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High intensity interval training for breast cancer patients receiving anthracycline-based chemotherapy

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High intensity interval training for breast cancer patients receiving anthracycline-based chemotherapy

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Content i
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

HIGH INTENSITY INTERVAL TRAINING FOR BREAST CANCER PATIENTS
RECEIVING ANTHRACYCLINE-BASED CHEMOTHERAPY

by

Kyuwan Lee

A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOKINESIOLOGY)

May 2019

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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

ACKNOWLEDGEMENTS

The time I spent in the doctoral program was the most challenging but also exciting
period in my life. I truly believe that the only reason I was able to accomplish my
doctoral degree on time is I met wonderful people and received great help and
support from them. I am very happy to express my appreciation for all of you.

First of all, I would give special thanks to my advisor Dr. Christina Dieli-Conwright
for her encouragement and constructive advice. I can never express enough how
much I appreciate her mentorship but one thing I can say for sure is that she was
always there for me to grow up with endless patience and supports. Her
enthusiasm in science always influences my motivation. I know I would not be able
to move to the next step of my career without her.

I also want to thank my dissertation committee Drs. Fred Sattler, George Salem,
Joanne Mortimer, and Wendy Mack for insightful comments. It was a great honor
to be mentored by professors who truly understand how to successfully conduct
scientific research and know how to train their trainee to be successful. I also
appreciate the Chair of the Biokinesiology and Physical Therapy Dr. Gordon for his
valuable suggestion, support and guidance throughout my doctoral program. I was
very honored to be taught by his knowledgeable and influential thoughts.

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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

I cannot express enough my gratitude to all my friends. I am grateful my
everlasting friendship with Sunkoo Rhee in Korea. I was so lucky to have him as
my friend in my life. I thank Ivan for everything he has done for me during my
doctoral training. I would not forget his consideration, patience, and sense of
humor. I also thank my colleagues Kaylie Zapanta, Theresa Serrano, Jessica
Goytizolo, Karina Ortiz, Ellice Wang, Jessica Van Fleet, Caia Rice, Citlalin Lopez-
Torres, Karla Santoyo for their helpful instructions and sincere supports. I hope we
can collaborate research projects in future.

I highly appreciate study participants who spent time and efforts for my research
project. I would also like to acknowledge funding from the National Center for
Advancing Translational Science (NCATS) of the U.S. National Institutes of Health
(UL1TR001855) and the Eunice Kennedy Shriver National Institute of Child Health
and Human Development of the National Institutes of Health under Award Number
(P2CHD086851) which enabled us to conduct this study.

Last but not least, I would like to express my deepest gratitude to my family. I thank
my wonderful family for their endless love and support. I would like to tell them that
I love you all and thank you for putting your trust in me as I progress through my
education. The best thing in my life is having them as my family. I will do my best to
make you all happy every single day.

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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

TABLE OF CONTENTS

ACKNOWLEDGEMENTS ......................................................................................... ii
LIST OF TABLES .................................................................................................... vi
LIST OF FIGURES .................................................................................................. vi
ABSTRACT ............................................................................................................. 1
CHAPTER I: OVERVIEW ........................................................................................ 5
CHAPTER II: BACKGROUND & SIGNIFICANCE ................................................. 10
CHAPTER III: FEASIBILITY OF HIGH INTENSITY INTERVAL TRAINING .......... 25
ABSTRACT ........................................................................................................ 25
INTRODUCTION ............................................................................................... 26
MATERIALS AND METHODS ........................................................................... 29
Participants/Consent ...................................................................................... 29
Experimental Design ...................................................................................... 30
Interventions ................................................................................................... 31
Outcome Measures ........................................................................................ 33
Statistical analyses ......................................................................................... 36
RESULTS .......................................................................................................... 37
DISCUSSION .................................................................................................... 42
CHAPTER IV: EFFECTS ON VASCULAR FUNCTION ........................................ 46
ABSTRACT ........................................................................................................ 46
INTRODUCTION ............................................................................................... 48
MATERIALS AND METHODS ........................................................................... 50
Participants/Consent ...................................................................................... 50
Experimental Design ...................................................................................... 51
Interventions ................................................................................................... 52
Outcome Measures ........................................................................................ 53
Statistical analyses ......................................................................................... 55
RESULTS .......................................................................................................... 56
DISCUSSION .................................................................................................... 58
CHAPTER V: EFFECTS ON EXTRACELLULAR MATRIX ................................... 64
ABSTRACT ........................................................................................................ 64
INTRODUCTION ............................................................................................... 65
MATERIALS AND METHODS ........................................................................... 67
Participants/Consent ...................................................................................... 67
Experimental Design ...................................................................................... 69
Interventions ................................................................................................... 69
Outcome Measures ........................................................................................ 70
Statistical analyses ......................................................................................... 71
RESULTS .......................................................................................................... 72
DISCUSSION .................................................................................................... 74
CHAPTER VI: SUMMARY AND CONCLUSIONS ................................................. 78
REFERENCES ...................................................................................................... 83
APPENDIX ............................................................................................................ 95
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

A.1 International Physical Activity Questionnaire…………………………………..95
A.2 3 day Diet Recall Form…………………………………………………………..101
A.3 High Intensity Interval Training for Breast Cancer Patients during Anthracycline
Use ……………………………………………………………………………………105
A.4 Rating of Perceived Exertion: Borg RPE Scale……………………………...111
A 5 Cycle Ergometer Test ………………………………………………………….112
A.6 Weekly high intensity interval training log…………………………………….113

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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

LIST OF TABLES

Table 1. Maximal cycling protocol based on cadence and torque………………….36

Table 2. Baseline Participant Characteristics………………………………….……38

Table 3. Feasibility of implementing high intensity interval training in breast cancer
patients undergoing anthracycline-based chemotherapy………..……………..…..42
Table 4. Mean differences on baFMD and cIMT between HIIT and DEL groups
across the 8 week intervention…………………………………………………….....…58
Table 5. Comparison of MMP-2 and -9 between HIIT and DEL groups……………73

LIST OF FIGURES

Figure 1. Theoretical Framework: Impact of HIIT on vascular endothelial function in
breast cancer patients during anthracycline-based chemotherapy…………………13

Figure 2. Degradation of the Extracellular Matrix Caused by Matrix
Metalloproteinases Activation…………………………………………………………..14

Figure 3. Study Timeline……………………..………………………………………....30
Figure 4. Sample HIIT workout…………………………………...…………………….32

Figure 5. CONSORT diagram of HIIT intervention………..………………………….39

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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

ABSTRACT

Breast cancer patients were at greater risk for cardiovascular disease (CVD)
mortality, compared to age-matched women without breast cancer. CVD mortality
was two times higher among breast cancer patients who receive chemotherapy.
Specifically, anthracycline-based chemotherapy was of particular concern due to
the impairment of vascular endothelial function and vascular wall thickness, as well
as dysregulation of extracellular matrix (ECM) in vasculature induced by increased
oxidative stress caused by anthracycline-based chemotherapy. One strategy to
offset these impairments was a form of exercise referred to as high-intensity
interval training (HIIT) which improved vascular endothelial function by decreasing
the level of oxidative stress, the main cause of the anthracycline-induced vascular
complication. The purpose of this study was to assess the feasibility of
implementing and conducting an 8-week HIIT in breast cancer patients undergoing
anthracycline-based chemotherapy. Further, we determined the effects of an 8-
week HIIT on vascular endothelial function, vascular wall thickness and the ECM-
regulating enzymes in breast cancer patients undergoing anthracycline-based
chemotherapy. We designed a pilot study to include 30 breast cancer patients
undergoing anthracycline-based chemotherapy. Following informed consent and
baseline measures, participants were randomized to either the HIIT group or the
delayed (DEL) group.
Chapter 3 was design to determine the feasibility of HIIT in breast cancer
patients undergoing anthracycline-based chemotherapy. Thirty women initiating
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

