Understanding and Addressing Disparities in Cancer Therapy Induced Inflammation and Associated Endothelial Dysfunction

Study Overview
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Brief Summary
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Very little is understood about the off-target vascular mechanisms of anti-cancer drug toxicity and the impact of exercise on these changes. Much of what has been learned about molecular pathways regulating vascular endothelial function has been established by logical expansion of knowledge obtained through experimental studies (e.g., discovery of endothelium-derived relaxing factor/nitric oxide). Within the last 10 years technological advancements of -omics approaches, such as RNA-sequencing and shotgun proteomics, have dramatically reduced the cost and technical challenge of accessing these tools for discovery-based research. Investigators are now able to obtain unbiased datasets showing changes in transcript or protein expression within complex samples. With cost and accessibility of sequencing is no longer being substantial bottleneck, one of major challenges researchers now face is determining how to meaningfully interpret profiles from large datasets. The extensive characterization of molecular pathways impacting inflammatory responses, endothelial function and angiogenesis, the pathway and network analysis tools will be an asset for identification molecular pathways relevant to alterations in microvascular endothelial function. The investigators preliminary studies on only a small number of samples highlights this potential of the proposed approach to lead to identify personalized medicine-based profiles that will predict patients are likely to develop microvascular endothelial dysfunction from CTx.

Official Title
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DECODE Heartland: Understanding and Addressing Disparities in Cancer Therapy Induced Inflammation and Associated Endothelial Dysfunction

Conditions
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Breast Cancer

Intervention / Treatment
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* Behavioral: Taking Charge during Treatment (TCT) Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥ 18 years) assigned female sex at birth Diagnosed with invasive non-metastatic breast cancer Receiving neo-adjuvant CTx (or adjuvant CTx and undergoing breast conserving surgery) that includes anthracyclines (such as DOX) and/or targeted anti-Her2 therapy Able to safely participate in moderate exercise and strength training based on MD approval Willing to complete all study activities Self-identifies as Black/African American or non-Hispanic White Exclusion Criteria: Unintentional weight loss > 10% in the past 6 months Current pregnant and lactating patients. Must have completed lactation prior to study start Metastatic disease Diagnosed cardiovascular disease as evidenced by cardiomyopathy (reduced regional or global LV contractility), diastolic dysfunction grade 2 or above, symptomatic coronary - artery disease, ejection fraction below 50% History of prior chemotherapy or targeted H2N Treatment Non-English speaking

