to senior centers and churches in the communities of residence of the cases. The 
research staff will approach the potential community control in the same manner as the cases 
and friend controls. Potential community controls will be asked to confirm eligibility by answering 
routine medical questions (See Appendix F). If the community control is eligible, she will be asked 
to provide consent (See Appendix L). If the control refuses the blood draw or is unable to provide 
a sample, she will be given a saliva kit for the purpose of collecting DNA. If she refuses either of 
these options for DNA collection, she is still eligible to participate. Controls are asked to wear an 
actigraph for one week to measure sleep. If the control refuses to wear the actigraph, she is still 
eligible to participate.  The control is also given the option of participating in neuroimaging. If she 
refuses the neuroimaging, she is still eligible to participate. 
 
If the friend or community control turns out to be ineligible for the research study, the research 
staff will destroy all information collected during the initial eligibility determination, except for any 
minimal information maintained for screening log purposes (e.g., control initials, date, age, race, 
source of recruitment and outcome of approach). The recruitment process outlined presents no 
more than minimal risk to the privacy of the controls who are screened and minimal PHI will be 
maintained as part of a screening log.  For these reasons, we seek a (partial) limited waiver of 
authorization for the purposes of (1) conversing with controls regarding possible enrollment; (2) 
handling of PHI provided by the potential subjects; and (3) maintaining limited information in a 
screening log of patients approached (if applicable). 
 
6.0 INFORMED CONSENT AND REGISTRATION AT ALL SITES 
 
6.1 Procedures at LCCC, MSKCC, Moffitt, COH, HUMC and IU Sites 
 
 
Research staff will obtain informed consent from eligible patients/controls. All participants will be 
informed as to their rights as volunteers in a research study. At Moffitt, COH and HUMC 
(discontinued study visits 1/2020), cases will be asked to sign three copies of the consent form, 
while at LCCC and IU, cases will be asked to sign two copies (See Appendix K). One copy will 
be given to the participant to keep and one copy will be stored in the participant's research file. 
At MSKCC, Moffitt, COH (discontinued study visits 11/2021) and HUMC (discontinued study 
visits 1/2020), the third copy will become part of the medical record (cases only). At LCCC, 
Moffitt, COH, HUMC (discontinued study visits 1/2020), and IU, non-cancer control group 
participants will sign two copies (Appendix L). One will be given to the participant and one will 
be kept in the research file. At MSKCC, in addition to signing the IRB Informed Consent, all 
patients must agree to the Research Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. Consent procedures for MSKCC are further 
outlined in the MSK Addendum document at their site. 
 
 
All protocols and consent forms will be reviewed and approved by the Institutional Review Board. 
All data gathered will be kept in a secure location and available only to members of the research 
study team. The key elements of the informed consent procedure which will be explained to 
participants are: 1) the research status of the study; 2) the potential risk and the provisions for it; 
3) the lack of guarantee of benefit from participation; 4) the voluntary nature of the study; 5) the 
lack of consequence to medical care of the decision to consent or refuse to participate; 6) the 
freedom to withdraw from the study or to refuse to answer specific questions or to participate in 
any aspect of the study at any time; and 7) the confidentiality of subjects’ responses to 
assessments.  

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Once the participant has consented, they will be registered for the study. 
                
During the registration process, research staff will record the following information (Appendices 
N and O): 
Registering Individual                                                                                    [Last, First Name] 
Notice of Privacy Status                                                                                      [Yes, No, N/A] 
Research Authorization                                                                                                    [Date] 
IRB Protocol#                                                                                                  
Attending of Record (if no Oncologist, then Surgeon) (cases only):               [Last, First Name] 
Primary Care Physician (optional) (controls only)                                           [Last, First Name] 
Consenting Professional (if different than registering staff)                           [Last, First Name] 
Informed Consent Date                                                                                    
Participant's Full Name                                                                                  [Last, First Name ] 
Participant date of birth                                                                                          [mm/dd/year] 
Participant MRN (cases only)                                                                          
Participant case/control status                                                                          
Participant study ID number                                                                            
Participant address, phone numbers, email, alternative addresses, cell phone numbers and 
schedules  
Participant alternative contact information                                                      
Registration will also include the completed signature page of the informed consent form (if written 
consent), the completed signature page of the Research Authorization and a completed Eligibility 
Checklist.  
 
6.2 Retention 
 
We will use several methods to retain registered cases and controls, including maintaining a file 
of contact information on friends and relatives who will know where to locate them, sending 
birthday and holiday greeting cards (with address corrections) and use of national directories to 
track women who have moved. We will use study branding, as well as the involvement of referring 
doctors to keep women engaged. In addition, we will send newsletters periodically on general 
health topics to keep women engaged. Annual luncheons will be held to thank subjects for their 
participation. Subjects will receive a letter in the mail informing them that their follow-up window 
is approaching so they can contact us to schedule or expect a call from our office. If we are unable 
to get in touch with them and their follow-up window is closing, we will send another letter in the 
mail informing the subject that we have been trying to contact them. If subjects are unable to 
complete their study visit during their follow-up window, we will still complete follow-up as close 
to the window as is possible. We will draw on the experience of our consumer advocate in 
maintaining contact with women. Our expertise in approaching older women and sensitivity to 
their needs and concerns will enhance our ability to retain women. On a case-by-case basis, if 
the patient is unable to find transportation to provide blood or neuroimaging, then they will be 
reimbursed for car service. Study visits can be done primarily by phone, lessening the burden. A 
home visit can also be done if needed. We have found that women are very willing to help other 
women like themselves and this altruism contributes to their continued participation in the study. 
Women generally enjoy the contact from the study team and look forward to follow-up and 
interactions. To support this, we will aim to maintain continuity as much as possible with study 
staff. We expect that the use of a research proxy and learning when subjects may be unavailable 
for extended periods of time will help follow-up retention.  
 

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      6.3 Criteria for removal from study 
Participants will be removed from the study if: 
• 
The participant chooses to discontinue participation at any time. 
• 
The study investigators believe it is in the participant’s best interest. 
• 
There is a participant self-report of new acute neurological insults (Stroke or Head 
Injury) between assessment points. However, if a participant experiences a TIA ≥12 
months before a follow-up appointment, they may continue to participate in the study. 
• 
There is a participant self-report of a diagnosis of a psychiatric disorder that has not 
(untreated or poorly treated) 
• 
Cases will be removed if they develop a cancer recurrence after baseline or if they 
progress to stage 4. 
• 
Cases and controls who develop a new cancer (except non-melanoma skin cancer) 
will be excluded 
• 
WRAT-4 test results of <3rd grade reading (making the participant unable to complete 
testing) (see below). 
• 
A score of <24 on the Mini-Mental State Examination or a score of >11 on the Blessed 
Orientation Memory Concentration Test to ensure ability to provide consent and 
complete the testing required (see below). 
 
7.0 
DATA COLLECTION 
7.1 Data Collection for patients and controls 
 
7.1a Enrollment Visit 
 
Once the participant is registered, research staff will first administer the MMSE or BOMC and 
WRAT-4 to ensure sufficient literacy and cognitive functioning to complete the study.  
 
Mini-Mental State Examination (MMSE)159 (In-person battery)- is a commonly used 
instrument to evaluate general cognitive function. The MMSE evaluates orientation, 
attention, short- and intermediate-term recall, language, and command-following 
capability. The conventional cutpoint of ≤24 is used to indicate impairment. A MMSE score 
of <24 will be considered a screen failure.  
 
Blessed Orientation Memory Concentration (BOMC). (Remote battery) This test is a 
cognitive screener to assess impairment. The score for 6 items are multiplied to yield a 
“weighted” score. The higher the total weighted score, the more likely the patient has 
cognitive disability. A score >11 is considered a screen failure. 
 
Wide Range Achievement Test – 4th Ed (WRAT-4) Reading Test.160,161.  This is a 42-word 
reading recognition/pronunciation test. It is commonly used as a measure of premorbid 
ability and/or literacy and has been used with ethnically diverse older individuals.162 It has 
been shown to have a one-year test-retest reliability of .90.163 A test result of <3rd grade 
reading on the WRAT-4 will be considered a screen failure.  
 
If participants fail either of these two tests, they will be thanked for their time, given the $50 cash 
or gift card incentive for their time and will be removed from the study. If the participant passes 
both screening tests, then they will continue with the study.  
 

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The enrollment time point consists of vital signs (if possible), collecting blood samples, 
administering the neuropsychological tests, administering the timed “get up and go” test if the 
subject is completing the in-person battery, measurement or self-report of the patients’ height 
and weight for BMI and completing the questionnaire. If the patient/control is unable to complete 
the questionnaire at the same time as the neuropsychological tests, the research staff will 
contact the participant to complete the questionnaire over the telephone as close to the testing 
date as is possible. If a subject cannot complete the survey over the phone, she may be given a 
copy of the survey to complete and mail back to study staff. Participants may complete the 
survey online via a personalized Redcap link. Participants will wear an actigraph for one week to 
measure sleep. 
 
All enrolled patients and controls will receive $50 cash or gift card for their time associated with 
participation. The $50 cash or gift card will be given for each assessment (every 12 months up to 
approximately 60-months post-baseline).  The procedures are detailed in the following sections. 
After each assessment, participants will also receive a thank you letter. After the 60 month follow-
up visit, they will receive a certificate of completion. 
 
Subjects who participate in optional neuroimaging will receive an additional gift card for $50 for 
their time and travel. The $50 gift card will be given for each assessment (every 12 months up to 
approximately 60-months post-baseline). 
 
7.2 Biospecimen Collection  
 
A total of up to 27ml of blood will be collected at each time point by trained staff. Subjects can 
have blood collected at their site’s clinic or office, or can choose to have a trained phlebotomist 
come to their home to draw the sample. Vital signs will be taken and then blood will be collected 
for APOE and COMT DNA testing, inflammatory biomarkers, plasma AD-pathology markers (Aβ1-
42, tau, p-tau, and neurofilament light chain [NFL]), the receptor for advanced glycation end-
products (RAGE) and danger-associated molecular patterns (DAMPs: Aβ, S100 proteins, and 
HMBG1) and for storage of DNA for future tests.  2-3 6mL lavender top vacutainer tubes 
containing ethylenediamine tetraaceticacid (EDTA) will be used for DNA extraction, biobanking 
and inflammatory biomarkers. One optional 4ml CPT tube can be collected for biobanking. Up to 
2 2.5ml PAXgene tubes will be collected for future DNA and RNA research. Blood samples will 
be stored at site labs until batched shipment. If the subject is unable to provide a blood sample at 
their visit, 2ml of saliva will be collected using Oragene DNA Collection kits. Trained staff will 
provide the participant with a small cup to fill with approximately 2mL of saliva. Once the sample 
is taken, the lid of the cup is attached, releasing a DNA preserving fluid that is then mixed with 
the saliva. Saliva samples will be stored at room temperature until batched shipment. If subjects 
are unable to provide a full specimen of blood or saliva, they can still participate in the study. 
Samples will be labeled with bar codes provided by the genetics lab that will include the patient 
ID number, and the date the sample was obtained. The date and time corresponding to when the 
sample was processed will be recorded by the Genetics lab and available in a database. 
Specimens will be labeled with appropriate biohazard labels and comply with federal regulations 
for transport (See Appendices S and W). If a sample is found to be insufficient for analysis, an 
additional sample will be requested.  
 
The site staff will maintain logs of specimens obtained, dates shipped, confirmation of receipt, 
and results. Blood or saliva collected for genetic testing will be stored at local sites and shipped 
in batches to the Indiana University Genetics Biobank. Samples will be mailed to: Indiana 
University Genetics Biobank, Attn: Colleen Mitchell (or appropriate designee), 980 West Walnut 
Street, R3-C102, Indianapolis, IN 46202.  

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The investigators conducting DNA genetic testing will be blind to patient/control, treatment status 
and cognitive test results. The lab has on-going quality assurance procedures.  
 
7.2.1 Procedures for APOE Testing 
  
At the Indiana University Genetics lab, QIAamp DNA Blood Maxi Kits are used for purification of 
total DNA whole human blood. After lysis, the lysate is loaded onto the QIAamp spin column. DNA 
binds to the QIAamp membrane while impurities are effectively washed away in two centrifugation 
steps. Finally, ready-to-use DNA is eluted. ApoE genotyping is performed using LightMix® Kit 
APOE C112R R158C (cat.No. 40-0445-16) from TIB and Roche Diagnostics LightCycler® 480 
instrument. The hybridization probes are used to determine the genotype by performing a melting 
curve analysis after the amplification cycles are completed and the amplicon is formed. Control 
DNA is used to allow accurate comparison with unknown samples. We will define women as 
having an ε4 allele vs. not based on the APOE assay results.  
 