anthracycline-based chemotherapy were randomized to either the HIIT or delayed
(DEL) groups. The HIIT group participated in an 8-week HIIT intervention occurring
3 times weekly. Adherence measures used to define feasibility were calculated for
each participant by computing (1) the average weekly minutes of HIIT over 8
weeks and (2) the number of sessions attended and multiplied by 100 (percentage
of sessions). The HIIT intervention was considered feasible if more than 50% of
participants completed both an average of 70% of weekly minutes (63/90 minutes)
and attended 70% exercise sessions (17/24 sessions). Feasibility was
demonstrated by: 12 of 15 participants met both feasibility criteria average weekly
minutes of exercise completed was 78±5.1 out of 90 min and 19.2±2.1 out of 24
sessions (82.3%).
Chapter 4 was conducted to demonstrate the effects of HIIT on vascular
endothelial function and vascular wall thickness in breast cancer patients
undergoing anthracycline-based chemotherapy. The HIIT group participated in an
8-week HIIT intervention occurring 3 times per week on a cycle ergometer. The
DEL group was offered the HIIT intervention after 8 weeks. Outcomes were
measured at week 0 and week 9. baFMD was measured from the brachial artery
diameter at baseline (D0) and 1min after cuff deflation (D1); percent change was
calculated by measuring brachial artery diameter 1min after cuff deflation relative
to the baseline [baFMD=(D1−D0)/D0×100]. The cIMT was obtained from the
posterior wall of common carotid artery 10mm below the carotid bulb. The region of
interest was identified at the intima and media on the far wall of the vessel.
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Vascular endothelial function was assessed using brachial artery flow-mediated
dilation (baFMD) and vascular wall thickness was measured using carotid intima
media thickness (cIMT). Post-exercise, baFMD significantly increased [4.3; 95%
confidence interval (CI): (1.5, 7.0), P=0.005] in HIIT versus delayed (DEL) group.
cIMT did not significantly change [0.003, 95% CI: (-0.004, 0.009), P=0.40] in the
HIIT group, while IMT significantly increased from baseline to post-intervention
(0.009, 95% CI: 0.004, 0.010, P=0.003) in DEL group.
Chapter 5 was focused on the effects of HIIT on ECM-regulating enzymes in
breast cancer patients undergoing anthracycline-based chemotherapy. The HIIT
group participated in an 8-week HIIT intervention occurring 3 times per week on a
cycle ergometer. The DEL group was offered the HIIT intervention after 8 weeks.
Outcomes were measured at week 0 and week 9. MMP-2 and -9 were tested as a
single batch at study completion and processed using the magplex suspension
bead array immuno-assays on a Luminex 100 Bioanalyzer (Luminex 100, Luminex
Corporation, Austin, Texas) according to the kit manufacturer’s instructions
(Milliplex ELISA kits, Millipore, MA). ECM regulating enzymes were measured
analyzing the level of matrix metalloproteinases (MMPs) in serum sample. There
was a significant within-group decrease in MMP-9 in the HIIT group (-37.4%;
P=0.01) while MMP-9 in the DEL group was not significantly changed (-21.7%;
P=0.10) following 8 weeks.
Overall, this dissertation demonstrated that HIIT is a feasible exercise
strategy for breast cancer patients undergoing anthracycline-based chemotherapy.
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

HIIT significantly improved baFMD along with maintenance of cIMT, and reduced
MMP-9 while MMP-9 was not altered in the DEL group. Unexpectedly MMP-2 was
significantly increased in both HIIT and DEL groups. This study may impact cancer
survivorship and future cardiovascular health by demonstrating that HIIT is a
lifestyle strategy that may improve vascular endothelial function in breast cancer
patients during chemotherapy, thereby reducing the risk of future CVD.

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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

CHAPTER I: OVERVIEW
The mortality rate of breast cancer has significantly decreased over the 30 years
from 33.2% to 20.3%, due to ongoing advances in cancer detection and treatment
(Siegel et al., 2018). However, breast cancer patients are at approximately 2 times
greater risk for cardiovascular disease (CVD) mortality, compared to age-matched
women without breast cancer (Bradshaw et al., 2016). Increased CVD mortality
was recently observed among breast cancer patients who received chemotherapy,
specifically anthracyclines compared with those who did not receive chemotherapy
(Bradshaw et al., 2016). Anthracyclines are the class of chemotherapy drugs used
to target rapidly dividing cancer cells by inhibiting replication and damaging cells in
ways that promote cell death (Tanaka et al., 2012). This is primarily achieved by
DNA intercalation, in which the chemotherapy substance inserts itself into the DNA
structure of a cell, binds to the DNA, and inhibits replication of cancer cell (Luna-
Moran et al., 2009). Although anthracyclines are an effective chemotherapeutic
agent for breast cancer patients, anthracyclines significantly increase oxidative
stress in vasculature via DNA intercalation which then induces vascular endothelial
dysfunction. Cardiomyopathy has been identified in breast cancer patients who
received anthracycline based chemotherapy up to 4 to 20 years after the
completion of chemotherapy (Steinherz et al., 1991; Thomas et al., 2016). This is
critical to note because vascular endothelial dysfunction is significantly associated
with coronary endothelial dysfunction and predicts cardiomyopathy (Schaefer et al.,
2012).
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Anthracyclines exert a negative effect on vascular endothelial function by
two mechanisms: 1) reactive oxygen species/nitric oxide and 2) dysregulation of
extracellular matrix (ECM). First, anthracyclines generate reactive oxygen species
during intercalation which disrupts the regulation of nitric oxide. Nitric oxide is a
major vasodilator molecule yet the bioavailability of nitric oxide is reduced due to
anthracycline-generated reactive oxygen species that scavenge nitric oxide. This
mechanism of action of vascular endothelial dysfunction is evidenced by reduced
brachial artery flow-mediated dilation (baFMD) and thickening of carotid intima
media (cIMT), which can be assessed via ultrasound imaging (Volkova and
Russell, 2011). Second, an additional negative influence of anthracyclines is
dysregulation of the ECM in vasculature which largely contributes to vascular
endothelial dysfunction. In particular, anthracyclines cause dysregulation of ECM-
regulating enzymes, known as matrix metalloproteinases (i.e. MMPs -2 and -9) in
the (ECM) of vascular endothelial cells (Gliozzi et al., 2016). This damage
contributes to vascular endothelial dysfunction by decreasing the availability of
nitric oxide thereby inducing abnormal vasodilation which precedes the
development of atherosclerosis (Langbein et al., 2016). These two mechanisms
are the major negative contributors to anthracycline-induced vascular endothelial
dysfunction. Thus, there is a critical need for effective interventions to offset
anthracycline-induced vascular endothelial dysfunction in breast cancer patients
during anthracycline-based chemotherapy.
7
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

One such strategy to improve vascular endothelial dysfunction is exercise
such as a novel form of aerobic exercise referred to as high-intensity interval
training (HIIT). HIIT includes intervals of low to vigorous forms of exercise, which
are beneficial in decreasing risk of CVD from heart failure (Adams et al., 2015),
and stroke (Camiletti-Moiron et al., 2015; Gurovich et al., 2011). HIIT increases
vascular endothelial dysfunction measured by baFMD in patients with CVD to a
greater degree when compared to continuous moderate intensity aerobic exercise
(Scharf et al., 2015). HIIT-induced improvements in vascular endothelial
dysfunction are mainly due to elevated shear stress which decreases oxidative
stress and upregulates vascular endothelial nitric oxide synthases (Gurovich et al.,
2011; Scharf et al., 2015). The upregulated nitric oxide synthases increase the
bioavailability of the vaso-protective molecule ‘nitric oxide’ which dilates blood
vessels and prevents vascular wall thickening (Forstermann and Munzel, 2006).
Collectively, this mechanism may offset anthracycline-induced vascular endothelial
dysfunction in breast cancer patients. HIIT-induced vascular endothelial
dysfunction can successfully be measured by high resolution ultrasound (i.e.
baFMD and cIMT) and ECM dysregulation can be measured by the activity of
ECM-regulating enzymes (i.e. MMPs -2 and -9) captured in the serum sample.
While the benefits of HIIT have been investigated in other clinical
populations, there are several concerns regarding the feasibility of implementing
aerobic exercise in breast cancer patients undergoing chemotherapy. Primary
perceived barriers include chemotherapy-induced fatigue (Herath et al., 2015),
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