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Taking Charge during Treatment (TCT) Intervention<br>Taking Charge during Treatment (TCT) Intervention. TCT is a 16-20week intervention that promotes adoption of the ACSM exercise guidelines for cancer survivors during treatment, including regular moderate to vigorous physical activity (150 minutes per week of moderate activity or 75 minutes per week of vigorous activity) and a minimum of twice weekly resistance training (RT) minutes during CTx and after. Participants will receive Take Charge program binder, 2-4 x weekly text messaging, activity tracker and resistance bands. | Behavioral: Taking Charge during Treatment (TCT) Intervention<br>* CT is a 16-20week intervention that promotes adoption of the ACSM exercise guidelines for cancer survivors during treatment, including regular moderate to vigorous physical activity (150 minutes per week of moderate activity or 75 minutes per week of vigorous activity) and a minimum of twice weekly resistance training (RT) minutes during CTx and after. Program components include (1) a binder of information, (2) weekly coaching, (3) 2-4x weekly text messaging and (4) exercise supplies. The TCT program is grounded in Social Cognitive Theory.<br>|
| No Intervention: Control Group<br>To ensure scientific rigor allowing us to test causal pathways associated with exercise, women will be randomized to the TCT intervention or control group arm. The control group will not receive the TCT intervention The investigators experience teaches us that to increase the likelihood of retaining control group participants, the investigators must offer some resources. Thus, the investigators will provide the control group with a one-page summary of the American College of Sports Medicine exercise recommendations, and the Take Charge program binder at the completion of the study. Participants will also receive resistance bands and activity tracker at the end of the study. 95 The investigators will also send weekly text messages with supportive content not related to exercise or lifestyle (i.e., a riddle, take a moment to smile today, a picture of a baby animal). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Exercise: Maximal oxygen consumption will be evaluated using cycle ergometry or treadmill to exhaustion as described in the Integrative Physiology Laboratory at each testing visit. | Investigators will use a graded protocol, starting at 50 watts followed by 30 watt increments every 2 minutes. Subjects will be connected to a breath-by-breath metabolic system (Cosmed, Italy) for measurement of VO2peak. A maximal effort will be defined as fulfillment of three of the following criteria: 1) A plateau in VO2 with an increase in work rate defined as an increase in VO2 of less than 50 ml/min; 2) A maximal HR within 10 beats of predicted maximal heart rate; 3) A respiratory exchange ratio of greater than 1.15; 4) No increase in heart rate with an increase in work rate (less than 3 beats); or 5) A rating of perceived exertion of 18 or greater on the Borg scale. These criteria are according to and consistent with the AHA exercise testing guidelines and performed regularly in Dr. Phillips' and Dr. Durand's laboratory groups59, 62-66. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Assessment of Cancer Therapy - General (FACT-B) | This survey measures physical, social, emotional, and functional wellbeing and wellness and symptoms associated with breast cancer and its treatments. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| The Distress Thermometer | This is a simple tool to effectively screen for symptoms of distress. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Perceived Stress Scale | This survey is a class stress assessment to help understand how different situations affect feelings and perceived stress, asking about thoughts and feelings. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Hospital Anxiety and Depression Scale | This will measure anxiety and depression in a general medical population of patients. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| The Functional Assessment of Chronic Illness Therapy - Fatigue | Participants will self-report fatigue and its impact upon daily activities and function. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| PROMIS - Social Support | This survey will assess how much social support each individual has in their personal network. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| PROMIS - Pain Interference | This instrument will measure the self-reported consequences of pain on relevant aspects of a person's life. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Assess mitochondrial DNA damage | Mitochondrial DNA damage will be assessed in isolated vessels from biopsies and total peripheral blood mononuclear blood cells (PBMCs) via a well-established PCR protocol. Similarly, a PCR based method is used to quantify levels of cell free mtDNA in plasma samples from study participants. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Cytokine analysis | Investigators will utilize Isoplex platform via CodePlex Human Cytokine Storm Panel-8 to quantify a large array of inflammatory cytokines using minimal amounts (<30 ul) of plasma sample. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Gene Express Profiling | Transcriptomic expression profiling of PBMC and endothelial cells will be performed utilizing existing infrastructure (Genomic Sciences and Precision Medicine Center at MCW). RNA sequencing will be performed Illumina on NovaSeq sequencer. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Endothelial function | Microvascular function from gluteal and surgical fat biopsies will be used to test the direct effect of clinically used chemotherapy on peripheral microvascular function (as surrogate for coronary microvessels). Investigators propose to perform studies before, after the chemotherapy regimen, and at 12 months follow up. Study team evaluate microvascular dilator capacity, both endothelial and smooth muscle mediated, and quantify levels of vasodilators (NO and H2O2) via fluorescent probes. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Flow Mediated Dilation | Flow mediated dilation of the brachial artery (large conduit vessels) will be assessed using ultrasound in a noninvasive manner. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Cardiac function - Echocardiagram | Echocardiograms: Aortic diameter, cardiac output, stroke volume, heart rate, end diastolic, and end systolic volume will be assessed at rest using two-dimensional echocardiography. With subjects in the left lateral position, measurements will be obtained using the two (Parasternal and Short Axis) and four-chamber view. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Cardiac function - Pulse Wave Velocity | Pulse Wave Velocity: A non-invasive technique will be used to measure arterial stiffness (pulse wave velocity and central pressures). Briefly, investigators will record waveforms at the carotid and femoral arteries using tonometry and a partially inflated pressure cuff placed over the upper arm and thigh. The distance between sites will be determined using a tape measure. | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) | 
| Cognitive Function | PROMIS - Cognitive Function Short Form: This is a short six-item sub-set scale of the full PROMIS Cognitive Function item bank that assesses patient-perceived cognitive deficits | T1 (baseline), T2 (18-24 weeks), and T3 (12 months) |