 At the Indiana University Genetics Lab, saliva samples will be transferred to a new 
microcentrifuge tube or 1.2 mL storage plate for manual processing after they are received. 
Buffers will be added and will bind to the DNA, then placed on an Agencourt SPRIPlate Super 
Magnet to separate out the DNA. The sample is rinsed with ethanol and is placed on the magnet 
again three times. The ethanol is then removed and a new buffer is added to the solution, then 
placed on the magnet until the solution is clear. The DNA is removed and stored at -80°C. 
 
 
 
     7.2.2 Procedures for COMT Testing 
 
The DNA will also be utilized for COMT 158val/met testing using Taqman gene expression assays 
from Applied Biosystems (Foster City, CA) for rs4680.  
 
  
 
      7.2.3 Plasma AD (Alzheimer’s Disease) Biomarkers 
We will use plasma Aβ1-42, tau, p-tau, and NFL. Plasma Aβ1-42 and p-tau may be AD-specific. 
Single Molecule assay (Simoa) kits are commercially available for these analytes and will be 
sent out for testing using the Quanterix platform. All testing will be done in one batch to limit 
variability.  
 
7.2.4 Procedures for RAGE 
Circulating levels of sRAGE and S100A8/9 will be performed in a blinded manner in the Hudson 
Laboratory on samples using ELISAs. These ELISAs include the Human RAGE Quantikine ELISA 
(R&D Systems) and Calprotectin (S100A8/9) Human ELISA kit (Hycult). We have found that inter- 
and intraassay variability for these assays to be <10%. Quality control will be monitored by 
inclusion of an internal laboratory control. Assays will be performed in duplicate, with all samples 
from each subject tested within the same plate. sRAGE and S100A8/9 levels are highly stable 
despite repeated freeze/thaw cycles.  
 
7.2.4 DNA storage for future testing 
 
As noted above, participants will also be asked for permission to store DNA for future evaluation 
of genetic polymorphisms related to other genes that may be related to chemotherapy-induced 
cognitive changes as they become clinically validated.  DNA will be frozen and stored at the 
Indiana University Genetics lab. If additional funding has not been obtained within 10 years, the 
stored DNA samples will be destroyed. 
 

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7.3 Blood Collection for Inflammatory Biomarkers 
 
Of the up to 27ml of blood collected at each time point, approximately 2ml of blood will be used 
for inflammatory biomarker analysis. Given diurnal variation, 263, 264 we will collect a morning 
sample for the inflammatory markers the day of the neuropsychological testing at baseline and all 
follow-up appointments; 265 most survivors have morning appointments for other services. If 
subjects cannot make a morning appointment, the blood draw will be done in the afternoon and 
the time will be noted so follow-up blood collection can be done in the same window of time. If 
subjects cannot do the blood collection the day of the neuropsychological testing, blood will be 
collected as close to the appointment as possible. Since exercise impacts cytokines, 266, 267 we 
will ask participants not to exercise the day of the visit; we will log NSAID use in the past 48 hours 
and any infection, illness, injury, diagnosis or exposure to COVID, medical procedures or 
vaccination in the past month or since their neuropsychological assessment, if it was over a month 
prior. 268 Whole blood will be collected in up to 2 6 ml EDTA tubes, placed in a cooler on ice, and 
centrifuged within 60 minutes. Plasma will be divided into aliquots and stored at -80C until being 
shipped in batches on dry ice to UCLA to avoid repeated freeze-thaw cycles. Staff and lab 
personnel will follow all routine safety precautions when handling specimens. Circulating levels of 
CRP (a generalized marker of systemic inflammation), IL6 (a pro-inflammatory cytokine), and 
sTNFRII (a surrogate marker of pro-inflammatory TNF activity) will be determined in a blinded 
manner in the UCLA Inflammatory Biology Core Laboratory on plasma samples using high 
sensitivity (CRP, IL6) and regular sensitivity (sTNFRII) ELISAs as previously described; 265 inter- 
and intra-assay variability for these assays was <10%. Due to differences in concentration ranges, 
these biomarkers cannot be multiplexed. Quality control will be monitored by inclusion of an 
internal laboratory control; assays will be performed in duplicate, with all samples from each 
subject tested within the same assay plate. Given the older age of our sample, we expect 
detectable levels on all markers. We will bank remaining specimens as a resource as additional 
markers are identified in the future. If women refuse blood collection, they are still eligible to 
participate in the study. 
 
 
7.4 Blood collection for banking 
Of the up to 27ml of blood to be collected at each time point, up to 15 mL of blood will be collected 
at each time point and sent to the Tissue Culture Shared Resource Lab at Georgetown University 
for storage. If a subject refuses blood collection, they are still eligible to participate in the study.  
 
All samples will be sent to: 
Tissue Culture Shared Resource 
New Research Building, W314 
Georgetown University 
3970 Reservoir Rd. NW 
Washington DC 20057-1468 
 
7.5 In-Person Neuropsychological testing-Patients and Controls  
 
Participants with an MMSE score >24 or a BOMC score >11 and a WRAT- 4 score >3rd grade 
reading will proceed to neuropsychological testing. Testing will be done at the hospitals (MSKCC 
and its affiliates in NYC, LCCC and its affiliates in DC, Moffitt and its affiliates in FL, COH 
(discontinued study visits 11/2021) and its affiliates in CA, HUMC (discontinued study visits 
1/2020) and its affiliates in the NJ area and IU and its affiliates in IN). If women cannot come to 
the hospital, study staff can conduct testing at the participant’s home under controlled conditions 
with no interruptions and quietness. Place of testing must be noted and considered in this 
analysis. Trained testers will follow a standard protocol to minimize observer biases. 

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The neuropsychological tests will be administered in a quiet room that has a desk, two chairs, 
and limited other objects/pictures in the room to minimize distraction to the participant. The 
participant will be seated across from the research staff. The research staff will then give a brief 
overview of the neuropsychological tests that they will be administering. The research staff will 
ensure that the patient understands the testing process and will answer any questions.   
 
The research staff will begin to administer the neuropsychological tests in the order specified on 
the neuropsychological test battery. (See Appendix P) To avoid fatigue, women will complete half 
of the tests, take a 10-minute break, and then will complete the remainder of the tests. Our battery 
takes 55 minutes to complete; this battery is similar to one developed by Dr. Ahles that was 
successfully used with older women.2 
 
7.5.1 Remote Neuropsychological Testing- Patients and Controls 
 
To accommodate our cohort and to maintain retention, the study will transition to remote 
neuropsychological testing of cases and controls. Approximately 100 women were randomized to 
complete both the in-person test as well as the remote test to guide statistical co-calibration. Tests 
will be administered using the mode available to subjects. Women will be able to complete the 
test by phone, smartphone, tablet or computer. Prior to administering the battery over the phone, 
tablet, smartphone or computer, study staff will review the process with subjects and ensure that 
there are limited disruptions or technical issues (Appendix FFF). The remote measure is 
approximately 40 minutes and the in-person battery is approximately 55 minutes long. Women 
who agreed to participate in the co-calibration and completed both the in-person battery and the 
remote battery received an additional $25 as compensation for their time and effort on the remote 
battery. The co-calibration was completed in October, 2021. Moving forward, women may choose 
the mode of administration that is preferable to them to ensure their safety and comfort.  
The neuropsychological tests in both the in-person battery and the remote battery that will be 
administered were selected based on one or more of the following criteria: 1) sensitivity to deficits 
associated with systemic therapy, 2) sensitivity to mild cognitive impairment, 3) available age- 
and education- and race-based normative data and established geriatric norms, 4) reliability and 
validity in older patients and good reliability across different education and literacy levels, 5) 
available alternate forms to diminish practice effects, 6) use in studies with diverse older 
individuals, including African Americans and ethnic minorities and 7) short and easy to 
administer.164-169  
 
Based on these considerations, we use tests from the Neuropsychological Assessment Battery 
(NAB)169 since it has good normative data. The NAB is a comprehensive battery of 33 
neuropsychological tests, each with two equivalent forms, developed to assess a wide array of 
cognitive functions in adults ages 18-97.  In the initial stages of test development, items for all 
NAB tests were rated by members of an advisory council of senior neuropsychologists (Drs. 
Cimino, Heaton, Larrabee, van Gorp, Welsh-Bohmer, and Williamson) with regard to potential 
ethnic/racial/cultural bias and applicability across different educational groups; all items viewed 
as being biased or inappropriate were deleted. The normative sample for the NAB consisted of 
approximately 1500 subjects; 47% were > 65 years and care was taken in the sampling to include 
adequate representation with respect to race/ethnicity, education, and geographic regions of the 
US. Reliability and validity has been well established in diverse older populations. 170  
 
1. Executive Functioning, Working Memory, and Psychomotor Speed (EWP). This is our primary 
cognitive outcome. There are 7 tests in this domain. For analysis we will create a summary 
composite z-score from the primary scores on each test. The tests are briefly outlined below. 

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Trailmaking – Part A (TMT-A).171(In-person battery) This commonly used test from the Halstead-
Reitan Battery is designed to measure psychomotor speed and visual scanning. Participants are 
required to quickly connect numbers spread about a page. In older patients the intra-item reliability 
ranges from .50-.98 and test-retest reliabilities are .64-.94. Psychometric properties of Trailmaking 
has also been studied in geriatric normative samples with ethnic and racial diversity and found to 
be reliable in all groups.165,166,168 Score is based on completion time. 
 
Trailmaking - Part B (TMT-B).171(In-person battery)  This commonly used test from the Halstead-
Reitan Neuropsychological Battery requires psychomotor speed, visual scanning and attention 
and ability to maintain and shift response sets. The subject is asked to connect a series of circles 
on a page sequentially, alternating between numbers and letters (alpha .50-.98). Test-retest 
reliabilities of .66-.88 have been reported in various groups including older subjects. The primary 
score is the completion time. 
 
Oral Trailmaking – Part A. (Remote battery) This is a neuropsychological measure that provides 
an assessment of sequential set-shifting without the motor and visual demands of the written 
TMT. Part A requires a subject to count from 1-25 as quickly as they are able.    
 
Oral Trailmaking – Part B. (Remote battery) This is a neuropsychological measure that provides 
an assessment of sequential set-shifting without the motor and visual demands of the written 
TMT. Part B requires a subject to alternate from numbers to letters from 1-A to 13-M. 
 
Digit Symbol Subtest-Wechsler Adult Intelligence Test-III.172(In-person battery)  This test 
measures visual-motor coordination, psychomotor speed, visual attention and incidental learning.  
Adequate performance on the test requires intact functioning across several domains, so it is very 
sensitive to impairment.173 Test-retest reliability in individuals age 75-89 years has been shown 
to be .91. Age-corrected scaled scores are used for summary scoring. 
 
Symbol Digit Modalities Test. (Remote battery) This test detects cognitive impairment by looking 
at visual attention and incidental learning. The test involves seeing the digit-symbol key and orally 
telling the examiner the correct number that is paired with a random symbol.  
 
Controlled Oral Word Association Test (COWAT).174 (In-person and remote battery) This test is a 
measure of verbal fluency, cognitive flexibility, and semantic knowledge. Alternate forms exist and 
have been studied in African Americans. Reliability ranges from .70-.90 in older individuals and 
test-retest reliability is .88. 166,168,174 Participants are given 3 one-minute trials to generate words 
as quickly as possible to each of 3 letter cues (F, A, and S). The test is scored based on the total 
number of words generated. 
 
Mental Control Subtest-Weschler Memory Scale (Remote battery) This subtest of the WMSIII 
assesses speeded performance for reciting the alphabet, counting forward and backward, days 
of the week forward and backward, months of the year forward and backward, counting by 6s 
while stating days of the week in order.  
 
Driving Scenes Test from the NAB.169(In-person battery)  This test of working memory, selective 
attention, and visual scanning is a Daily Living test with excellent ecological validity.175 
Participants are shown a color line drawing of a road scene (from the driver’s perspective) each 
for a 30-second exposure and then shown another scene and asked to report new and missing 
items from the previous scene; this is repeated 6 times. Scores range from 0 (worst) to 70 (best). 
Reliability (G coefficient) is reported as 0.89 in older and in low education groups. The 

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demographically-corrected t-score based on norms for age, education, and gender will be used 
in scoring.   
 