poor adherence (Tang et al., 2017), and loss of balance (Anton and Garg, 2010).
One approach to minimizing these barriers to exercise during chemotherapy may
be the use of HIIT which alternates between high intensity bouts and lower
intensity recovery periods. As suggested by previous studies, HIIT may be a potent
therapeutic intervention to decrease fatigue (Baguley et al., 2017; Smith et al.,
2009). Using a stationary bike, HIIT can be performed in a safe manner with
postural support that may be lacking with treadmill exercise (Trippo et al., 2017).
Further, HIIT leads to superior effects on vascular endothelial dysfunction and
quality of life compared to continuous moderate intensity exercise (Benda et al.,
2015). However, there is no evidence demonstrating the feasibility of HIIT
performed by breast cancer patients receiving anthracycline-based chemotherapy.
Therefore, the overall goal of this proposal is to demonstrate that HIIT is a feasible
exercise strategy that can reduce vascular endothelial dysfunction in breast cancer
patients during anthracycline-based chemotherapy.
In this two-armed randomized pilot study we sought to determine whether
the HIIT intervention was feasible, and assessed the effects of the HIIT intervention
on vascular endothelial function, vascular wall thickness and ECM-regulating
enzymes in breast cancer patients undergoing anthracycline-based chemotherapy
when compared the DEL group. The DEL group was asked to maintain their
sedentary lifestyle behavior and was offered the same optional HIIT intervention
following the 8-week HIIT intervention. Thus we tested the following aims:
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Aim 1. To determine the feasibility of an 8-week supervised HIIT intervention in
early-stage breast cancer patients receiving anthracycline-based chemotherapy.
We hypothesized that an 8-week HIIT intervention is a feasible exercise training
approach during the 8-week course of anthracycline-based chemotherapy,
whereby more than 50% of patients randomized to the HIIT intervention are able to
complete both an average of 70% (63/90 minutes) of total prescribed weekly
minutes of exercise and attend more than 70% (17/24 sessions) of total exercise
sessions.
Aim 2. To determine the effects of an 8-week supervised HIIT intervention on
vascular endothelial dysfunction in early-stage breast cancer patients receiving
anthracycline-based chemotherapy. We hypothesized that an 8-week HIIT
intervention significantly increases baFMD in the HIIT group compared the DEL
group. As an exploratory sub-aim, we sought to determine the effects of an 8-week
supervised HIIT intervention on vascular wall thickening in early-stage breast
cancer patients receiving anthracycline-based chemotherapy. We hypothesized
that an 8-week HIIT intervention would maintain cIMT in HIIT group compared to
DEL group.
Aim 3. To determine the effects of an 8-week HIIT intervention on ECM regulating
enzymes in early-stage breast cancer patients receiving anthracycline-based
chemotherapy. We hypothesized that an 8-week HIIT intervention improves
circulating serum MMP-2 and -9 in the HIIT group compared to the DEL group.
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

If HIIT is deemed feasible, this research has the potential to impact cancer
survivorship by providing a strategy to offset vascular endothelial dysfunction
worsened by anthracycline-based chemotherapy, thereby reducing the risk of CVD
mortality later in life. These results will be used to plan and conduct a large,
randomized controlled exercise intervention trial for breast cancer patients during
anthracycline-based chemotherapy to reduce the risk of CVD mortality. Overall, a
long-term objective is to incorporate HIIT as a form of cancer rehabilitation early on
in the cancer treatment trajectory to promote vascular health and prevent cardio-
toxic side effects of anthracycline-based chemotherapy.

CHAPTER II: BACKGROUND & SIGNIFICANCE

This work is significant because 1) we targeted a population of breast cancer
patients who are at a higher risk of CVD as a result of undergoing anthracycline-
based chemotherapy, and 2) we utilized a non-pharmacologic strategy in the form
of an exercise intervention to target CVD-related side effects of anthracycline-
based chemotherapy.
Breast cancer patients are at a higher risk of CVD as a result of undergoing
anthracycline-based chemotherapy and therefore are in need of an interventional
strategy to offset anthracycline-induced vascular dysfunction. CVD is the main
cause of death in women with early-stage breast cancer (Bradshaw et al., 2016;
Mozaffarian et al., 2016). Breast cancer patients have 1.8-fold increased risk of
CVD mortality in comparison with age-matched counterparts, and those who
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

receive chemotherapy have a 1.7 fold increased risk of CVD mortality than those
who receive only radiotherapy and endocrine therapy (Bradshaw et al., 2016). In
particular, anthracyclines, a form of chemotherapy, result in profound, negative
consequences on the cardiovascular system such as the increased risk for
coronary heart disease and heart failure (Murtagh et al., 2013; Sawyer, 2013).
Anthracycline is a primary class of chemotherapy regimens used in the
treatment of early and advanced stage breast cancer with the exception of non-
invasive breast cancer (i.e. Lobular carcinoma In Situ and Ductal Carcinoma In
Situ). This regimen is used to kill invasive breast cancer cell which consists of
hormone receptor positive and negative, pre-operative, post-operative, recurrent
and stage IV disease (Spain et al., 2017). The increased use of anthracycline is
due to its effectiveness which leads to higher survival and lower recurrence.
Anthracycline-based chemotherapy is significantly associated with lower rates of
breast cancer recurrence and improved survival, compared to non-anthracycline-
based chemotherapy such as cyclophosphamide, methotrexate, and fluorouracil
(CMF) (Zare et al., 2013). For example, the 15-year breast cancer mortality was
32.4% for patients who received anthracycline compared to 42.4% for CMF
patients (P<0.001) and breast cancer recurrence was 41.1% for patients who
received anthracycline compared to 53.5% for those who received CMF. Further, in
the early breast cancer trialists’ collaborative group overview of chemotherapy,
anthracycline-based chemotherapy showed a 12% reduction in the annual odds of
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

recurrence (p=0.006) and an 11% reduction in the annual odds of death (P=0.02)
compared to CMF (Henson et al., 2016).
Although anthracycline-based chemotherapy is one of the most effective
and commonly used (neo)adjuvant chemotherapy regimens, the clinical use can be
limited due to its dose-dependent cardiovascular toxicity (Petrelli et al., 2012). For
example, patients with cardiac issues (e.g. reduced ejection fraction) are not
eligible to receive anthracycline-based chemotherapy. The major cardiovascular
toxicity of anthracycline-based chemotherapy is due to oxidative stress (Figure 1).
While the exact mechanisms by which anthracyclines cause cardiovascular
dysfunction are still unknown, it is plausible that anthracycline-induced oxidative
stress may be responsible for vascular endothelial dysfunction (Sterba et al.,
2013b). During normal aerobic metabolism, coupling of electron transport to
oxidative phosphorylation results in adenosine triphosphate generation and about
2% of the electrons escape the electron transport system (ETS) and react with
molecular oxygen to form reactive oxygen species (Noh et al., 2010). However,
anthracyclines generate substantial oxidative stress due to their ability to divert
electrons from the ETS of vascular mitochondria, resulting in higher rate of reactive
oxygen species during intercalation. Intercalation is the major mechanism of
anthracycline in which the anthracycline substance inserts itself into the DNA
structure of a cell and binds to the DNA which inhibits replication of cancer cell
(Searle et al., 2003). During anthracycline intercalation, oxidative stress is caused
by the increased production of reactive oxygen species (ROS) and an imbalance
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

between the activity of endogenous pro-oxidative enzymes (such as NADPH
oxidase or the mitochondrial respiratory chain) and anti-oxidative enzymes (such
as superoxide dismutase, and paraoxonase) (Hood et al., 2014). The increased
oxidative stress induces vascular endothelial dysfunction defined as a functional
impairment of the endothelium which plays an important role in the pathogenesis of
cardiomyopathy. In clinical setting, vascular endothelial dysfunction is measured by
brachial artery flow mediated dilation which is significantly associated with coronary
endothelial dysfunction and predicts future cardiovascular events such as
cardiomyopathy and heart failure (Schaefer et al., 2012).

Figure 1. Theoretical Framework: Impact of HIIT on Vascular Endothelial Function in
Breast Cancer Survivors during Chemotherapy. Reactive Oxygen Species; ROS, Nitric
Oxide; NO, Matrix Metalloproteinases; MMPs, Brachial Artery Flow-Mediated Dilation;
baFMD, Carotid Intima-Media Thickness (cIMT)
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

In addition, oxidative stress further increases damage in the ECM which
structurally support surrounding endothelial cells (Nikitovic et al., 2014). ECM
surrounding endothelial cells is mainly regulated by its enzyme called matrix
metalloproteinases (MMPs). Particularly MMP-2 and MMP-9, of the ECM are over-
activated by ROS during anthracycline intercalation, and this is the another
pathway which contributes to the vascular endothelial dysfunction and thickening of
carotid vascular wall by degrading connective tissue and basement membrane
(Figure 2) (Kandasamy et al., 2010; Kelly et al., 2008; Nagareddy et al., 2012). For
example, anthracycline-based chemotherapy markedly increased the activity of
MMP-2 and MMP-9 in the carotid artery and plasma/serum blood following eight
weeks of treatment in rats (Ivanova et al., 2012a). Notably, anthracycline-induced
vascular endothelial dysfunction occurs at a more rapid rate than that induced by
metabolic diseases (e.g. obesity, metabolic syndrome and type 2 diabetes), which

