Clinical trial NCT03451383: Older Breast Cancer Patients: Risk for Cognitive Decline
Official title: Older Breast Cancer Patients: Risk for Cognitive Decline. The Thinking and Living With Cancer (TLC) Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cancer, Breast
Age-related Cognitive Decline
Cognitive Decline
Keywords: breast cancer
cognitive decline
Lead sponsor: Georgetown University
Sponsor class: OTHER
Collaborators: name: Memorial Sloan Kettering Cancer Center
name: Indiana University
name: H. Lee Moffitt Cancer Center and Research Institute
name: City of Hope Medical Center
name: Hackensack Meridian Health
First posted: 2018-03-01
Enrollment: 1700
Sex: FEMALE
Minimum age (years): 60
Maximum age (years): 105
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Women age 60+ with a newly diagnosed breast adenocarcinoma staged 0-3 and matched controls.

Brief summary: The goal of this study is to evaluate the impact of systemic therapy on cognition in older breast cancer patients, explore change in APE, LM and Cognition domains, measure associations between cognitive decline and QOL, and describe how genetic polymorphisms, inflammatory biomarkers, sleep and physical measures moderate cognitive outcomes. This study is being done nationally, with recruiting sites at Georgetown University, Montgomery General Hospital, Virginia Cancer Specialists, Washington Hospital Center, Reston Breast Care Specialists, Memorial Sloan-Kettering, Moffitt Cancer Center, City of Hope National Medical Center, Hackensack University Medical Center, Indiana University and University of California, Los Angeles.

Detailed description: Cancer is the leading cause of death in the US and breast cancer is the second most common cancer among women in our country. Older women (women 60 and older) presently account for nearly half of all new cases of breast cancer. With the "graying of America" and advances in treatment for breast cancer, the absolute number of older women undergoing breast cancer treatment and surviving their disease will almost double by the year 2030. Systemic hormonal and non-hormonal chemotherapy is credited with improvements in survival, and rates of use of these modalities have increased substantially over the past two decades. Preliminary work has found that older women are interested in chemotherapy even for small returns in survival extension. However, cognitive impairment has been demonstrated in most studies of breast cancer systemic treatments, but virtually all of this research has been conducted in younger populations. Since aging itself is associated with cognitive declines, it seems very likely that older women are particularly vulnerable to the adverse cognitive effects of systemic therapy; our preliminary work strongly suggests that this is the case, but this has never been empirically tested.

This study will be the first large-scale, prospective, controlled investigation to evaluate cognitive changes in older cancer patients and it will provide the basis for the next generation of mechanistic, treatment and intervention studies. These will be important since data from younger patients cannot be directly translated into the older population. Investigators 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 a 60 month period, explore change in APE, LM and Cognition domains, test associations between cognition and quality of life (QOL), and evaluate whether genetic polymorphisms, inflammatory biomarkers, sleep and physical measures moderate cognitive outcomes.

To achieve these objectives, investigators 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 National Medical Center (COH), Hackensack University Medical Center (HUMC), Indiana University (IU), Boston University (BU), University of California (UCLA), University of South Florida (USF) and their satellites, will work together to prospectively enroll 850 newly diagnosed older breast cancer cases from LCCC, MSKCC, Moffitt, COH, HUMC, IU and tertiary referral centers with high volumes. An equal number of non-cancer friend controls will be recruited. Friend controls were chosen since they will be similar to patients in most ways except for exposure to cancer and its treatments and they should be motivated to participate. If friends are not available, controls matched to cases on age, education, race, and area (DC/NY/FL/CA/NJ/IU) will be recruited from the community.

Investigators will administer baseline neuropsychological testing prior to any systemic treatment (or at enrollment for controls), survey women about subjective cognitive function, sleep, psychosocial factors, QOL and activities of daily living (IADLS). Subjects will take part in physical measurements, including grip strength, sit to stand and walk speed tests. Investigators will abstract clinical data from medical records. Investigators will obtain blood or saliva to test for APOE, COMT and other genetic polymorphisms at enrollment; these results will not be provided to participants since this is considered a research test). Subjects have the option to provide blood for biomarker research and for biobanking. Subjects will also provide one week of sleep monitoring. Subjects at IU will have the option to participate in neuroimaging. Investigators conduct follow-up interviews and repeat the neuropsychological testing, physical measures, blood/saliva collection, sleep monitoring and optional neuroimaging 12 months after baseline assessment; this time point corresponds to 3-6 months post-treatment among women who receive chemotherapy. Our primary cognitive outcome will be change in summary score on tests in the Attention, Processing Speed, and Executive Function domain, Learning and Memory domain, and Subjective Cognition domain. In secondary analyses, investigators examine changes in scores on additional domains to assess broader cognitive function and examine questions of differential impact.