The Timed Instrumental Activities of Daily Living (TIADL).176(In-person battery)  The TIADL is a 
standardized timed assessment of performance of five instrumental activities of daily living: finding 
a telephone number in a phone directory, finding and counting out correct change, finding and 
reading out the first 3 ingredients on a food can, finding 2 specific food items on a shelf of food, 
and finding and reading the directions on a medicine container. Each task has a preset maximum 
time duration after which the task is terminated. Scoring is based on a combination of the 
completion time and an error code for each task. Times for the 5 tasks are converted to z scores 
using normative data and summed to yield a total score. The total score has been associated with 
self-reported performance of IADLs and neuropsychological assessments of processing 
speed.176,177 
 
Figure Drawing from the NAB – Organization Subscale.169,178(In-person battery)  This subscale of 
the test is designed to measure fragmentation, planning, and overall organizational skill.  The 
complex figure is presented and the participant is instructed to copy the figure on a separate piece 
of paper. The examiner switches the color pen the participant is using in order to record the order 
in which the figure was drawn.  The forms will be alternated for each visit, with form 1 administered 
at baseline, form 2 at 12-month follow-up, and form 1 at 24-month follow-up. Planning and 
fragmentation of the lines are together scored to give an overall organization score. Figure copy 
organization scoring has an interrater reliability of .93.   
 
2. Language. A summary score for this domain will be based on scores for the following 2 tests: 
 
Boston Naming Test (BNT).179 (In-person battery)  The BNT is the most commonly used test of 
confrontation naming (i.e., lexical retrieval) and has been found to be sensitive to minor or early 
aphasic deficits. We use the 30-item short form test180 that has extensive geriatric norms and 
internal reliability of .57-.75.  We calculate an age, education, and gender- corrected standard 
score, based on the number correct. 
 
Verbal Naming. (Remote Battery) The measure is a nonvisual measure of word finding with 
stimuli chosen based on rare frequency of usage in spoken English. Fifty-five objects or verbs 
are described and subjects must name the object or verb. Subjects are given a phonemic cue if 
they are unable to find the correct word.  
 
Category Fluency Test. (In-person and remote battery) This test is a measure of verbal fluency 
and ability to access semantic knowledge. Test-retest reliability is 0.56 and normative data exist 
for older Whites and African Americans.166,181 Participants are given one minute to name as many 
words as possible that belong to a particular semantic category (e.g., animals). The overall score 
is the number of words correctly generated. 182 
 
3. Attention 
 
NAB Digits Forward.169 (In-person and remote battery) This test is a version of the commonly 
used digit span paradigm, which evaluates auditory attentional capacity.  The NAB test involves 
7 items, each with two trials, in which the examinee is asked to repeat series of digits orally, with 
spans ranging from 3 to 9 digits.  Reliability (G coefficient) is reported as 0.87 in older subjects.  
We will calculate a demographically-corrected t-score. 
 

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NAB Digits Backward.169 (In-person and remote battery) This test is considered a measure of 
attention and to a lesser extent, working memory.173  It involves 7 items, each with two trials, in 
which the examinee is asked to repeat series of digits orally in reverse order. Reliability is 0.88 in 
older subjects. The demographically-corrected t-score will be used in calculating the overall score. 
 
Brief Test of Attention. (Remote battery) is a commonly used neuropsychological measure of 
auditory-divided attention that was developed to reduce the influence of confounding task 
demands such as motor speed and visual scanning.  
 
4. Learning and Memory. This secondary cognitive outcome is comprised of a summary score 
on two tests:  
 
Logical Memory I and II, Wechsler Memory Scale (WMS-IV).172,183 (In-person and remote battery) 
This test is one of the most commonly used measures of verbal memory. It involves the examinee 
listening to a brief paragraph/story and then immediately freely recalling as much as remembered.  
Following a 30-minute delay, the examinee is asked to recall as much as possible from one story 
only (IA and IIA). There have been numerous psychometric studies of the WMS-IV with excellent 
reliability in most all age/education groups (alpha for older adults =.76).173 We will use the Scaled 
Score for Logical Memory II in our summary score. 
 
List Learning from the NAB.169 (In-person and remote battery) This is a 12-word list learning task 
with 3 learning trials, followed by an interference list, and then a short delay free recall. The word 
list includes 3 embedded semantic categories with 4 words in each category. Following a 10-15 
minute delay, there is a free recall of the initial list, followed by a 36-item forced-choice recognition 
task. The test is very similar in structure to the CVLT, though its shorter length is better suited for 
older subjects. Reliability is reported as 0.80 in older adults.170 The two alternative forms of the 
NAB list have been shown to be highly equivalent. Therefore, the forms will be alternated for each 
visit with Form 1 being administered at baseline, Form 2 at 12-month follow-up, and Form 1 at 
24-month follow-up. Scores resulting from this test include measures of sensitivity to interference, 
the use of semantic encoding as an organizational mnemonic strategy, delayed free recall, 
improvement from free recall to recognition, and discrimination. The result for this test will be the 
demographically-corrected t-score for the total number of words recalled over the 3 trials.  Recent 
studies have evaluated the application of the NAB List Learning to differentiate participants with 
amnestic MCI (aMCI) from those with Alzheimer’s disease (AD) (Gavett et al., 2009). The test has 
a sensitivity of .47 and a specificity of .91 in identifying aMCI and a sensitivity of .65 and a 
specificity of .97 in identifying AD.  
 
5. Visual-spatial Functioning  
 
 
Figure Drawing from the NAB – Copy Subscale169,178 (In-person battery) This subscale of the test 
is designed to measure visuospatial and visuoconstruction skills. A complex figure is presented 
and the participant is instructed to copy the figure on a separate piece of paper. The examiner 
switches the color pen the participant is using in order to record the order in which the figure was 
drawn. The forms will be alternated for each visit. Form 1 will be administered at baseline, Form 
2 at 12-month follow-up, and Form 1 at 24-month follow-up. The primary score used in this 
visuospatial domain is based on the ability to reproduce the figure correctly/accurately, distinct 
from the organizational aspects of the production.  The reliability (G coefficient) of this variable 
has been shown to be .77.  
 
7.6 Physical Measures 
1. Timed Get Up and Go Test (In-person battery) 

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At the conclusion of the neurocognitive testing, the research staff will then administer the Timed 
“Get up and Go” test (See Appendix R). The Timed Get Up and Go Test measures basic functional 
mobility, motor strength, position sense and balance in people who are able to walk on their own 
using a combination chair test and timed walk. This test is also an excellent measure of frailty. 
(The staff will have set up the testing room prior to the participant’s arrival using the necessary 
materials for this test as outlined in the protocol). The staff will explain the test and then 
demonstrate the test to the participant. The participant will be asked to sit in a straight-backed 
chair that has no arms, get up from the chair without using her arms or other aids, walk a 
designated distance of ten feet, turn around, and return to the chair and sit down without using 
her arms or other aids. After explaining and demonstrating the test, the participant will be asked 
if she feels safe doing this test. If not, this will be noted on the scoring sheet and this test will not 
be continued. If yes, then the RA will proceed with the test. Participants who use a cane or other 
mobility assist device are allowed to use this for the walking portion of the test (but not to get out 
of the chair). The RA will time the tests and record and score the data.  
 
2.  Actigraphy 
To obtain an objective assessment of both daytime and nighttime sleeping, participants will wear 
the actigraph on the dominant wrist (unless that arm is paralyzed) for one week. The Actigraph 
Motionlogger (Ambulatory Monitoring, Inc. Ardsley, NY), is a wrist-mounted actigraph that records 
activity and illumination exposure using an accelerometer, a light transducer and a 
microprocessor. Commercially available software uses validated algorithms that take into account 
wrist movement immediately before and after an epoch of interest; wrist activity below an 
established threshold is interpreted as sleep and wrist activity above that threshold is interpreted 
as wakefulness as validated in older adults. Agreement between wrist actigraphy and EEG (the 
gold standard method for sleep assessment) scoring of sleep variables (e.g., total sleep time) is 
89-95% in older adults. Subject will also fill out a modified Pittsburgh Sleep Diary (PghSD) during 
the week of wear.  
  
3.  Grip Strength Test 
The participant should be in a standing position, arms at their side, not touching their body. Keep 
elbow bent slightly. If subjects are unable to stand comfortably, they will be seated in a chair with 
their feet touching the ground with their elbow bent to 90 degrees and the arm against their trunk 
with a neutral wrist. Participants squeeze the Jamar Plus Digital dynamometer as hard as they 
can for a count of three. The dynamometer provides a digital reading of force in pounds. A practice 
trial at less than full force and one test trial are completed with each hand. The test takes 
approximately three minutes to administer and is recommended for ages 3-85. Dominant vs. Non-
Dominant Hand (i.e., handedness) is assessed at the outset.  
 
4. 
 Four Meter Walk Gait Speed Test 
The Four Meter Walk Gait Speed Test is adapted from the 4 meter walk test in the  
Short Physical Performance Battery.  Participants are asked to walk a short distance (four  
meters) at their usual pace.  Participants complete one practice and then two timed trials.  Raw  
scores are recorded as the time in seconds required to walk four meters on each of the two  
trials, with the better trial used for scoring. The test takes approximately three minutes to  
administer (including instructions and practice). 
 
5.  Body Mass Index (BMI) 
 
The research staff will measure or abstract height and weight from medical records to calculate 
their BMI. If a subject does not have height and weight included in their records, the subject can 
provide this information as self-reported.  

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6. Sit to Stand Chair Test (30 seconds) 
Research staff will count the number of times a subject can fully stand up from a seated position 
without using their hands to push up in 30 seconds. After explaining and demonstrating the 
test, the participant will be asked if she feels safe doing this test. If not, this will be noted on 
the scoring sheet and this test will not be continued. If yes, then the RA will proceed with the 
test.  
7.8 Patient Interviews-Questionnaire 
 
Research staff will give a brief overview of the questionnaire and answer any questions the patient 
may have, then continue with the questionnaire. If the participant is too tired, the session will end 
and women will be given a copy of the questionnaire and the 30-45 minute interview will be 
scheduled over the telephone within one week of the cognitive testing or the subject can mail it 
back to research staff to decrease participant burden. Subjects will also be given the option of 
completing the survey online through REDcap. No identifying information will be collected. All 
interviews need to be completed within 1 week after neuro-cognitive testing. The women will be 
called at a date and time that is convenient for them. The interviewer will establish rapport and 
administer the structured interview. The same staff person who administered the 
neuropsychological tests will do the telephone interview if possible. Once the questionnaire is 
completed, the participant will receive 50 cash or gift card for their time. 
 
7.8.1 Questionnaire Data Collection 
 
The Measures that will be used are summarized on Table 1.  
 
Individual Influences 
 

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Factors that will be used as controlling variables for patients and controls include: 1) socio-
demographics, 2) health habits and history, 3) social and other support, 4) personality, 5) mood, 
6) fatigue, and 7) physical 
ability/activity. 
(See 
Appendices U, V and W) 
 
Socio-demographics. We 
will measure age, family 
history 
of 
dementia, 
marital status, education, 
occupation, 
race, 
ethnicity and insurance. 
Education 
will 
include 
years 
of 
school 
and 
vocational 
training. 
Occupation will capture 
job 
category 
(clerical, 
administrative, 
management, etc) and 
length of time working, 
since 
occupation 
is 
closely 
related 
to 
cognition and cognitive 
reserve. 
Race/ethnicity 
will 
be 
self-identified 
using 
standard 
categories (e.g., Hispanic 
vs. non-Hispanic; white, 
black, 
AAPI, 
etc). 
Insurance 
will 
include 
Medicaid 
and 
private 
insurance in addition to 
Medicare and HMO vs. 
non-HMO setting of care.  
 
Health 
habits/history 
includes factors that may 
affect cognition and/or QOL, including prior use of hormonal replacement therapy (total years 
used), age of menopause, self-reported cigarette and alcohol use (alcohol abuse will be defined 
as use of daily intake of >2 drinks per day). 
 