Figure 2. Degradation of the ECM by MMPs activation. ECM, extracellular matrix;
MMP, matrix metalloproteinases
Normal ECM ECM Degradation
15
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

does not occur until 24 weeks in patients with metabolic syndrome (Acevedo et al.,
2009).
Exercise is a non-pharmacologic strategy to offset the CV-related side
effects of anthracycline-based chemotherapy. Exercise after breast cancer
diagnosis reduces the risk of breast cancer-specific death and all-cause mortality
(Schmid and Leitzmann, 2014); this epidemiologic evidence supports the need to
incorporate this intervention strategy into one’s lifestyle. Exercise is a safe and
cost-effective strategy to target many health outcomes (i.e., cardiorespiratory
fitness and vascular endothelial function) in breast cancer patients (Currie et al.,
2015). Perhaps, exercise is a desirable method to offset cancer treatment side
effects given the burden of pharmaceutical treatments experienced by breast
cancer patients. The benefits of exercise in breast cancer patients have been well-
established and include eliciting improvements in physical function, quality of life,
activities of daily living, emotional well-being, overall health and disease risk
modification (Capozzi et al., 2016; Swisher et al., 2015). Furthermore, exercise
reduces the risk of developing comorbid illnesses including hypertension,
metabolic syndrome, and type 2 diabetes (Khan et al., 2014). As it pertains to the
outcomes of this study, exercise may promote the upregulation in vascular shear
stress which decrease oxidative stress (i.e. reactive oxygen species; major issue
caused by anthracycline-based chemotherapy) (Yoshida et al., 2014). While
exercise has been shown to decrease oxidative stress in non-cancer populations
such as metabolic syndrome, it is unknown that exercise can decrease the level of
16
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

oxidative stress while anthracycline-based chemotherapy (Conti et al., 2015;
Kurban et al., 2011).
Exercise decreases oxidative stress which improve vascular endothelial
dysfunction by enhancing the bioavailability of nitric oxide.(Gurovich et al., 2011)
For example, a sample of 15 postmenopausal (mean±SD of 63±4 years) women
performed moderate interval aerobic exercise for 30 min 5 days/week for 12 weeks
resulted in significantly increased plasma concentrations of nitric oxide.(Maeda et
al., 2004) This increased level of nitric oxide was accompanied by increased anti-
oxidant molecules such as (glutathione and superoxide dismutase). More directly
to this study, Beck et al. (2013) demonstrated that a 12-week moderate intensity
exercise program including 30 min of aerobic exercise (3 days/week) resulted in
enhanced baFMD and cIMT along with increased levels of plasma glutathione in
prehypertensives (Beck et al., 2013). Forty-three prehypertensive subjects were
randomly assigned to either an endurance exercise training (n = 22) or time-control
group (n = 21). Exercise training significantly improved baFMD, and plasma
glutathione (22%, P < 0.05). This study provides evidence that exercise has
beneficial effects on vascular endothelial dysfunction and anti-oxidant molecules.
This increased vascular elasticity translates into constant blood volume and blood
pressure by accommodating rapidly changing blood pressure despite the pulsating
nature of blood flow (Rossow et al., 2014). This is mediated through the exercise-
induced reduction of oxidative stress, whereby the latter is excessively generated
during anthracycline-based chemotherapy (Vinetti et al., 2015). Therefore,
17
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

exercise, as a non-pharmacologic strategy, may be an effective intervention in
breast cancer patients to target anthracycline-generated oxidative stress.
Aside from observational studies, no clinical studies have been conducted to
confirm that exercise offsets negative vascular side effects of anthracycline-based
chemotherapy among breast cancer patients. This necessitates a critical need to
identify effective interventions to improve vascular endothelial dysfunction in breast
cancer patients undergoing vascular toxic chemotherapy. Overall, exercise can
significantly impact CVD risk in breast cancer patients in the absence of
pharmaceutical interventions to offset cancer treatment side effects and thus
appropriate interventions should be tested to allow for the establishment of
exercise guidelines for this population. Furthermore, this study supports the notion
that exercise is a vital component of the cancer rehabilitation process that is
needed for the betterment of physical, psychological, and emotional health of
cancer patients.
This work is innovative because 1) we utilized a novel exercise strategy,
HIIT, to target CVD-related side effects of anthracycline-based chemotherapy and
2) we assessed important biomarkers, matrix metalloproteinases, as indicators of
the dysregulation of ECM remodeling and tumor progression.
HIIT is a novel exercise strategy for breast cancer patients undergoing
anthracycline-based chemotherapy. HIIT is an exercise strategy that maximizes
exercise intensity by using bursts of concentrated effort alternated with recovery
periods (Cockcroft et al., 2015). HIIT allows clinical patients to perform vigorous
18
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

intensity exercise due to the ‘on-off’ pattern of exercise. The “on” portion of HIIT
typically involves 1-4 minutes performed at 80%-90% of peak power output (PPO)
or maximum heart rate (MHR), followed by the “off” period (2-3 minutes active
break (10% PPO or 40-50-60% of MHR) (Adams et al., 2015). This strategy has
been shown to be more effective than moderate continuous intensity aerobic
exercise for improving vascular endothelial dysfunction among healthy adults and
people with cardiovascular disease (Boyne et al., 2015; Currie et al., 2015; Sawyer
et al., 2014). This protective effect of HIIT on vascular endothelial dysfunction has
been mainly focused in patients with CVD, regardless of etiology of the disease.
This finding may be extended to breast cancer patients since these group of
patients share the similar underlying pathophysiological mechanism of reduced
nitric oxide by oxidative stress. In a previous study, a 6-week HIIT program
consisting of 3, 30 min exercise bouts resulted in a significant improvement in
vascular endothelial dysfunction assessed baFMD in thirty-one patients (mean±SD
of 58±6 years) with type 2 diabetes mellitus or metabolic syndrome when
compared to moderate intensity continuous aerobic exercise. This superior effect
may be due to HIIT-induced reductions in excessive oxidative stress which is the
major cause of cardiovascular dysfunction during anthracycline-based
chemotherapy (Sterba et al., 2013b), as noted in the theoretical framework of this
study described in Figure 1.
In a previous study, only HIIT group decreased oxidative stress compared to
control group and baseline (p<0.05), although both training groups showed
19
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

improvements over markers of lipid profile and fitness. In addition, there was an
increase in shear stress compared to the group of continuous aerobic training and
baseline only in HIIT group (p<0.05). Sixteen healthy men completed three
exercise bouts of treadmill running for 30 minutes at 55% VO2max; 20 minutes at
75% VO2max or 5 minutes at 100% VO2max (maximal) in a random order
(McClean et al., 2015). Shear rate was higher immediately after exercise in the
maximal trial compared to mild exercise (P<0.05). Importantly, nitric oxide showed
a significantly higher increase in HIIT group compared to continuous intensity
training group baseline (p<0.05). This finding suggests that HIIT is more effective in
the normalization of vascular endothelial dysfunction, impacting positively on the
shear stress. More importantly, lower volumes of HIIT compared to moderate
continuous intensity exercise elicit better cardiovascular and physical fitness
outcomes such as vascular endothelial dysfunction and VO2max, therefore it is a
time efficient exercise option that promotes greater gains in cardiovascular
outcomes (Boyne et al., 2015). Our study utilized a HIIT protocol that includes 7
bouts of 1 minute of high intensity exercise followed by 2 minutes of active
recovery. A similar protocol was used by Boyne et al, which found that HIIT is
superior to moderate aerobic exercise to improve vascular endothelial dysfunction
in chronic stroke patients. This study included 16 stroke patients (58 ± 10 years;
years post stroke, 4.3 ± 2.9) who were randomized to HIIT (n=11) or moderate
intensity continuous exercise (n=5); each 25 min, 3x/week for 4 weeks. HIIT
involved repeated 1 minute bursts of treadmill gait at maximum tolerated speed
20
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