Data from this study will guide future interventions to better select older women for whom the benefits of systemic therapy outweigh the harms and to develop approaches to mitigate negative consequences of systemic treatment when it is indicated, improving the quality of care for the growing population of older breast cancer patients.

Eligibility criteria: 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 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.

Exclusion:

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).
* 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

Primary outcomes:
measure: Change in Attention, Processing Speed, Executive Function (APE) Domain
timeFrame: Baseline and annually up to 5 years
measure: Change in Learning and Memory (LM) Domain
timeFrame: Baseline and annually up to 5 years
measure: Change in Cognition Domain
timeFrame: Baseline and annually up to 5 years
Secondary outcomes:
measure: Change in Quality of Life
timeFrame: Baseline and annually up to 5 years
measure: Change in Quality of Life
timeFrame: Baseline and annually up to 5 years
measure: Change in Quality of Life
timeFrame: Baseline and annually up to 5 years
measure: Change in cancer-related symptoms (including fatigue, sleep, pain, anxiety and depression)
timeFrame: Baseline and annually up to 5 years
measure: Biomarkers of aging (genotype, inflammatory biomarkers, telomere length, p16, miRNA)
timeFrame: Baseline and annually up to 5 years
measure: Grip Strength Test
timeFrame: Baseline and annually up to 5 years
measure: Actigraphy/Change in Sleep
timeFrame: Baseline and annually up to 5 years
Other outcomes:
Locations:
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
Study officials:
affiliation: Lombardi Comprehensive Cancer Center
name: Jeanne Mandelblatt
role: PRINCIPAL_INVESTIGATOR
References:
citation: McDonald BC, Van Dyk K, Deardorff RL, Bailey JN, Zhai W, Carroll JE, Root JC, Ahles TA, Mandelblatt JS, Saykin AJ. Multimodal MRI examination of structural and functional brain changes in older women with breast cancer in the first year of antiestrogen hormonal therapy. Breast Cancer Res Treat. 2022 Jul;194(1):113-126. doi: 10.1007/s10549-022-06597-1. Epub 2022 Apr 27.
citation: Bethea TN, Zhai W, Zhou X, Ahles TA, Ahn J, Cohen HJ, Dilawari AA, Graham DMA, Jim HSL, McDonald BC, Nakamura ZM, Patel SK, Rentscher KE, Root J, Saykin AJ, Small BJ, Van Dyk KM, Mandelblatt JS, Carroll JE. Associations between longitudinal changes in sleep disturbance and depressive and anxiety symptoms during the COVID-19 virus pandemic among older women with and without breast cancer in the thinking and living with breast cancer study. Cancer Med. 2022 Sep;11(17):3352-3363. doi: 10.1002/cam4.4682. Epub 2022 Mar 22.
citation: Dilawari A, Rentscher KE, Zhai W, Zhou X, Ahles TA, Ahn J, Bethea TN, Carroll JE, Cohen HJ, Graham DA, Jim HSL, McDonald B, Nakamura ZM, Patel SK, Root JC, Small BJ, Saykin AJ, Tometich D, Van Dyk K, Mandelblatt JS; Thinking and Living with Cancer Study. Medical care disruptions during the first six months of the COVID-19 pandemic: the experience of older breast cancer survivors. Breast Cancer Res Treat. 2021 Nov;190(2):287-293. doi: 10.1007/s10549-021-06362-w. Epub 2021 Sep 13.
citation: Carroll JE, Small BJ, Tometich DB, Zhai W, Zhou X, Luta G, Ahles TA, Saykin AJ, Nudelman KNH, Clapp JD, Jim HS, Jacobsen PB, Hurria A, Graham D, McDonald BC, Denduluri N, Extermann M, Isaacs C, Dilawari AA, Root J, Stern RA, Mandelblatt JS; Thinking and Living With Cancer Study. Sleep disturbance and neurocognitive outcomes in older patients with breast cancer: Interaction with genotype. Cancer. 2019 Dec 15;125(24):4516-4524. doi: 10.1002/cncr.32489. Epub 2019 Sep 25.
citation: Tometich DB, Small BJ, Carroll JE, Zhai W, Luta G, Zhou X, Kobayashi LC, Ahles T, Saykin AJ, Clapp JD, Jim HSL, Jacobsen PB, Hurria A, Graham D, McDonald BC, Denduluri N, Extermann M, Isaacs C, Dilawari A, Root J, Rini C, Mandelblatt JS; Thinking and Living with Cancer (TLC) Study. Pretreatment Psychoneurological Symptoms and Their Association With Longitudinal Cognitive Function and Quality of Life in Older Breast Cancer Survivors. J Pain Symptom Manage. 2019 Mar;57(3):596-606. doi: 10.1016/j.jpainsymman.2018.11.015. Epub 2018 Nov 23.