Social support will be measured using the MOS social support scale (emotional, tangible, 
affectionate, positive social interaction, and additional support).184 We have used this scale with 
excellent reliability (.85) in our research with older women.185 
 
Mood includes depression and anxiety. We will use the short form of CES-D (20 items) to measure 
depressive symptoms.188 The CES-D has been widely used in epidemiological studies of 
depression,  has strong data supporting its validity and reliability, is a good screening tool and 
produces valid results in older populations.189 Patients are asked to rate how frequently they have 
experienced symptoms on a 4-point scale ranging from "Rarely or none of the time" to "Most or 
all of the time".   
Table 1. Summary of Measures, Source, & Time of Collection 
Variable 
Source 
Base- 
line* 
Follow-
ups 
One-
time 
during 
COVID-
19  
Predictors 
 
 
 
 
    Patient/Control 
Staff 
√ 
 
 
    Systemic therapy  
Chart 
√ 
√ 
 
Moderator 
 
 
 
 
    APOE E4, COMT, 
inflammation, DAMPS, AD-
plasma biomarkers 
Venipuncture 
√ 
√ 
 
Controlling Variables 
 
 
 
 
    Treatment propensity  
Physician 
√ 
 
 
    Sociodemographics 
Patient 
√ 
 
 
    Comorbidity 
Patient 
√ 
√ 
 
    Frailty, IADLs 
Patient 
√ 
√ 
 
    Medications used, HRT 
Patient 
√ 
√ 
 
    Age of menopause 
Patient 
√ 
 
 
    Health habits  
Patient 
√ 
√ 
√ 
    Psychosocial, literacy 
Patient/WRAT 
√ 
 
 
    Mood, Fatigue  
Patient 
√ 
√ 
√ 
    Tumor characteristics 
Chart 
√ 
 
 
    Surgery, recurrence 
Chart 
√ 
 
 
    Site (type of control) 
Staff 
√ 
 
 
    Physician factors 
Physician 
√ 
 
 
   Social Support 
Patient 
√ 
 
√ 
    Time from Rx to F/U 
Charts 
 
√ 
 
   Impact of COVID-19 
Patient 
 
 
√ 
Outcomes 
 
 
 
 
   Cognitive domains 
Neuropsych tests  
√ 
√ 
 
   Self reported cognition** 
Patient 
√ 
√ 
√ 
   QOL- FACT B, MOS SF12 
Patient 
√ 
√ 
 
* Baseline is at enrollment and before systemic therapy.   
** This will be used for exploratory analysis.  

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We will use the 20-item State Anxiety scale (the level of current anxiety) from the Spielberger 
Inventory to measure anxiety. Extensive data on reliability and validity support the utility of this 
test.190  
 
We will also use the Visual Analog Mood Scale (VAMS) at in-person study visits.191 The VAMS 
consists of eight scales with 100mm vertical lines, each evaluating a different mood state. Each 
scale displays a specific cartoon-like mood face at the bottom, and a neutral cartoon-like face at 
the top. The word “neutral” is printed above the neutral face, and the name of the mood (i.e. “sad,” 
“tense,” etc.) is printed below the corresponding mood face.  By printing the word along with the 
face, issues of impaired facial recognition are avoided.  While the addition of a mood word also 
provides additional information for individuals who are able to interpret and retain the word, it is 
not necessary for completing the task.  The patient places a horizontal mark across the line to 
indicate current mood state.  This mark is converted to a 0-100 scale based on distance in mm 
from the top of the scale (i.e., Neutral pole).  Therefore, a score of 100 indicates extreme 
endorsement of the specific mood.  The faces have a minimum number of features in order to 
avoid excessive subtleties and detail. Several validation studies have examined the VAMS with 
samples varied by age, neurologic deficit.  
 
Fatigue will be assessed using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F), 
a 13-item self-report measure designed to assess the presence and intensity of fatigue, as well 
as its perceived interference with quality of life.192  
 
Physical activity/ability can affect cognition. We will use the physical function sub-scale of the 
MOS SF-12 to assess general activity level since it is brief and has excellent reliability in general 
and older populations. The SF-12 contains one or two items that measure each of the eight 
concepts included in the original SF-36. We will be using the Physical Component Summary. The 
SF-12 is a reliable measure of overall health status, and has often been used in large population 
health surveys. 193,194 In addition, we will use the International Physical Activity Questionnaire 
(IPAQ) to assess level of activity. The IPAQ contains 4 questions looking at the level of vigorous 
and moderate physical activities, as well as time spent sitting.218 An ad hoc list of other activities, 
such as trivia, crossword puzzles and reading will look at cognitive reserve.  
 
We will also use the “timed get up and go” described above (combination of the chair test and the 
timed walk), as well as a grip strength test and sit to stand chair test at in-person visits as another 
measure of physical function and frailty.195 We chose these measures since it is a sensitive 
indicator of physical activity and mortality in geriatric populations and involves minimal patient 
burden.159 
 
Functional Assessment of Cancer Therapy-Cognition (FACT-Cog)196We have used this tool in our 
prior research with good reliability and ease of administration over the telephone with older 
women.81 This 29-item tool includes self-reported difficulty in memory, concentration, and 
intellectual activities. Responses are rated from 0 "not at all" to 4 "very much". Scores correlate 
more with emotional well-being than objective measures of cognition, suggesting that self-report 
and standardized tests capture different aspects cognition. 196 We will use the summary (and sub-
scale) scores in exploratory analyses of systemic treatment effects on self-reported cognition. 
 
We will use the FACT-B to measure QOL outcomes (QOL is also included as a controlling variable 
in analyses of cognition outcomes). We will describe QOL at follow-up, controlling for baseline. 
The FACT-B is a 44-item disease-specific tool that includes general and breast cancer specific 
items that capture physical, emotional, functional and social domains; the breast specific concerns 

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will not be asked of controls. The scales have excellent reliability in our prior studies with older 
women (.76-.96), can detect change over time,197 and have been correlated with changes in 
cognition.111  
 
Sleep 
To measure sleep, we are employing both objective and subjective measures. Subjects will 
wear a Motionlogger watch to monitor their sleep for one week. With the monitor, they will fill out 
a daily sleep log. Subjects will also complete the Pittsburgh Sleep Quality Inventory, Berlin 
Sleep Apnea Questionnaire and the Insomnia Severity Inventory.  
 
7.8.2 Questionnaire Data Collection- Clinical control variables 
 
Clinical factors are considered as controlling variables in our model and will largely be used to 
create treatment propensity scores. For patients we will measure pathological stage, treatment 
(mastectomy, breast conservation, node dissection or sentinel node biopsy and radiation), ER 
status, HER2 expression (if done) and tumor grade from records. For patients and controls we 
will measure self-reported baseline comorbidity, current medications and frailty.  
 
Comorbidity will be defined along two dimensions. First, we will ascertain all chronic illnesses, 
including major vascular diseases (e.g., CHF, angina, MI, peripheral vascular disease). We will 
also ask women to list all medications, with special attention to drugs that could affect cognition, 
such as narcotics, anxiolytics and anti-depressants, and statins. We will also use the Instrumental 
Activities of Daily Living (IADLs) in the two months prior to diagnosis (or enrollment). This scale 
assesses the need for and degree of assistance required in bathing, dressing, shopping, and 
other activities. We will query women at the follow-up about new diagnoses and changes in IADLs.  
 
Frailty will be assessed at enrollment using a modification of the Frailty Index developed by Fried 
and colleagues.34 This index predicts disability, hospitalization and death.198 It includes 
unintentional weight loss >10 pounds, items on exhaustion from the CES-D and the Functional 
Assessment of Cancer Treatment-Fatigue (FACT-F), and low physical activity/ability. We will also 
use the “timed get up and go” test described above 159 as a frailty measure. Results for frailty 
indicators will be summed by adapting the algorithm developed by Fried.  
 
 
 
7.8.3 Questionnaire data collection- COVID-19 survey 
 
Physical activity, sleep, social isolation, and a sedentary lifestyle are well-reported factors in 
overall quality of life and well-being. The COVID-19 pandemic has had significant psychosocial 
effects on a global scale. Populations with chronic illnesses such as cancer and people over the 
age of 60 are particularly at risk for worse infections and outcomes from the disease. With the 
unprecedented spread of this virus in so many areas of the world, an increase in anxiety, stress, 
social isolation, and sleep disturbance are inevitable. In many areas, the socially isolating 
effects of prolonged quarantine will likely be reported in all populations and these factors could 
particularly impact the elderly. Although the goals of the TLC study focus on the study of cancer-
related cognitive decline, the enrolled participants and future subjects of this study will inevitably 
be impacted by the COVID-19 virus pandemic in significant ways and accounting for this major 
life event will be important in analyzing information from the study moving forward. Studying 
these factors in the setting of such an active, ongoing global health issue will be important in the 
understanding of this virus’s impact on health in the future. Initiating an examination of 
psychosocial factors stemming from this pandemic is a time-sensitive opportunity to capture 
data from this cohort.  
 

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During the COVID-19 pandemic, we will conduct a one-time survey with all active TLC 
participants. As of May 2020, there are 565 active participants (participants who are still eligible 
to participate and who have not completed their 60-month follow-up). 
 
We have email addresses for 64% of participants. These subjects will receive an email with 
language from the consent script introducing the survey and providing a link where they can 
complete the survey online through REDCap. We will email them up to three times. If they do 
not respond to the third email, we will try calling them up to three times. For participants without 
email addresses on file, we will call them up to six times. 
 
Participants with email addresses and internet access can complete the survey online. 
Participants who express interest in completing the survey online will receive a unique link for 
REDCap. They will read the online consent addendum (Appendix BBB) and click “I consent” to 
access the survey and complete it. 
 
Participants can also complete the survey by phone with an RA. The RA will read the phone 
consent script (Appendix CCC) and obtain verbal consent. If possible, the RA will email the 
survey to the participant so that she can have the questions and answer options in front of her. 
The RA will enter the answers into the participant’s REDCap during the phone call. Appendix 
DDD has answers to potential FAQs. This will be 1) sent on the email to participants, 2) on the 
bottom of the REDCap consent page, and 3) sent to RAs so that they can use it if questions 
arise during the phone consent. 
 
Participants will be compensated  25 for completing the survey. When RAs are safely able to 
return to work on site, they will mail the compensation to participants. 
 
 
7.9 Actigraphy  
 
Actigraph GT3X (stopped 1/11/2021) 
 
We have added objective measurement using the ActiGraph GT3X (ActiGraph, Pensacola, 
FL) as a secondary measure to provide data on actual physical activity levels that affect 
cognition and biomarkers. It uses a piezoelectric accelerometer to monitor and store the 
degree and intensity of motion, sampling every second. Wrist and waist placements 
demonstrate comparable output. 269 Actigraphy has been used in several studies of cancer 
patients and older adults, 270-273 and shows good criterion 269, 342 and predictive validity for 
functional status and quality of life. 5 Data will be downloaded and transformed into METs 
using the Crouter 274 two-regression model, which has been shown to be more accurate than 
other algorithms in calculating METs across a range of activity levels. 275 We will require at 
least four valid days for inclusion of data in analysis. We will look at continuous data or 
established categorical levels; we will also examine cut-points based on sample distributions. 
276 We will consider in analyses of physical activity the distribution of season at by survivor-
control group. Since each participant is assessed at the same time each year, there should 
be minimal impact of season on intra-individual variations.  
 
The ActiGraph GT3X will be given to subjects with graphic instructions on use. Study staff will 
review procedures in person or by phone. Participants will be instructed to wear the Actigraph 
on their waist for 7 days and to return the devices in person or by mail. Preferably the 
Actigraph will be worn the week prior to cognitive testing. If this timing is not possible due to 
treatment schedules, subjects should wear the Actigraph as close to their appointment as 

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possible, for as close to 7 days as possible.  If the Actigraph is worn after the appointment, 
subjects will be given an envelope and prepaid postage to mail it back to study staff. If 
needed, study staff will send a reminder letter to subjects who have not returned Actigraphs. 
Older adults and cancer survivors show high compliance (88%) with actigraphy (e.g., worn 4-
7 days of over a 7-day period). 
 
Motionlogger 
To obtain an objective assessment of both daytime and nighttime sleeping, participants will wear 
the actigraph on the dominant wrist (unless that arm is paralyzed) for one week. The Actigraph 
Motionlogger (Ambulatory Monitoring, Inc. Ardsley, NY), is a wrist-mounted actigraph that records 
activity and illumination exposure using an accelerometer, a light transducer and a 
microprocessor. Commercially available software uses validated algorithms that take into account 
wrist movement immediately before and after an epoch of interest; wrist activity below an 
established threshold is interpreted as sleep and wrist activity above that threshold is interpreted 
as wakefulness as validated in older adults. Agreement between wrist actigraphy and EEG (the 
gold standard method for sleep assessment) scoring of sleep variables (e.g., total sleep time) is 
89-95% in older adults. Subject will also fill out a modified Pittsburgh Sleep Diary (PghSD) during 
the week of wear.  
 