(based on gait stability), alternated with 60 sec rest periods. Moderate intensity
exercise group involved continuous treadmill gait at 45-50% MHR. In the HIIT
group, significant improvement was found VO2max and 10 min walk test.
Multiple previous studies have utilized aerobic interventions in breast cancer
patients undergoing chemotherapy yet these have involved continuous aerobic
exercise rather than the on/off interval strategy of HIIT. Further, HIIT has been
safely utilized for improvement of endurance and quality of life in breast cancer
patients who completed chemotherapy and/or radiation therapy (Schulz et al.,
2018). The exercise protocols varied with common exercise prescription including
3-5 times per week of 30-75 minutes moderate intensity (40% to 70% predicted
max heart rate) moderate intensity continuous exercise (MICE). Unfortunately,
previous program designs have failed to identify the optimal type, timing, and
intensity of exercise intervention to prescribe exercise in breast cancer patients
undergoing chemotherapy. Therefore, due to the superior benefits of HIIT
previously described, HIIT is a more novel form of aerobic exercise, which
challenges the traditional MICE strategy. Given the potential barrier of compliance
during chemotherapy in breast cancer patients to regular exercise participation,
HIIT is an intriguing option for increasing cardiovascular benefits with shorter
exercise duration which serves as an efficient and alternative to traditional
endurance-based exercise training (Lee et al., 2016). Specifically, HIIT improves
anti-oxidant molecules to a greater extent when compared to MICE (Scharf et al.,
2015). The improved anti-oxidant molecules decrease oxidative stress and thereby
21
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

increasing endothelial oxidative stress by upregulating endothelial nitric oxide
synthases (Gurovich et al., 2011; Scharf et al., 2015). The upregulated nitric oxide
synthases generate the vaso-protective molecule, nitric oxide, which dilates blood
vessels and prevents atherosclerosis (Forstermann and Munzel, 2006). Further,
HIIT is a clinically proven safe, cost-effective intervention (Buffart et al., 2015;
Casla et al., 2015). A recent study investigating HIIT in patients with heart failure
with reduced ejection fraction revealed that the number of adverse events were not
statistically different between HIIT group and moderate intensity exercise group
(Ellingsen et al., 2017). Overall, this is the first study demonstrating the feasibility
and effects of HIIT in breast cancer patients undergoing anthracycline-based
chemotherapy. HIIT is a time-efficient exercise strategy that successfully improves
vascular endothelial dysfunction in patients with severe CVD such as coronary
heart disease (Currie et al., 2015), heart failure (Holloway et al., 2014), and stroke
(Boyne et al., 2015), without serious adverse events. Therefore, HIIT may have the
unique capacity to improve vascular endothelial dysfunction and vascular wall
thickening in breast cancer patients who are undergoing chemotherapy.
Particularly, our approach is the first study to utilize a HIIT intervention in breast
cancer patients undergoing anthracycline based chemotherapy.
Matrix metalloproteinases (MMPs) are overexpressed in the dysregulation of
ECM related to vascular endothelial dysfunction. Vascular endothelial function and
vascular wall thickening are mainly determined by smooth muscle cells, which not
only control vessel wall tension but also synthesize the major structural
22
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

components of the vessel wall: collagens, elastin, proteoglycans, and glycoproteins
(Wanjare et al., 2015). These components interact to form a complex network, the
ECM, which provides vasculature with structural support and their elastic
characteristics (Hong et al., 2012). Continual mechanical stresses (i.e., shear
stress) cause weakening of the vessel wall if the structural integrity and physical
properties of the ECM are not maintained. The composition of ECM determines its
cellular components via growth factor activation by MMPs. Connective tissue repair
and remodeling to maintain ECM integrity involves the synthesis and removal of
MMPs. There are proteinases which interact to achieve homeostasis of the vessel
wall: MMPs. MMPs are known to be expressed in human atherosclerotic plaques
by both smooth muscle cells and foam cells (Jager et al., 2016). Vascular wall
thickening and vascular endothelial dysfunction are major detrimental impacts of
anthracycline-based chemotherapy which impair vascular endothelial dysfunction
and cardiac autonomic dysfunction, decreased diastolic pressure, and coronary
perfusion (Kelly et al., 2014; Masugata et al., 2014). These detrimental impacts are
significantly correlated with dysregulation of ECM remodeling measured by the
level of MMPs; the overexpression of certain MMPs may contribute to vascular
endothelial dysfunction in patients with CVD (Azevedo et al., 2014). For example,
the level of MMP 2 in patients with metabolic syndrome was significantly (P<0.05)
higher (4,260±326 pg/ml) compared to subjects with normal metabolic condition
(3,452±429 pg/ml). Once the MMPs are activated, ECM is degraded. In particular,
MMP-2 and -9 are responsible for the degradation of connective tissue in
23
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

endothelial cells contributing to the development of vascular wall thickening.
Therefore, we measured MMPs as novel biomarkers to assess ECM degradation.
MMPs have been targeted to decrease vascular endothelial dysfunction and
vascular wall thickening in CVD patients as well as animal models utilizing
exercise. A 10-week treadmill exercise combined with a western diet intervention in
mice decreased MMP-2 and -9 levels in aorta even when the mice remained on a
high fat diet (diet not specified). The mice in the exercise group were trained on a
treadmill with a rubber belt driven at a controlled speed for 30 min/day, 5
days/week. The treadmill speed was 7 m/min on the first day, and then it was
increased by 1 min each day until the maximum speed of 17 m/min was reached at
the end of the second week. More directly, evidence was found with changes in
oxidative stress in an animal model. This study examined the effects of aerobic
exercise for 6 weeks, and reported a reduction in MMP-2 as part of a vascular-
protective mechanism against the injury induced by oxidative stress (Jaoude and
Koh, 2016). Aged rats that performed a 45-minute aerobic exercise on a treadmill
for up to 12 weeks (5 days/week) showed decrease in both MMP-2 in carotid artery
(Donley et al., 2014). In consistence with these animal studies, human models
have revealed similar results. Fifty overweight patients with type 2 diabetes were
randomly assigned to two groups: an exercise group (n=25), 150 min/week; and a
control group (n = 25) (Kadoglou et al., 2010). All participants took oral antidiabetic
drugs, and none had diabetic complications. Compared with controls, the exercise
group showed a significant decrease in systolic and mean blood pressure,
24
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

cholesterol, and HbA(1c) (P < 0.05). Further, the improvement of blood pressure
was significantly correlated with decreased levels of MMP-9 (P=0.028), whereas
MMP-2 was not significantly changed. This study was supported by another
previous study in patients with metabolic syndrome. MMP-2 and -9 in plasma
decreased following aerobic exercise training in male and female subjects with
metabolic syndrome (Roberts et al., 2006). Patients with metabolic syndrome were
given an 8 week of aerobic exercise training to decrease MMPs while participating
in a 30-minute treadmill exercise program (3 days/week) for 8 weeks. Following the
intervention, there was a significant decrease in MMP-2 and -9. These data may
suggest that exercise has a significant impact on regulating MMPs in vascular
dysfunction. With superior effects of HIIT to target vascular endothelial dysfunction,
chemotherapy-induced over expression of MMPs may be better reduced in breast
cancer patients undergoing chemotherapy. Taking into consideration that abnormal
cholesterol levels are not the major issue in the pathogenesis of cardiovascular
diseases in these patients, decreasing excessive expression of MMPs is a critical
step to preventing the pathogenesis of the vascular endothelial dysfunction.
Importantly, the circulating levels of MMP-2 and -9 have been strongly linked to
intima-media thickness in breast cancer patients on anthracycline-based
chemotherapy, which emphasizes the role of HIIT in the development of vascular
wall thickening in breast cancer patients undergoing chemotherapy.

25
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

CHAPTER III: FEASIBILITY OF IMPLEMENTING HIGH INTENSITY INTERVAL
TRAINING IN BREAST CANCER PATIENTS UNDERGOING ANTHRACYCLINE-
BASED CHEMOTHERAPY

ABSTRACT
Purpose Anthracycline-based chemotherapy is associated with reduced vascular
endothelial function in breast cancer patients. High intensity interval training (HIIT)
induces greater benefits on vascular endothelial function than moderate continuous
aerobic exercise in patients with heart failure and stroke. The study purpose was to
determine whether a HIIT intervention is a feasible exercise strategy for breast
cancer patients undergoing anthracycline-based chemotherapy.
Methods Thirty women initiating anthracycline-based chemotherapy were
randomized to either the HIIT or delayed (DEL) groups. Participants performed a
maximal cycling fitness test to measure peak power output (PPO) during maximal
oxygen uptake (VO2max). The HIIT group participated in an 8-week HIIT
intervention occurring 3 times weekly. Adherence measures used to define
feasibility were calculated for each participant by computing (1) the average weekly
minutes of HIIT over 8 weeks and (2) the number of sessions attended and
multiplied by 100 (percentage of sessions). The HIIT intervention was considered
feasible if more than 50% of participants completed both an average of 70% of
weekly minutes (63/90 minutes) and attended 70% exercise sessions (17/24
sessions).
Results Participants were 46.9±9.8 (mean±SD) years old, diagnosed with clinical
stage II (30%) or III (63%) breast cancer. The average weekly minutes of exercise
26
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

completed was 78±5.1 (mean±SD) out of 90 min. Twelve of 15 (80%) participants
met both feasibility criteria, attending 19.2±2.1 out of 24 sessions (82.3%) with no
adverse event. Three participants were not adherent due to fatigue.
Conclusions HIIT is a feasible exercise intervention in breast cancer patients
receiving anthracycline-based chemotherapy, as demonstrated by the high
adherence to the intervention.