7.10 Neuroimaging 
 
Controls enrolled at Indiana University School of Medicine are eligible to participate in optional 
neuroimaging at any time point in the study. Cases must be enrolled prior to the start of 
systemic treatment. Participants will be asked to arrive 30-45 minutes early to review and fill out 
safety screening forms and receive instructions for the scan. All participants will be familiarized 
with the experimental procedures including familiarization with tasks. The MRI experimental 
session will last approximately one hour with a set-up time of approximately 10-15 minutes to 
allow the subjects to move between tasks. Scanning begins with a short scan (~1:00 min) used 
to position subsequent acquisitions. The scans collected will include both structural connectivity 
using diffusion tensor imaging (DTI) with 55-directions (~8:00 min) and functional connectivity 
computed from resting state fMRI scan (~6:00 min). Additional scans include a high-resolution 
structural scan (~9:00 min) and a 3D FLAIR to detect white matter lesions (7:55 min). Two 
working memory fMRI scans will be collected using the N-back (6:09 each) and Episodic 
memory tasks (5:15 min). A short scan (~2:37 min) to identify distortions in the magnetic is also 
collected for use in the analysis of the fMRI data.  
 
7.11 Physician data 
 
We will ask patients’ physicians (oncologists or if no oncologist, surgeon) to complete a one time 
Physician Assessment Form at the start of the study (when their first patient is enrolled) to capture 
demographics, practice patterns, tendencies to prescribe systemic treatment and attitudes 
towards patient participation in decisions. (See Appendices Z and AA) We have used this 
approach in our prior work,42 and have shown that physician tendency to recommend 
chemotherapy is related to actual treatment.  Since these data will only be used in analyses of 
treatment propensity for cases, these data will not be collected from providers of controls. 
 
7.12 Clinical data and Exposure to Systemic Therapy  
 
For cases only, we will collect data from medical records on tumor size and number of nodes, 
estrogen receptor and HER2 status and treatment received (surgery including reconstruction, 

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radiation and systemic therapy). (See Appendix BB) If women may get care from more than one 
provider, consent (and HIPAA waivers) will include permission to contact all physicians providing 
cancer care. 
 
We will use the medical records to define exposure to systemic therapy (chemotherapy and 
hormonal therapy). Our primary definition will be any use vs. none. However, since some women 
may not complete treatment, we will also measure quantity of exposure to explore dose response 
effects (e.g., none, <75% of cycles, completed >75% or more cycles but <100%, completed 
100%). We will base this categorization on dates and cycles expected based on standard 
regimens as defined by our clinicians and professional groups.11 We will collect dose data, but it 
will be more difficult to explore medication doses and dose reductions because many agents are 
adjusted for individual metabolism (e.g., based on renal and liver function). Thus, we will only 
consider regimens as dose-dense vs. routine. We will also measure types of agents for 
exploratory analysis. Hormonal treatment will classified as any vs. none, as well as compliance 
during time recommended (e.g., takes all doses, misses 1-2 per week, or misses > 2 doses per 
week on a regular basis). We will record type of hormonal therapy (e.g., tamoxifen, AIs, etc.). We 
will also measure time from therapy initiation and completion to follow-up (at follow-up visits, 
patients on hormonal therapy will still be taking medication since it is recommended for >5 years 
of treatment). 
 
After each follow-up visit, an annual medical record review will be performed. (See Appendix 
ZZ) We will record data from medical records on vital status (alive or deceased), recurrence 
status, Herceptin administration, and hormonal therapy administration. 
 
7.13 Follow up visits: Every 12 months up to approximately 60 months post-
baseline 
 
We will contact participants (Appendices II, JJ, KK) for follow-up every 12 months up to 
approximately 60 months after baseline to collect blood, measure BMI and vital signs if possible, 
repeat neuropsychological testing (See Appendices Q and P), repeat optional neuroimaging and 
conduct a brief interview to assess self-reported cognition and QOL using the same measures 
used in the enrollment visit (See Appendices V and W). Subjects will wear an actigraph for one 
week at each follow-up to measure physical activity and sleep. After each follow-up visit, an 
annual medical record review will be performed. If a participant was enrolled under the previous 
grant and consented only to 24 months, she will be contacted and given the opportunity to 
continue in the study, no matter how long she has been off-study. Subjects will be complete their 
follow-up assessments as close to 12-, 24-, 36-, 48-, and 60 months after baseline as their 
schedule allows. When possible, the same interviewer who conducted the baseline interview will 
contact women for follow-up to maintain continuity. 
 
The neuropsychological tests to be administered are as follows: (Please refer to section 7.2 for 
full test descriptions) 
 
Baseline and 12-month Assessments (In-person visits): 
 
• 
Visual Analog Mood Scale (VAMS) 
• 
NAB Digits Forward 
• 
NAB Digits Backward 
• 
NAB List Learning-Immediate Recall and Short Delay 
• 
Digit Symbol Test 
• 
NAB Driving Scenes 

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• 
NAB List Learning-Long Delay and Recognition 
• 
NAB Figure Drawing 
 
TEN MINUTE BREAK 
 
• 
Controlled Oral Word Association Test (COWAT) 
• 
Logical Memory I 
• 
Trail Making 
• 
The Timed Instrumental Activities of Daily Living (TIADL) 
• 
Timed Get-Up-and-Go 
• 
Logical Memory II 
• 
Category Fluency Test 
• 
Boston Naming Test (BNT) 
 
24-, 36-, 48-, and 60-month Assessments (In-person visits): 
• 
Visual Analog Mood Scale (VAMS) 
• 
NAB List Learning-Immediate Recall and Short Delay 
• 
NAB Digits Forward 
• 
NAB Digits Backward 
• 
Digit Symbol Test 
• 
NAB Figure Drawing 
• 
NAB List Learning-Long Delay and Recognition 
 
TEN MINUTE BREAK 
 
• 
Controlled Oral Word Association Test (COWAT) 
• 
Logical Memory I 
• 
Trail Making 
• 
The Timed Instrumental Activities of Daily Living (TIADL) 
• 
Timed Get-Up-and-Go 
• 
Logical Memory II 
• 
Category Fluency Test 
• 
Boston Naming Test (BNT) 
 
Baseline, 12-, 24-, 36-, 48-, 60- month visits (Remote visits) 
• 
NAB List Learning – Immediate Recall and Short Delay 
• 
NAB Digits Forward 
• 
NAB Digits Backward 
• 
Verbal Naming 
• 
Mental Control Test 
• 
NAB List Learning – Long Delay and Recognition 
• 
Logical Memory I 
• 
Oral Trail Making A 
• 
Oral Trail Making B 
• 
COWAT 
• 
Category Fluency 
• 
Brief Test of Attention 
• 
Logical Memory II 
• 
Symbol Digit Modalities Test 

November, 2021 - Version  63  (Cognition Protocol- Version 63, H:\CPC\COGNITION )  43  
 
 
The measures in the participant follow-up questionnaires are as follows: (Please refer to section 
7.6 for full test descriptions) 
 
• 
Socio-Demographics: change in socio-demographic information 
• 
Insurance: change in insurance 
• 
SF-12: A 12-item short-form health survey 
• 
Health Habits/History, International Physical Activity Questionnaire (IPAQ): change in self-
report of cigarette and alcohol use and physical activity 
• 
Functional Assessment of Cancer Treatment-Breast (FACT-B) 
• 
Functional Assessment of Cancer Treatment-Cognition (FACT-Cog) 
• 
MOS Social Support Survey 
• 
Depression Scale (CES-D) 
• 
State-Trait Anxiety Inventory (STAI) 
• 
OARS Instrumental Activities of Daily Living 
• 
Functional Assessment of Cancer Treatment-Fatigue (FACT-F) 
• 
Comorbidities and medications: any new illnesses and list of medications 
• 
Pittsburgh Sleep Quality Index (PSQI) 
• 
Berlin Sleep Apnea Questionnaire 
• 
Insomnia Severity Inventory 
• 
Adverse Childhood Experiences 
• 
Everyday Discrimination 
• 
Impact of Events Scale (cases only) 
• 
Perceived Stress Scale 
• 
Adult Life Stress measure 
• 
Unintentional Weight Loss 
 
8.0 
PRIMARY OUTCOMES 
Our principal cognitive outcome is change (12-, 24-, 36-, 48, up to 60- months vs. baseline) in the 
EWP Domain summary score; secondary domains include Language, Attention, Learning and 
Memory, and Visuospatial. This will allow us to focus our hypothesis testing and also see which 
domains are most sensitive to systemic therapy. For each domain we will sum the primary scores 
from the tests included within the group to calculate a domain-specific cognition score at each 
time point. We will do this by first using z-transformations for each test (using the mean and 
standard deviations of the control group). The z-scores will then be summed to create the domain 
summary score. We will examine changes over time, where decline is defined as failure to show 
the expected practice effect or to show improvement with repeat administration.  
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 Power and Data Analysis  
 
9.1a Power 
 
We use the numbers of participants anticipated to have complete data for power analyses to 
provide conservative estimates for the minimal effect size to be detected. Because we do not 
expect 100% pair-matching through the use of friend controls, our power calculation assumes 
frequency matching. We assume that some women will be lost to or refuse follow up (10%) or will 

November, 2021 - Version  63  (Cognition Protocol- Version 63, H:\CPC\COGNITION )  44  
die (10%) in the up to approximately 60 month study period, resulting in about 342 surviving 
patients (and controls) of the 850 enrolled per group that complete all assessments. We assume 
similar attrition rates across treatment and patient/control groups. Since our current study with 
older women indicates that 40-50% of women are accepting chemotherapy, but national rates are 
somewhat lower, we estimate that 30-40% of women enrolling will receive chemotherapy.199 We 
also estimate that 80% of these women will also receive hormonal therapy (the proportion that 
will be ER positive).17,200 The remaining 20% of the women receiving only chemotherapy will be 
ER negative. Among the 60-70% of women not receiving chemotherapy, we estimate that 80% 
will receive a hormonal agent based on ER status and that the remainder will receive no systemic 
treatment.  
 
The first hypothesis tests whether acute survivor declines will persist, late effects will manifest, 
and there will be trajectory differences by survivor-control and survivor-treatment groups.  In the 
first set of analyses, we will model longitudinal changes in cognitive function between the survivor 
and control groups using MLM. Each model will include fixed effects of time, group (survivor vs. 
control), a time by group interaction, and subject-level random effects. We will also test polynomial 
effects given the richness of the longitudinal follow-up with five measurement points. The latter 
analyses will allow us to evaluate whether the changes in either group level off or accelerate at 
any point in the follow-up period. These analyses evaluate the hypothesized poorer performance 
among the survivors vs. controls and the differences among the two survivor groups based on 
treatment exposure (chemotherapy +/- hormonal vs. hormonal; we can repeat these analyses 
excluding those receiving chemotherapy alone). We will use propensity methods described above 
to assess confounding by indication and conduct sensitivity analysis to evaluate the impact of 
unmeasured confounders. 
 
Although the above analyses are informative as to the group-level changes over time, they do not 
consider the inter-individual differences in intra-individual change in cognitive function. Therefore, 
to complement the standard MLM analyses, we will use 
growth 
mixture 
modeling 
(GMM) 
to 
examine 
heterogeneity of change over time and identify 
trajectories of each participant’s cognitive function 
(growth curve) over time. 257-262 The assumption of 
GMM is that women’s individual growth curves can be 
classified into distinctive patterns such as the three 
trajectories 
(“latent 
classes”) 
described 
in 
our 
conceptual model: normal aging, phase shift, and 
accelerated decline. Figure 2 provides an example of 
possible GMM results using hypothetical cognitive data. 
These may not be the exact patterns that we find. What 
makes GMM useful is that it uses statistical fit indices 
to determine the actual number and types of latent 
classes. Once the latent classes are identified, we will evaluate the association between survivor-
control and treatment exposure-control status and the identified trajectories by using chi-square 
tests. Moreover, we will compare the latent classes on key variables (e.g., multi-morbidities, 
genotype, physical activity level) that distinguish the groups using a multinomial logistic regression 
model with the latent class membership as the outcome. These analyses will allow us to identify 
risk factors for accelerated as well as possible non-linear patterns (e.g., initial decline, later 
improvement). 
 
Figure 2. Exemplar Cognitive Trajectories 

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For the next hypothesis (aim #2), non-modifiable phenotypes and genotypes will decrease 
cognitive function, while modifiable lifestyle factors will protective, controlling for time and 
covariates, and effects will be moderated by treatment exposure.  
 
We will use MLM to identify factors that affect cognition during the 4 years of follow-up by 
comparing factors of interest (e.g., APOE ε4+ vs ε4-) with respect to continuous standardized 
cognitive domain score across time (from baseline up to 60 months). The main predictors are 
multi-morbidity, gene polymorphisms, and physical activity; treatment group (chemotherapy vs. 
hormonal vs. control) is the moderator, where we expect a time by factor interaction, which, if 
statistically significant would suggest that the factor exerts a differential effect on changes in 
cognitive function depending upon treatment group. Based on our conceptual framework, if the 
three-way interaction is significant, we will use separate models for the survivors and controls to 
evaluate individual risk factors in terms of the main effects of non-modifiable (e.g., multi-morbidity 
[or cardiovascular illness or frailty], genotype) and modifiable (e.g., physical activity, cognitive 
stimulation) variables controlling for time and covariates (e.g., age, education, race, and site), and 
consider other factors like anxiety (State-Trait) and fatigue (FACT-fatigue) as confounders if they 
are associated with cognition and the predictor. The IPAQ will be the primary measure of physical 
activity since we will have these data from all assessments. We will examine distributions over 
time of physical activity measures (continuous and categorical on self-report and objective 
measurement) to review variability and sensitivity to change over time. We will also examine 
correlations between self-reported activity on the IPAQ and actigraphy and evaluate if there are 
any differences by groups based on season. We will aim for at least 4 valid days of actigraphy for 
inclusion in analysis. Next, we will look for multi-morbidity interactions with treatment based on 
our baseline results. If significant, these characteristics would identify factors that make persons 
susceptible to longitudinal declines. 
 
For the model that includes survivors only, we will consider the effects of treatment exposure and 
use propensity score methods to correct for chemotherapy selection bias. This will be interesting 
because the chemotherapy group, which was the healthiest and best-educated group, 
experienced the steepest declines in the initial phase of the study. If this pattern persists, then 
propensity score adjusted results could show a greater impact of treatment exposure than 
analyses that do not consider this favorable (for cognitive function) effect of treatment selection. 
We can repeat analyses excluding the ER-negative cases that only received chemotherapy to 
directly compare the differences between chemotherapy + hormonal treatment to hormonal 
treatment alone. In secondary analyses, we will use the same methods to evaluate self-reported 
declines of 7+ points on the FACT-cog and conversion to MCI.  We will also assess relationships 
between objective and self-reported cognitive changes. In analysis of genotype effects, we will 
consider the effects of APOE and COMT individually and jointly such that persons may have low 
genetic burden (APOE ε4- and COMT met), moderate burden (APOE ε4+ or COMT val+) or high 
burden (APOE ε4+ and COMT val+). Last, we will repeat analyses for QOL.  
 
For the third hypothesis (aim #3), levels of inflammatory markers will co-vary with trajectories of 
cognition; and H3b: Inflammation will mediate the protective effect of physical activity and risk of 
multi-morbidity on cognitive decline. Based on current evidence, we will measure IL6, CRP, and 
sTNF-RII. Each will be used separately as a continuous measure. Although there are no 
established cut points for these markers in relationship to cognition, we will also explore as 
dichotomous variables levels such as CRP < 3 mg/L vs. > 3 based on cardiac risk. 317,318     
 
Log transformations are expected to be necessary for analyses of inflammatory biomarker 
concentrations. As in other aims, our primary cognitive outcome is based on neuropsychological 
testing; we will also examine how inflammation relates to secondary outcomes, including self-

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reported cognition and conversion to MCI.  We will consider covariates such as sleep, fatigue, 
BMI, etc. in these analyses. Also, since cancer and its treatments affect inflammation, we will 
consider stage, surgery, radiation, and systemic therapy in survivor-only analyses. Similar to 
Aim 1, we will use MLMs to evaluate how each inflammation marker co-varies with trajectories 
of cognition. We will include subject-level random effects and run models treating the markers of 
inflammation as time-varying covariates to determine if changes in inflammation co-vary with 
changes in cognitive performance. For the second part of the aim, we will perform longitudinal 
mediation analyses to explore how inflammation mediates over time the relationship between 
changes in levels of physical activity (or multi-morbidity) and trajectories of cognition. In these 
models, we will apply a latent difference score approach to estimate the direct effects of 
physical activity (considering season if needed) on changes in cognition, and indirect effects 
acting through changes in inflammation. These models have the advantage of allowing changes 
between time intervals (e.g., from baseline to 12 months or 36 months to 48 months) to be 
different and for the roles of the mediators to change dynamically over time. Last, we will 
evaluate independent contributions of each marker in multiple mediator models. We will 
examine correlations between inflammatory markers to evaluate whether creating a composite 
score will be reasonable in secondary analyses.  
 
9.1b Analysis Plan 
 
Our primary outcome is the standardized score on the attention, psychomotor speed, and 
executive function domain; global decline and the other domains will also be examined. Test 
scores are standardized to baseline controls (since not all tests have external norms), and z-
scores are combined into domain scores. Self-reported cognition, conversion to MCI, and QOL 
are added outcomes.  
 
We selected multi-level models (MLM) to evaluate our study outcome based on our prior research 
277 and because they: 1) capture the intra-individual correlation and clustering within sites; 2) allow 
testing of inter-individual differences in patterns of responses over time; 3) allow for inclusion of 
all available data, providing greater flexibility and statistical power than other methods (e.g., 
repeated-measures MANOVA); 278 4) handle heteroscedascity and departures from assumptions; 
5) can incorporate covariates and strategies to correct for treatment selection bias if needed (e.g., 
propensity score adjustments); and 6) can readily deal with unbalanced follow-up times, a design 
element that may occur in this study. 279 Prior to statistical modeling, we will examine distributions 
of variables and descriptive statistics, describe missing data patterns, and evaluate the 
association of missingness with enrollment characteristics. We will consider multiple imputation 
techniques for missing data. 280, 281 We will also evaluate the impact of potential covariates that 
relate to cognitive function and treatment exposure; evaluate the impact of additional covariates, 
such as anxiety, depression, and fatigue; and confirm that the distribution of genotypes continues 
to be comparable among survivor and control groups.  
 
Since predictors of chemotherapy selection can affect longitudinal cognitive function independent 
of treatment, propensity score analyses will address treatment selection: 1) using the propensity 
score as a covariate, 2) using propensity score matching methods, and 3) using the inverse 
probability of treatment weighting method. 282-284 We will repeat analyses excluding DCIS cases. 
Lastly, we will evaluate adjustment for multiple testing (e.g., using false discovery rate 
procedures). 285, 286 
 
We start with 850 survivors and 850 matched controls.  At each time period we assume that 5% 
of women will die each year and that 5% may become ineligible due to cancer 
recurrence/occurrence or stroke since this is a fairly healthy volunteer sample, for a range of 90-

November, 2021 - Version  63  (Cognition Protocol- Version 63, H:\CPC\COGNITION )  47  
95% survival in each period.  We estimate a retention rate of 80% based on current experience.  
Thus, the estimated sample sizes per group vary from 342-360 alive (274-288 complete) at 12 
months to 250-308 alive (200-246 complete) at 60 months. If rates vary from expectation, we will 
supplement enrollment to ensure robust power. Among survivors, based on current data, a 
minimum of 30% is estimated to receive chemotherapy. APOE ε4+ is expected in 20-25% of 
women and any COMT val+ allele is expected in approximately 75%, with 26% homozygous for 
val. 287 Power calculations are provided only for primary domain (attention, psychomotor speed, 
and executive function).  
 
Aim #1. Conduct assessments every 12 months up to approximately 60-months to identify 
trajectories of longitudinal cognitive function (normal, phase shift, or accelerated aging). H1: 12-
month declines among survivors will persist; late effects will manifest; and there will be sustained 
trajectory differences in the treatment-exposure survivor groups (chemotherapy, hormonal) vs. 
the controls.   
 
In the first set of analyses, we will model longitudinal changes in cognitive function between the 
survivor and control groups using MLM. Each model will include fixed effects of time, group 
(survivor vs. control), a time by group interaction, and subject-level random effects. We will also 
test polynomial effects given the richness of the longitudinal follow-up with five measurement 
points. The latter analyses will allow us to evaluate whether the changes in either group level off 
or accelerate at any point in the follow-up period. These analyses evaluate the hypothesized 
poorer performance among the survivors vs. controls and the differences among the two survivor 
groups based on treatment exposure (chemotherapy +/- hormonal vs. hormonal; we can repeat 
these analyses excluding those receiving chemotherapy alone). We will use propensity methods 
described above to assess confounding by indication and conduct sensitivity analysis to evaluate 
the impact of unmeasured confounders. 
 
Although the above analyses are informative as to the group-level changes over time, they do not 
consider the inter-individual differences in intra-individual change in cognitive function. Therefore, 
to complement the standard MLM analyses, we will use growth mixture modeling (GMM) to 
examine heterogeneity of change over time and identify trajectories of each participant’s cognitive 
function (growth curve) over time. 257-262 The assumption of GMM is that women’s individual 
growth curves can be classified into distinctive patterns such as the three trajectories (“latent 
classes”) described in our conceptual model: normal aging, phase shift, and accelerated decline. 
Figure 2 provides an example of possible GMM results using hypothetical cognitive data. These 
may not be the exact patterns that we find. What makes GMM useful is that it uses statistical fit 
indices to determine the actual number and types of latent classes. Once the latent classes are 
identified, we will evaluate the association between survivor-control and treatment exposure-
control status and the identified trajectories by using chi-square tests. Moreover, we will compare 
the latent classes on key variables (e.g., multi-morbidities, genotype, physical activity level) that 
distinguish the groups using a multinomial logistic regression model with the latent class 
membership as the outcome. These analyses will allow us to identify risk factors for accelerated 
as well as possible non-linear patterns (e.g., initial decline, later improvement). 
 
Power for the MLM is based upon standard conventions.288 With our projected sample, five 
assessments (baseline, every 12 months up to 60 months), and two groups (survivor vs. control), 
we can detect a 5% (Cohen’s d = .05) group difference in slope of the change in cognition scores 
in the attention, psychomotor speed and executive function domain, and 20% differences at the 
level of the intercept for any given covariate (d = .2), with .80 power, alpha of .05.  Further, the 
study is powered to detect small effect size differences at the 60 month point (d = .25), so is very 
well powered to detect even larger cognitive declines in survivors than those expected based on 

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aging in the controls.  In comparing those exposed to chemotherapy vs. hormonal vs. controls 
(three groups), the power is .80 to detect a three-group effect size of f = .15. For the GMM portion 
of the analysis, there is no general consensus on adequate sample size. Adequate extraction of 
latent classes depends upon a number of characteristics such as the magnitude of between-class 
differences, the heterogeneity of change processes, relative group sizes and reliability of 
measurement. 262 Given the heterogeneity in change that we have observed in our earlier work 
and the reliability of our primary domain, we are confident that the sample size will allow for the 
adequate identification of latent classes with GMM. 
 
Aim #2. Identify risk factors for decline in cognitive function in the period up to 60 months post-
enrollment. H2: Some non-modifiable phenotypes (e.g., multi-morbidity) and genotypes (APOE 
and COMT) will decrease cognitive function, while modifiable factors (e.g., physical activity) will 
be protective of declines; and these main effects will be moderated by treatment exposure 
(chemotherapy>hormonal>control).   
 
We will use MLM to identify factors that affect cognition during the 4 years of follow-up by 
comparing factors of interest (e.g., APOE ε4+ vs ε4-) with respect to continuous standardized 
cognitive domain score across time (from baseline up to 60 months). The main predictors are 
multi-morbidity, gene polymorphisms, and physical activity; treatment group (chemotherapy vs. 
hormonal vs. control) is the moderator, where we expect a time by factor interaction, which, if 
statistically significant would suggest that the factor exerts a differential effect on changes in 
cognitive function depending upon treatment group. Based on our conceptual framework, if the 
three-way interaction is significant, we will use separate models for the survivors and controls to 
evaluate individual risk factors in terms of the main effects of non-modifiable (e.g., multi-morbidity 
[or cardiovascular illness or frailty], genotype) and modifiable (e.g., physical activity, cognitive 
stimulation) variables controlling for time and covariates (e.g., age, education, race, and site), and 
consider other factors like anxiety (State-Trait) and fatigue (FACT-fatigue) as confounders if they 
are associated with cognition and the predictor. The IPAQ will be the primary measure of physical 
activity since we will have these data from all assessments. We will examine distributions over 
time of physical activity measures (continuous and categorical on self-report and objective 
measurement) to review variability and sensitivity to change over time. We will also examine 
correlations between self-reported activity on the IPAQ and actigraphy and evaluate if there are 
any differences by groups based on season. We will aim for at least 4 valid days of actigraphy for 
inclusion in analysis. Next, we will look for multi-morbidity interactions with treatment based on 
our baseline results. If significant, these characteristics would identify factors that make persons 
susceptible to longitudinal declines. 
 