INTRODUCTION
Anthracycline-based chemotherapy is a primary class of chemotherapy regimens
used in the treatment of early and advanced stage breast cancer which consists of
hormone receptor positive and negative (estrogen/progesterone receptor), pre-
operative, post-operative, recurrent and stage IV disease (Gradishar et al., 2018).
Although anthracyclines are an effective chemotherapeutic agent for breast cancer
patients, anthracycline-based chemotherapy may induce multiple adverse effects
such as reduced ejection fraction, cardiorespiratory fitness, fatigue, low quality of
life, fat gain, and muscle loss (Bernhorster et al., 2008; Boekel et al., 2016;
Goldstein et al., 2012). Cardiotoxicity is of particular concern due to development
of overt pathologic changes on cardiomyocyte within hours after a single dose of
anthracyclines (Pearson et al., 2017; Shachar et al., 2017), and heart failure or
coronary artery disease years after chemotherapy (Gujral et al., 2018; Pinder et al.,
2007).
27
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Exercise interventions have been utilized in breast cancer patients
undergoing anthracycline-based chemotherapy to minimize adverse effects yet
these studies have failed to identify the optimal type, timing, and intensity of
exercise intervention to prescribe exercise to breast cancer patients undergoing
anthracycline-based chemotherapy (Courneya et al., 2007; Courneya et al., 2013).
One novel exercise strategy is a form of exercise referred to as high-intensity
interval training (HIIT). HIIT is designed to include intervals of low to high intensity
forms of exercise, which induces greater benefits on improving cardiorespiratory
fitness than moderate continuous aerobic exercise in patients with heart failure
(Ellingsen et al., 2017) and stroke (Boyne et al., 2015). Therefore, HIIT is a novel
form of exercise that should be considered for use among breast cancer patients
receiving anthracycline-based chemotherapy.
HIIT has been typically prescribed by percentage of maximum heart rate (or
heart rate reserve) in previous clinical settings with heart failure and stroke
(Ellingsen et al., 2017; Larsen et al., 2015; Pimenta et al., 2015; Sawyer et al.,
2014). However, breast cancer patients have varying resting/maximal heart rates
and heart rate recovery, especially during chemotherapy treatment; therefore
utilizing the heart rate to prescribe HIIT in breast cancer patients during
chemotherapy does not guarantee the “true high intensity” level of exercise training
required for this method of prescription. Another measure used to prescribe HIIT in
breast cancer patients undergoing chemotherapy is rated perceived exertion (RPE)
(Mijwel et al., 2017). However, breast cancer patients may have experience
28
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

different symptoms each day which does not allow for consistent prescription of
HIIT intensity based on an individual’s perception of exertion during exercise.
Due to limitations in use of heart rate and RPE to prescribe exercise, the feasibility
of HIIT in breast cancer patients undergoing chemotherapy is unclear. Peak power
output (PPO) has been used to prescribe exercise intensity during HIIT, and has
the potential to be used in cancer patients undergoing chemotherapy because it is
not only an objective measure of physical fitness, but it is a direct measure of the
rate of external work performed by each individual (Currie et al., 2015; Currie et al.,
2012; Patterson and Moreno, 1990). For example, a HIIT training bout may include
a 1 minute interval performed at 90% PPO followed by a 2 minute interval
performed at 10% PPO (Adams et al., 2015; Ellingsen et al., 2017). The threshold
of PPO has been utilized in previous studies utilizing a HIIT intervention with
ranges of 80%-100% in patients with coronary artery disease and heart failure
(Adams et al., 2015; Boyne et al., 2015; Cockcroft et al., 2015; Sawyer et al.,
2014). While the benefits of HIIT have been investigated in breast cancer patients
(Mijwel et al., 2017), implementing HIIT prescribed by PPO in breast cancer
patients undergoing anthracycline-based chemotherapy has not been studied.
Primary perceived barriers include chemotherapy-induced fatigue (Goldstein et al.,
2012), poor adherence (Blanchard et al., 2008), and loss of balance (Anton and
Garg, 2010).
The purpose of this pilot study was to determine whether an 8-week HIIT
intervention prescribed by PPO is a feasible exercise strategy for breast cancer
29
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

patients during anthracycline-based chemotherapy. We hypothesized that an 8-
week HIIT exercise intervention is a feasible exercise training approach, whereby
more than 50% of patients randomized to the HIIT condition are able to complete
both an average of 70% (63/90 minutes) of total prescribed weekly minutes of
exercise and >70% (17/24 sessions) of total exercise sessions. This method of
feasibility was set forth because previous studies reported that the adherence of
exercise intervention in cancer patients ranges from 68% to 80% (Blanchard et al.,
2008; Courneya et al., 2007; Courneya et al., 2013; De Jesus et al., 2017).
Particularly, exercise adherence is lower in the studies which included cancer
patients undergoing chemotherapy (Courneya et al., 2007), whereas higher
adherence was reported in patients who completed cancer treatment (Dieli-
Conwright et al., 2018).

Methods
Participants/Consent. Participants who met the following requirements were
eligible: 1) women >18 years of age diagnosed (I-III) with a primary invasive breast
cancer; 2) planned (neo)adjuvant anthracycline-based chemotherapy; 3) able to
initiate exercise intervention within 1 week of initiation of anthracycline-based
chemotherapy; 4) less than 30 minutes of physical activity per week; 5)
nonsmokers (i.e., not smoking during previous 12 months); 6) willing to travel to the
exercise facility at USC; 7) able to provide physician clearance to participate in the
exercise intervention; 8) women of all racial and ethnic backgrounds will be
30
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

included in the study enrollment process. The exclusion criteria were: 1) history of
chronic disease including diabetes uncontrolled hypertension or thyroid disease; 2)
weight reduction > 10% within past 6 months; 3) metastatic disease; 4) overt CVD
(myocardial infarction, stroke, angina and etc.); 5) contra-indications to exercise; 6)
participation in regular exercise.

Experimental Design (Figure 3). This pilot study was designed to determine the
feasibility of HIIT in 30 sedentary women undergoing anthracycline-based
chemotherapy for the treatment of breast cancer. Participants were recruited from
the breast cancer clinics at the Norris Comprehensive Cancer Center and the Los
Angeles County hospital. Once patients were eligible to participate in the study
during their screening visit, and following informed consent, participants were
randomized either to the HIIT group or the delayed group (DEL). All participants
completed their baseline tests at the Integrative Center for Oncology Research in

Figure 3. Study Timeline. HIIT, high intensity interval training; DEL, delayed
31
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Exercise (ICORE) within 1 week prior to the start of chemotherapy. Participants
randomized to the HIIT group participated in an 8-week HIIT intervention including
3 HIIT sessions per week with each session lasting 30 minutes in duration for a
total of 90 minutes during the anthracycline-based chemotherapy period.
Participants randomized to the DEL group were asked to maintain their current
level of physical activity, which should not exceed 30 minutes of total structured
exercise per week. The DEL group were offered the same HIIT intervention upon
completion of the initial 8-week study period and post-exercise outcome measure
testing was conducted on week 17. All participants return to the ICORE within one
week following completion of the 8-week study period for post-testing. Outcome
measures are obtained at baseline within 1 week prior to the first cycle of
anthracyclines (week 0), and at week 9, within 2-5 days from the last exercise
session. The protocol and informed consent were IRB-approved (HS-12-00141)
and registered (ClinicalTrials.gov:NCT01140282).