For the model that includes survivors only, we will consider the effects of treatment exposure and 
use propensity score methods to correct for chemotherapy selection bias. This will be interesting 
because our data to date indicate that the chemotherapy group, which was the healthiest and 
best-educated group, experienced the steepest declines. If this pattern persists, then propensity 
score adjusted results could show a greater impact of treatment exposure than analyses that do 
not consider this favorable (for cognitive function) effect of treatment selection. We can repeat 
analyses excluding the ER-negative cases that only received chemotherapy to directly compare 
the differences between chemotherapy + hormonal treatment to hormonal treatment alone. In 
secondary analyses, we will use the same methods to evaluate self-reported declines of 7+ points 
on the FACT-cog and conversion to MCI.  We will also assess relationships between objective 
and self-reported cognitive changes. In analysis of genotype effects, we will consider the effects 
of APOE and COMT individually and jointly such that persons may have low genetic burden 
(APOE ε4- and COMT met), moderate burden (APOE ε4+ or COMT val+) or high burden (APOE 
ε4+ and COMT val+). Last, we will repeat analyses for QOL.  

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Given the five assessments (baseline, every 12 months up to 60 months) and expected sample 
sizes for the levels of the modifiable and non-modifiable factors of interest (e.g., multi-morbidity, 
APOE, COMT, physical activity, and cognitive stimulation), we will have 80% power to detect 
small to moderate effect sizes for comparisons with respect to the primary cognitive domain at 60 
months, at a significance level of 0.05. The mean differences will range from 0.25 SDs (e.g., for 
the comparison of high vs. low multi-morbidity levels) to 0.36 SDs (e.g., for the comparison of high 
vs. low physical activity). We will be able to detect smaller effect sizes with 80% power at the 
other time points where the expected sample sizes are larger. Given the large effect seen for the 
APOE ε4 genotype in our preliminary analyses, we will have >95% power (at alpha=.05) to detect 
changes in cognitive function by genotype. For the stratified analyses by treatment group 
(survivors vs. controls), we will have 80% power to detect small to moderate effect sizes of 
modifiable and non-modifiable factors on cognitive function at 60 months, ranging from 0.36 to 
0.53 SDs, at a significance level of .05.  
 
Aim #3. Assess inflammation as a potential mechanism for cognitive decline. H3a: Levels of 
circulating inflammatory markers (CRP, IL6, and sTNFRII) will co-vary with trajectories of 
cognition; and H3b: Inflammation will mediate the protective effect of physical activity and risk of 
multi-morbidity on cognitive decline. 
 
Log transformations are expected to be necessary for analyses of inflammatory biomarker 
concentrations. As in other aims, our primary cognitive outcome is based on neuropsychological 
testing; we will also examine how inflammation relates to secondary outcomes, including self-
reported cognition and conversion to MCI.  We will consider covariates such as sleep, fatigue, 
BMI, etc. in these analyses. Also, since cancer and its treatments affect inflammation, we will 
consider stage, surgery, radiation, and systemic therapy in survivor-only analyses. Similar to Aim 
1, we will use MLMs to evaluate how each inflammation marker co-varies with trajectories of 
cognition. We will include subject-level random effects and run models treating the markers of 
inflammation as time-varying covariates to determine if changes in inflammation co-vary with 
changes in cognitive performance. For the second part of the aim, we will perform longitudinal 
mediation analyses 289 to explore how inflammation mediates over time the relationship between 
changes in levels of physical activity (or multi-morbidity) and trajectories of cognition. In these 
models, we will apply a latent difference score approach to estimate the direct effects of physical 
activity (considering season if needed) on changes in cognition, and indirect effects acting through 
changes in inflammation. These models have the advantage of allowing changes between time 
intervals (e.g., from baseline to 12 months or 36 months to 48 months) to be different and for the 
roles of the mediators to change dynamically over time. Last, we will evaluate independent 
contributions of each marker in multiple mediator models. We will examine correlations between 
inflammatory markers to evaluate whether creating a composite score will be reasonable in 
secondary analyses. 290 
 
For analyses of the extent to which inflammation covaries with cognition, we have 80% power to 
detect correlations of at least +0.16 within a single exposure group (chemotherapy, hormonal, 
control). These values are smaller than the correlation reported by Ganz and colleagues265 (r = -
.34) between changes in proinflammatory cytokines (e.g., sTNF-RII) and changes in memory 
complaints. For the power for mediation analyses, we used methods of Vittinghof et. al.291 
implemented in R by Qiu. 292 In our sample, we have 80% power to detect a reduction of 13% in 
the total effect of changes in physical activity on changes in cognitive performance among all 
participants, and a reduction of 20% for the within exposure group analyses.   
 
Aim #4: To use neuroimaging to assess structural and functional effects of cancer treatment. 

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MRI data analysis will use a combination of data analysis software packages including Statistical 
Parametric Mapping (SPM). Statistical analyses will be performed to examine group differences 
related to case vs. control status. Results for imaging cases will be compared to their own prior 
pre-treatment baseline studies (if available) and matched controls at yoked time points. Correction 
for Multiple Comparisons will use Gaussian random field theory, which takes into account not only 
the multiplicity of simultaneous tests but also the spatial smoothness of the data.219 The parameter 
estimate maps from the first-stage (single-subject) analysis will also be used in an ROI analysis.  
 
 
10.0      DATA  MANAGEMENT  
The research staff will be responsible under the direction of the PIs for data collection, abstraction 
and entry, data reporting, regulatory monitoring, problem resolution and prioritization, and 
coordination of the activities of the protocol study team.  Research staff will receive training in 
data collection and management; all staff will sign confidentiality agreements and will maintain 
human subjects certification.  
 
Patients and controls will be assigned a unique study identification number (ID) that includes a 
code for the study site, physician (for the cancer patients), case/control status, and a randomized 
number.   
 
Data will be managed through Georgetown University and entered by individual recruitment 
sites.  Registration information, as well as consent information, neuropsychological test scores, 
APOE and COMT test results, inflammatory biomarkers, clinical variables, interview responses 
and physician survey data will be captured through a secure, central electronic data capture 
system (EDC) managed and maintained through Georgetown. The data system will have logical 
checks and error codes for out of range values. The program will not allow the operator to exit 
without saving the data.  
 
All recruitment sites will be required to maintain hard copies of all study source documents.  The 
PIs will maintain the hard copy forms with the link between ID number and patient name in a 
separate locked file.   
 
Data and applications will be stored on secure servers managed by the Georgetown University 
Information (UIS) or a UIS-approved vendor. In all cases servers are secured and maintained 
using industry-standard best practices, including twenty-four hour a day security, failover 
protection, power backup, environmental controls, fire suppression, and nightly off-site back-
ups.  User access will be controlled via ID/password authentication, and users may only be 
granted access with the approval of authorized study management personnel with authority to 
grant permissions.  Administrator privileges to the systems are tightly controlled and monitored. 
UIS and its vendors use security systems that are HIPAA-compliant. 
 
If a subject chooses to have their blood drawn at home by a third party trained phlebotomist, 
research staff will schedule the appointment through the secure and HIPAA compliant client 
portal.  
 
No reports will identify patients or physicians by name in reports or publications.  
 

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10.1 Training and Quality Assurance 
The project coordinator will ensure that all staff are trained in study procedures. Staff will undergo 
online completion of a course on human subjects’ research. Training for neurocognitive testing 
will be coordinated by Dr. Root. Training for interviews and chart reviews will be led by 
Georgetown. All staff will use a project field manual with detailed instructions on all study 
procedures to ensure that we have standard procedures. We will have the research staff from 
each site talk on monthly conference calls convened by the project coordinator to discuss issues 
in data collection. 
 
In order to ensure that subject eligibility procedures are being followed, this study has a checklist 
for eligibility. Study personnel use this checklist to ensure all subjects approached for participation 
are eligible. While filling out follow-up eligibility checklists, study staff will ask the participant for 
up to three alternate contacts at each time point. 
 
Project staff will audit these checklists on a regular basis to ensure participants meet eligibility 
criteria. In terms of questionnaire data collected, regular checks are performed of data collected 
to ensure that questionnaires completed by participants contain all study items.  Weekly reports 
will be generated to monitor patient accruals and completeness of registration and interview data.  
Routine data quality reports will be generated to assess missing data and inconsistencies.  
Accrual rates and extent and accuracy of evaluations and follow-up will be monitored periodically 
throughout the study period and potential problems will be brought to the attention of the study 
team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study team, 
at a minimum of two times per year, more frequently if indicated. 
  
The training for patient recruitment, consenting, interviews, records review and cognitive testing 
will include a multi-day session at the start of the project and will include modules on: 1) the study, 
its design, research ethics and procedures for obtaining informed consent; 2) background material 
on breast cancer and medical terms; 3) cultural sensitivity; 4) interacting with older patients and 
controls; 5) data collection procedures and maintenance of study forms and data security; 6) 
interviewing techniques; and 7) cognitive testing procedures. For interview training, we include 
didactic sessions, practice obtaining consent and interviewing volunteers, being videotaped 
conducting an interview, and having that session reviewed by trainers. We will have volunteers 
role-play difficult situations. Staff will also receive training and practice on the REDcap database. 
The coordinator will ensure that data are complete and that staff receive feedback on any 
systematic errors in use of the system. The coordinator will listen in on telephone interviews (or 
in-person) periodically (with knowledge of the patients) to ensure fidelity to the protocol. Training 
for review of the medical records will include education about cancer treatment, practice 
completing the forms using de-identified medical records, re-reviewing each other’s abstractions, 
and review of completeness and accuracy.  
  
To assure that all neuropsychological evaluations are administered and scored in a reliable and 
consistent fashion across sites and examiners, extensive training procedures will be employed 
for study staff under the direction of Dr. Root. Within the training, most of the time will be dedicated 
to cognitive testing procedures. All examiners will be required to review and study training 
materials, including written administration and scoring guidelines and a training video of two 
complete "gold-standard" mock examinations. After studying these materials, examiners will 
practice administering and scoring the neuropsychological battery several times, with questions 
and answers regarding administration and scoring reviewed. Following training, each examiner 

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will submit a videotape of a practice protocol, which will be evaluated for examiner 
behavior/rapport, administration instructions and scoring accuracy. Examiners will receive 
comprehensive written and oral feedback on their practice case. If the examiner is not deemed 
ready to begin testing, additional training and a repeat video evaluation will be conducted and 
rated. Examiners will submit a videotape of test administration every six months for review by Dr. 
Root for the first year. In order to maintain consistency throughout the project, any questions 
regarding administration and scoring procedures will be posted and answered by Dr. Root via 
email. In addition, a sub-sample of subjects' test protocols will be scored a second time by another 
staff member at the same site. Inconsistencies will be discussed and if a consensus cannot be 
reached by the two scorers, the question will be posted for a final determination by Dr. Root. 
 
10% of all test files will be reviewed on a regular basis for scoring, appropriate notations and 
record form completion, and data entry. Testers will receive feedback on any errors with the 
specific action required to correct the error. Each file audited will be checked for scoring errors, 
correct form use (which form used and appropriately labeled with date and ID#), appropriate 
notations (e.g., when queries were made, error correction), and to ensure the record forms were 
appropriately entered.  
 
10.2 Data Sharing 
All data will be available for use by outside investigators after review by the investigators.  All work 
will be HIPAA compliant and no patient identifying information will be shared as per both IRB 
regulations and the Privacy Rule under HIPAA regulations.  No protected health information, 
including personally identifiable information such as name, address, telephone, medical record 
number, or other identifying information will be shared outside of the research team. 
  
We will invite other investigators not associated with the study to also analyze data that we have 
collected, as we see this study as an important resource for examining issues in care of older 
breast cancer patients. Any such requests from non-study investigators will be reviewed by the 
investigators, to ensure that it does not conflict with planned analyses, is otherwise respectful of 
the study participants, and complies with relevant IRB and HIPAA regulations. 
  
We will make study data available to other investigators under data sharing agreements that 
ensure that the data will be used only for research purposes, that any individual participant’s data 
will not be disseminated, that the data will not be used to identify an individual participant, that 
data will be protected under appropriate security measures including encryption and password 
protection, and that the data will be destroyed or returned to us upon completion of relevant 
analyses. If appropriate, we will also determine whether at least one study investigator should be 
involved scientifically in any projects that result from data sharing requests. 
 
 
11.0 
PROTECTION OF HUMAN SUBJECTS 
Prior to enrollment the risks, benefits, and study objectives will be reviewed with each participant. 
There are no specific benefits to participants, and the risks are limited to those of phlebotomy and 
potential mild psychological distress as a result of completing the assessment battery.  
 
Some minor physical pain may result from having the blood sample drawn. The overall physical 
risks associated with drawing blood for laboratory tests, such as momentary local pain and 
bruising are minimal, but will be explained to subjects. Should a participant require medical 
assistance, the oncologist on-call will be notified.  Blood will be drawn by an experienced 
phlebotomist who is familiar with and practices standard precautions when drawing blood. 

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Additionally, it is possible that some patients may find some of the neuropsychological and 
psychological tests difficult to complete, and this may be associated with mild, transient 
psychological distress. Minimal risk of psychological distress may also be posed by study 
questions that ask participants to identify their current problems. However, since study items were 
chosen to reflect what are likely to be existing concerns, the present study is not expected to 
markedly increase participants’ psychological distress above their routine concerns. Patients may 
refuse to answer questions that they find distressing.   
 
Informed consent will be obtained and documented according to institutional policy. No patient 
identifiers will be used in any reports or publications that result from this study. Patients may 
terminate participation in the study at any time, although information that has already been 
acquired will not be removed from the overall analysis. Any hard copy records containing patient 
identifiers will be maintained in a secure location. Electronic records will be maintained on 
Georgetown, MSKCC, Moffitt, COH (discontinued study visits 11/2021), HUMC (discontinued 
study visits 1/2020) and IU servers, with password protected log-on and secure back-ups per 
procedures. Appropriate authority for review of medical records will be obtained by means of the 
Research Authorization. 
  
We will identify breast cancer patients or controls who either: 1) screen positive for clinical 
depression on the CES-D (based on score of 16 or above), 2) have high scores on anxiety scales 
(>2 SD), 3) show moderate or severe cognitive declines at the follow-up, or 4) elicit any concerns 
by the study staff. We will refer these participants to the designated study clinicians at each site 
from our study team - Dr. Tim Ahles (at MSKCC), Dr. Scott Turner (neurologist at LCCC) and Dr. 
Kimberly Davis (psychologist at LCCC) and on-call clinicians at COH (discontinued study visits 
11/2021), Moffitt, HUMC (discontinued study visits 1/2020) and IU. They will evaluate the 
participant and refer for clinical care if needed. We will also forward the relevant study information 
(with explicit written permission) to the participant’s physicians (oncology team if applicable and 
primary care providers). The details of protection against risk are further detailed for each study 
procedure.  
 
1. Overall burden-We have designed the data collection to minimize burden to participants. For 
example, we will attempt to collect blood at times when patients are otherwise scheduled to come 
to the hospital for other reasons, or to ease subject burden, they can choose to have their blood 
drawn at home by a third party trained phlebotomist. The battery can be given over landline, 
smartphone, tablet or computer to accommodate the subjects’ access to modes of administration. 
 
We also provide the option of staggering the telephone interviews and cognitive testing to 
minimize time that participants must spend at any one time. Women will receive  50 cash or gift 
card for their time and travel for each assessment. Overall, we think that the participant burden is 
reasonable.  
 
Women who agree to participate in the co-calibration period and complete both the in-person 
battery and the remote battery will receive an additional  25 as compensation for their time and 
effort on the remote battery. 
 
2. Genetic and inflammatory biomarker testing-The main risk of undergoing venipuncture to obtain 
blood for this study is mild discomfort and the possibility of bruising. They will have the subject 
sitting in a comfortable blood drawing chair, explain the procedure, and be as gentle as possible. 
They will apply gentle pressure to the site after the blood draw to stop bleeding and minimize 
bruising. These are the same procedures used in our sites’ laboratories, so we expect to minimize 

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risk. Standard infection control/sterile procedures will be used in all blood and saliva testing and 
handling procedures for the protection of the subject and the research staff Another potential risk 
associated with having blood or saliva drawn for genetic testing is that it might create anxiety 
about the results. Participants will be told that the test is only used for research at this point in 
time and that we will not provide results.  
 
3. Neuropsychological testing-The main risks associated with completing the test battery are 
fatigue and mild performance anxiety. To avoid fatigue, we have selected tests that take 30-55 
minutes to complete, compared to standard 2-hour batteries; tests were selected for ease in older 
populations. To minimize any anxiety, the research staff will explain the study rationale, describe 
procedures, and put women at their ease. Women will be told that there are no wrong answers, 
only that we want to know how they are doing at the time of testing. We will also assure women 
that their information will not be shared with anyone (except as below for problems) and that their 
names will not be used. All materials will be labeled with study ID numbers.  
 
Staff will undergo rigorous training so that they are familiar with concerns and needs of older 
women. Our consumer advocate will participate in this training. Our staff is experienced, will 
undergo rigorous training and will be working in existing testing centers that have experience in 
conducting these exams and in putting subjects at ease, so that these measures should be very 
effective.  
 
If women show moderate or severe cognitive impairment or decline on follow-up testing, they will 
be referred for evaluation to the site study clinician (e.g., Dr. Ahles at MSKCC, Dr. Turner or Dr. 
Davis at Georgetown) and on-call clinicians at COH (discontinued study visits 11/2021), Moffitt, 
HUMC (discontinued study visits 1/2020) and IU. The study clinician will evaluate the participant 
and make appropriate referrals; women will be asked for permission to share results with their 
primary care provider and (for patients) oncology team if indicated.  
 
4. Interviews-Most women enjoy these interviews, but some women may feel a bit anxious about 
talking about their cancer experience (for cases); friend controls could also be a bit anxious 
because of their friend’s cancer. We will use trained interviewers; the same interviewer will talk to 
women for each of the interviews (baseline, every 12 months up to 60- month). This familiarity 
and continuity should decrease any discomfort. Women will also be told that they do not have to 
answer any questions that they are uncomfortable with and that they can take a break if they need 
to. We will also schedule interviews at times that are convenient for women so that they are 
comfortable and undisturbed and can talk in private. Women will be told that we only use study 
ID numbers on the surveys and that they will not be identified by name. In our past studies in this 
age group, women were able to easily complete similar interviews and found them and the staff 
very pleasant. In the rare instance that the interview uncovers problems (e.g., scores on the CES-
D in the range of clinical depression based on score of 16 or above) women will be referred to our 
study clinicians for evaluation and any needed referrals. During routine weekly meetings, the 
interviewers will also discuss participants that they felt had any other difficulties needing attention 
by the team.  
 
5. Neuroimaging-Some women may feel anxious about the requirements of neuroimaging, which 
includes lying still in the scanner for approximately 60 minutes. To attenuate any fears, subjects 
have the ability to visit the imaging lab prior to their participation to lay in a mock scanner that 
allows them to understand and feel comfortable with the process. Subjects will also be in constant 
visual and verbal contact with research staff and will have access to television and movies in the 
scanner to make them more comfortable.  
 

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Since the MRI technique is non-invasive, there are few potential risks associated with this 
technique. It uses powerful magnetic fields and weak electromagnetic radiation, which have not 
been associated with significant adverse biological effects in patients. The 3.0T MRI system 
meets FDA requirements for field strength, gradient switching and RF power disposition for all 
acquisitions used in the proposed research. Some possible risks include anxiety in the scanner 
and noise during the MRI experiments. Due to the small bore of the scanner, very claustrophobic 
subjects may not tolerate the confinement in the magnet and the head coil. Subjects will be in 
visual and verbal contact with the experimenter throughout the scan and can be removed quickly 
at their request. Some subjects have experienced dizziness or a metallic taste if they move their 
heads rapidly in the magnet. This, however, is only temporary and does not occur if the head is 
still. Acoustical noise is generated by the charging and discharging of the gradient coils, which 
create the magnetic fields used to generate an image. Generally, this is not a significant problem 
in clinical scanners, but we will take the added precautions of providing the subjects with earplugs 
that reduce acoustic noise >30dB. All possible measures will be taken to educate research 
personnel concerning the dangers of metallic projectiles in the magnet room and any individuals 
entering the magnet room will be thoroughly screening for ferromagnetic material.  
 
6. Physician Assessment Form-Most physicians are very busy, so we have designed this one-
time survey to be as short (15-20 minutes) and easy as possible. There are no risks to the 
physicians in completing this, except any minimal inconvenience. We allow them to fax the survey 
back, or to complete the survey over the phone if this is more convenient. We have gotten 
excellent responses in our prior work (>95% completion), so we expect that these procedures are 
adequate. 
 
7. Actigraphy (Motionlogger): Most women are familiar with physical activity and sleep monitors 
with the popularity of Fitbits, etc. We expect women will enjoy this aspect of the study. Study staff 
will help women understand how the device should be worn and how it works and will be available 
to answer any questions they have throughout the week of use. The device is easy to use and is 
minimally burdensome. If women do not feel comfortable with this monitoring, they can opt out of 
wearing the device and are still eligible to participate.  
 
 
             11.1 Privacy 
MSKCC: It is the responsibility of the Research Staff to ensure that protocol subjects receive the 
Center’s Notice of Privacy Practices.  If the subject has not received one, MSKCC personnel will 
provide a Notice of Privacy Practices and obtain acknowledgment before the subject participates 
in the study. 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form.  The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form.  A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
Georgetown University/ LCCC sites: Georgetown University may disclose health information for 
medical research that has been approved by one of the official research review boards, which 
has evaluated the research proposal and established standards to protect the privacy of the 
patient’s health information. Georgetown may disclose the patient’s health information to a 
researcher preparing to conduct a research project. 
 
Moffitt: Moffitt may disclose protected health information collected for research purposes only as 
approved by the University of South Florida Institutional Review Board approved protocol 

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covering the research. Moffitt may disclose the patient's health information to a researcher 
preparing to conduct a research project. 
 
COH (discontinued study visits 11/2021): COH may disclose protected health information 
collected for research purposes only as approved by the City of Hope Comprehensive Cancer 
Center Institutional Review Board approved protocol covering the research.  
 
HUMC (discontinued study visits 1/2020): HUMC may disclose protected health information 
collected for research purposes only as approved by the HUMC Institutional Review Board 
approved protocol covering the research. 
 
IU: IU may disclose protected health information collected for research purposes only as 
approved by the IU Institutional Review Board approved protocol covering the research.  
  
      11.2 Serious Adverse Event (SAE) Reporting 
We do not expect any SAEs since this is not an intervention or treatment study. If women show 
moderate or severe cognitive impairment or decline on follow-up testing (based on testing) or 
depression (based on CES-D scores of 16 or above), they will be referred for evaluation to the 
site study clinician (e.g., Dr. Ahles at MSKCC, Dr. Turner or Dr. Davis at Georgetown) and on-call 
clinicians at COH (discontinued study visits 11/2021), Moffitt, HUMC (discontinued study visits 
1/2020) and IU). The study clinician will evaluate the participant and make appropriate referrals; 
women will be asked for permission to share results with their primary care provider and (for 
patients) oncology team if indicated. We expect that our patients could be hospitalized related to 
their cancer. However, due to the nature of our questionnaire/interview study, we do not expect 
that these events will be related to our procedures, so will not consider these SAEs.  
If there are any events that might be considered SAEs, they will be reported to the IRB as soon 
as possible but no later than 5 calendar days. The AE report will be delivered to the Institutional 
SAE Manager (307 East 63rd Street, 1st Floor at MSKCC, SW104 Med-Dent Building, 3900 
Reservoir Road, NW, Washington, DC 20057 at Georgetown, 3702 Spectrum Blvd., Suite 155 
UTA, Research Park at Moffitt, 1500 East Duarte Road, Modular 141 at COH, the eIRB of 
HUMC and the IRB of IU) containing the following information: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of   
 
MSKCC, LCCC/Georgetown, Moffitt, COH, HUMC and IU) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the study procedures 
• 
If the AE was expected 
• 
The severity of the AE 
• 
Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form, the      
PI’s signature and the date it was signed are required on the completed report.  

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12.0 
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13.0 APPENDICES 
 
 
Please see attached documents.