Intervention (Figure 4). The HIIT intervention consisted of an 8-week, thrice
weekly intervention. All exercise sessions were supervised by a certified exercise
trainer, performed on a stationary bike (Life Fitness 95 Elevation Series,
Rosemont, IL), and took place at the ICORE. Exercise intensity for HIIT
intervention was prescribed based on PPO measured by maximal fitness test.
Each session consisted of a 5-minute warm-up performed at 10% PPO followed by
32
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

a 20-minute HIIT stimulus (90% PPO/10% PPO), and 5-minute cool-down (10%
PPO; Figure 4). This specific HIIT protocol was successfully utilized to improve
vascular endothelial function in patients with stroke (Boyne et al., 2015), and
coronary artery diseases (Currie et al., 2015), thus we have chosen to use the
same protocol in breast cancer patients. Each HIIT bout consisted of a seven 1-
minute high-intensity intervals performed at 90% PPO followed by a 2-minute low-
intensity recovery interval performed at 10% PPO for the 20-minute period. Pedal
rate or cadence, measured in revolutions per minute (rpm), was a critical
component influencing power output during cycling. As for preferred pedal rates
when reaching PPO, previous studies revealed that average between 60–80 rpm
was optimal cadence used in maximal aerobic capacity testing, and previous HIIT
protocols have successfully utilized 60 rpm (Ahlquist et al., 1992; Takaishi et al.,
1996). Therefore we chose to utilize the HIIT intervention with the consistent 60
rpm. Heart rate was recorded at the beginning and end of each one-minute, high-

Figure 4. Sample HIIT workout. Grey bars indicate high-intensity intervals at
90% peak power output and black bars indicate the 2-minute rest interval at 10%
peak power output.
33
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

intensity interval as well as at the end of the 2-minute recovery interval (Appendix
A.1). Participants were encouraged to complete each exercise session with one full
day of rest in between sessions and to complete sessions on days when they did
not receive chemotherapy infusion. If a participant preferred to perform 2-3
consecutive sessions in one week due to chemotherapy-induced side effects (i.e.,
fatigue), this was documented on the exercise session form and the number of
session with consecutive sessions in a week was counted (Appendix 6). The
purpose of this documentation was to plan for future intervention studies and to
inform researchers on the preference of exercise schedules of this patient
population. Participants were encouraged to make up any missed sessions in the
same week, and had the ability to schedule their exercise sessions at days and
times convenient for the participant alongside their individual treatment schedule.

Outcome measures
Feasibility. Overall feasibility of HIIT was assessed using average weekly minutes
of exercise completion (>63/90 minutes per week) of all participants in the HIIT
group. The exercise intervention was considered feasible if more than 50% of
patients randomized to the HIIT condition were able to complete both an average
of 70% (>63/90 minutes) of prescribed weekly exercise and number of session
attended across all participants randomized to the HIIT group (>17/24 sessions;
70%). Previous studies in cancer patients mainly determined feasibility only by the
ratio of the number of exercise sessions attended to the total number of exercise
34
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

session offered (Blanchard et al., 2008; Courneya et al., 2007; De Jesus et al.,
2017). Therefore we expanded on this work and defined the feasibility of this study
as including both an average of completed weekly exercise minutes
(>63/90minutes: 70%) and an average of completed weekly exercise sessions
(>17/24 sessions: 70%). For example, if participants did not complete an average
of 70% of the weekly exercise time, but attended 70% of the exercise sessions
then the exercise intervention was classified as not feasible. In the event that a
participant was not able to complete the entire exercise session, the number of
minutes (out of 30 minutes) completed during each exercise session was
documented.
Further, in order to assess if the timing of the chemotherapy infusion
influences the feasibility of implementing HIIT, we measured the mean number of
days between each cycle of chemotherapy infusion (prescribed every 2 weeks for
a total of 4 cycles of anthracycline-based chemotherapy) and when the participants
came to the HIIT sessions (based on their preference). By assessing the number of
days during which participants were not receiving chemotherapy infusion, we were
able to assess how many days were available for these patients to perform HIIT
sessions on the week of chemotherapy in order to plan for future studies involving
exercise during chemotherapy.

PPO and VO2max. Prior to initiation of the HIIT intervention, all participants
underwent a baseline fitness test (Week 0; Table 1) using a maximal cycling
35
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

protocol to measure PPO during maximal oxygen uptake (VO2max) (Boyne et al.,
2015) (Boyne et al., 2015). The specific VO2max protocol comprised a 10W
increase in workload every one minute, starting at 40W. This testing was
performed with standard equipment for indirect calorimetry (Parvo Medics Inc, Salt
Lake City, UT) in an incremental protocol until exhaustion on a recumbent bike
(Appendix 5). Before the fitness test was performed, participants were familiarized
with the testing protocol using the same standardized verbal instructions that
indicate the duration of each stage, maintaining the same RPM throughout the test,
and increases of torque during the test. Participants wore a silicone face mask
used to collect samples of expired air in order to determine their VO2 and
ventilatory equivalent every 20 seconds. Following this testing, PPO was obtained
at the last stage of maximal cycling testing, and the PPO was used to prescribe
intensity of HIIT.

36
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Table 1. Maximal cycling protocol based on cadence and torque (Life Fitness,
Rosemont, IL)
Stage Cadence
(RPM)
Level
(Torque)
Time Power
Stage 1 60 1 (0.67 Nm) min 0 - min 1 40 W
Stage 2 60 4 (1 Nm) min 1 - min 2 60 W
Stage 3 60 8 (1.33 Nm) min 2 - min 3 80 W
Stage 4 60 10 (1.67 Nm) min 3 - min 4 100 W
Stage 5 60 11 (1.83 Nm) min 4 - min 5 110 W
Stage 6 60 12 (2 Nm) min 5 - min 6 120 W
Stage 7 60 13 (2.17 Nm) min 6 - min 7 130 W
Stage 8 60 14 (2.33 Nm) min 7 - min 8 140 W
Stage 9 60 15 (2.5 Nm) min 8 - min 9 150 W
Stage 10 60 16 (2.67 Nm) min 9 - min 10 160 W
Stage 11 60 17 (2.83 Nm) min 10 - min 11 170 W
Stage 12 60 18 (3 Nm) min 11 - min 12 180 W

Statistical analyses. This study was designed as a single center pilot study, so a
formal sample size calculation (i.e., to estimate numbers needed to detect a given
intervention effect size) was not performed. Based on our previous work [30], we
37
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

aimed to recruit roughly 2.5 participants per month in anticipation of reaching 30
participants within 1 year. Descriptive statistics were performed for all participant
baseline characteristics and compared across groups to test for equivalence
across the groups, using t-tests (or non-parametric Wilcoxon rank sum) for
continuous variables and chi-square tests for categorical variables. The adherence
measures used to define feasibility were calculated for each participant by: (1)
computing the average weekly minutes of HIIT exercise (averaged over the 8 week
intervention); and (2) assessing the number of sessions attended over 24 sessions
and multiplied by 100 (percentage of sessions). Each of these adherence
measures was averaged across all participants in HIIT group. The number and
percent of HIIT participants who met both of the two feasibility criteria (average
weekly minutes at least 63, and at least 17 sessions attended) was calculated.
Cohen’s d effect size for the change in VO2max was also calculated using the
difference in means from pre- and post-intervention and dividing by the pooled
standard deviation. Data were analyzed using SPSS for Windows version 22 (IBM,
Armonk, NY, USA).

Results
The study CONSORT diagram is presented in Figure 5. All 30 participants
completed their planned 8-week anthracycline-based chemotherapy. Descriptive
baseline characteristics are presented in Table 2. On average, participants were
46.9± 9.8 years old, primarily Hispanic white (73%), with BMI 31.0 7.5 kg/m
2
. Most
38
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

participants were clinical stage III (63%), and prescribed chemotherapy in the
neoadjuvant setting (77%).
Table 2. Baseline Participant Characteristics (n=30)
All
(N=30)
HIIT group
(N=15)
DEL Group
(N=15)
Mean age (SD), years* 46.9 (9.8) 49.1 (7.9) 44.7 (11.2)
Menopausal status
Premenopausal
Postmenopausal

11 (37)
19 (63)

5 (33)
10 (67)

6 (40)
9 (60)
Body Weight, kg, mean (SD) 77.7 (18.3) 80.9 (17.7) 74.5 (18.8)
Height, cm, mean (SD) 158.4 (8.2) 156.5 (6.6) 160.3 (9.9)
BMI, kg/m
2
, mean (SD) 31.6 (7.7) 33.1 (7.6) 30.1 (7.7)
Race/ethnicity
Non-Hispanic white
Hispanic white
African American
Asian/Pacific Islander

4 (13)
22 (73)
2 (7)
2 (7)

3 (20)
11 (74)
0 (0)
1 (6)

1 (6)
11 (74)
2 (14)
1 (6)
Disease stage
Stage I
Stage II
Stage III

2 (7)
9 (30)
19 (63)

1 (6)
5 (30)
9 (64)

1 (6)
4 (24)
10 (70)
Chemotherapy
Neo-adjuvant
Adjuvant

23 (77)
7 (23)

11 (73)
4 (27)

12 (80)
3 (20)
39
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Figure 5. CONSORT Diagram. Data are presented as No. (%) unless otherwise
indicated. No significant baseline differences between groups were observed
(p>0.05) by independent sample t tests for continuous variables and Pearson X
2

and Fisher’s exact tests for categorical variables. Abbreviations: BMI, body mass
index; DEL, delayed, HIIT, high intensity interval training, SD, standard deviation.

Figure 5. CONSORT diagram of the HIIT intervention. HIIT, high intensity
interval training; DEL, delayed; USC, University of Southern California; NCCC,
Norris Comprehensive Cancer Center; LAC, Los Angeles County
40
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Accrual and Retention. Figure 3 describes the flow of study participants through
the intervention. Participants were recruited from August 15
th
2017 to August 13
th

2018. Of 53 eligible patients recruited, 24 patients declined participation (41.4%).
The recruitment rate was 56% over the 12-month period. The primary reason for
refusal of study participation was lack of interest in exercise during chemotherapy
(n=23). There were 5 women who were ineligible due to lack of willingness to travel
to the ICORE (n=1), pre-existing chronic cardiac condition (n=1), did not speak
English or Spanish (n=2), high level of current physical activity participation (n=1).
Of 30 enrolled patients, all patients completed the 8-week HIIT intervention (100 %
retention).

Feasibility. The mean adherence to sessions attended out of 24 sessions was
82.3%. Overall, 80% (12 of 15) of HIIT participants met both criteria; attended
19.2±2.1 (mean±SD) of 24 sessions and completed an average of 78±5.1
(mean±SD) of 90 weekly minutes of exercise over 8 weeks. Importantly, all
participants in the HIIT group were able to complete each HIIT session once they
initiated the HIIT session. Therefore weekly minutes of 78±5.1 resulted from
missing sessions, not due to the discontinuation of a given HIIT sessions. Three
participants were not adherent (did not meet the adherence criteria: <70%) and
reported by phone call or text message that it was due to fatigue. There were no
adverse events. The HIIT group did not experience dose-delays of anthracycline-
based chemotherapy implying that a HIIT intervention does not impact
41
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

chemotherapy dose and schedule. Potentially future larger trials may examine the
impact of exercise on dose-delay or tolerance of anthracycline-based
chemotherapy. The mean number of days between each chemotherapy infusion
and the self-selected timing of the first HIIT session each week was 1.9±0.9 days
(range from 1 to 5 days) The number of HIIT sessions (mean±SD) performed
during each anthracycline-based chemotherapy cycle was as follows: 1st cycle:
2.79±0.58 sessions, 2nd cycle: 2.64±0.93, 3rd cycle: 2.21±1.1, and 4th cycle:
1.29±1.38. There were no adverse events in patients enrolled in the HIIT group.
The mean number of days between each chemotherapy infusion and the self-
selected timing of the first HIIT session each week was 1.9 ± 0.9 days (range from
1 to 5 days), and was consistent throughout the 4 cycles of anthracycline-based
chemotherapy for the HIIT group (Table 3).

PPO and VO2max. There was no statistically significant change from baseline to
post-intervention in VO2max (18.3 ± 7.7 to 18.3 ± 7.7 ml/kg/min) in the HIIT group
(p=0.94). There was a significant decrease in VO2max (19.3 ± 4.0 to 16.2 ± 3.2
ml/kg/min) in the CON group from baseline to 8 weeks (p=0.001). There was no
group (HIIT vs CON) x time interaction (Pre vs Post) on VO2max (p=0.36). There
was no significant change in PPO from baseline to post-intervention in the HIIT group
(122.0 ± 13.7 to 123.1±20.1; p=0.96). There was a significant decrease in PPO
(116.4 ± 22.0 to 105.5 ± 21.1 watts) in the CON group from baseline to 8 weeks post-
randomization (p=0.001). The Cohen’s d effect size using the pooled standard
42
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

deviation for the changes in VO2max (SD of change = 2.18) and PPO (SD of change
= 2.54) was 1.45 and 1.19 respectively.

Table 3. Feasibility of implementing HIIT in breast cancer patients undergoing
anthracycline-based chemotherapy
HIIT group
(n = 15)
Sessions of HIIT attended, % 82.3
Minutes of HIIT per week, mean
(SD)
78 ± 5.1 minutes
Number of HIIT sessions per
each cycle of chemotherapy
cycle, mean (SD)
1
st
cycle
2
nd
cycle
3
rd
cycle
4
th
cycle

2.79 ± 0.58
2.64 ± 0.93
2.21 ± 1.10
1.29 ± 1.38
Note. Data are presented as % unless otherwise indicated. No significant baseline
differences between groups were observed (p>0.05) Abbreviations: HIIT, high
intensity interval training; DEL, delayed; SD, standard deviation.

Discussion
Our study is the first to explore the feasibility of implementing HIIT in breast cancer
patients specifically receiving anthracycline-based chemotherapy. We found that
HIIT is a feasible intervention method as the patients were adherent to the
intervention and no adverse events occurred. Therefore, HIIT is safe and feasible
intervention in breast cancer patients undergoing anthracycline-based
chemotherapy.
43
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

We hypothesized that an 8-week HIIT exercise intervention is a feasible
exercise training approach, whereby more than 50% of patients randomized to the
given condition are able to complete an average of 70% (63/90 minutes) of total
prescribed weekly minutes of exercise and >70% (17/24 sessions) of total exercise
sessions. Based on our hypothesis, implementing HIIT during anthracycline-based
chemotherapy was highly feasible in terms of both adherence to the training
session and the training time prescribed. The mean adherence to the HIIT
intervention was 82% and the retention rate was 100%. The high adherence
compares favorably with other studies in breast cancer patients undergoing
chemotherapy (68%- 72%) (Courneya et al., 2007; Courneya et al., 2013; Tang et
al., 2017). The higher adherence reported in our study could be attributed to
flexible session timing (6am to 7pm, 7 days per week or per request of the patient)
and one-on-one supervision by a certified exercise trainer. While we chose a 1min
high intensity: 2 min low intensity interval protocol, other durations such as 4min
high intensity: 3 min low intensity interval protocol or 1min high intensity: 1min low
intensity interval protocol have been investigated in cancer patients. Although we
chose a 1min:2min HIIT protocol due to the high adherence to exercise reported in
a previous study (Boyne et al., 2015), perhaps our outcomes may have been
different from what we have observed in this study if participants performed a
different HIIT protocol. A current gap in the literature is that the optimal duration of
HIIT in cancer patients has not been addressed adequately. Future trials are
44
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

warranted to compare the effects of different duration of HIIT on vascular
endothelial function in cancer patients.
Although an exploratory aim, the HIIT group did not experience significant
improvements in VO2max or PPO, while there was a significant decrease in both
VO2max and PPO among women randomized to the DEL group. Of importance,
breast cancer patients experience significantly impaired cardiorespiratory fitness
(~10%) following anthracycline-based chemotherapy (Burnett et al., 2013).
Declines in cardiorespiratory fitness may not return to baseline, even years after
the cessation of cancer treatment (Frydenberg et al., 2015), thus maintaining
cardiorespiratory fitness during cardio-toxic chemotherapy is a favorable finding in
our study. Therefore, our study supports the use of a short-term HIIT intervention
as an option to maintain cardiorespiratory fitness during anthracycline-based
chemotherapy. This finding may be informative for a sufficiently powered trial to
maintain cardiorespiratory fitness and health-related outcomes in breast cancer
patients undergoing chemotherapy.
Strengths and innovations of our study include a focus on a single
chemotherapy regimen, use of a novel exercise prescription using PPO, and
thorough assessment of feasibility measures, with the number of sessions and
number of minutes attended captured. Particularly, we utilized PPO to prescribe a
HIIT intervention since cancer patients during chemotherapy have unstable
resting/maximal heart rate and heart rate recovery (Kirkham et al., 2018); thus
measuring heart rate may not be valid when prescribing a HIIT intervention. As our
45
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

study cohort successfully performed HIIT interventions prescribed by PPO, PPO
appears to be a useful method for prescribing/performing HIIT in breast cancer
patients undergoing anthracycline-based chemotherapy. The success of feasibility
was of importance because our study is the first that involved ethnically diverse
samples, particularly Hispanic minority cohort (73%).
In conclusion, we demonstrated that HIIT prescribed by PPO for breast
cancer patients receiving anthracycline is feasible, acceptable and safe. The
findings await urgent confirmation in an adequately powered study to evaluate the
benefits of exercise intervention on health-related outcomes. The benefits of longer
HIIT intervention and the potential for a sustained lifestyle change also need to be
explored. Taking into account increasing remission rates and extending survival
improved by anthracycline-based chemotherapy,(Zare et al., 2013) this study
provides evidence to develop a timely effective exercise intervention that may
minimize the burden of pharmaceutical treatment experienced by breast cancer
patients. Further using PPO to prescribe exercise intensity can be a feasible
strategy to implement HIIT in breast cancer patients undergoing chemotherapy.
Our results will make an important contribution to the development of rehabilitation
program for breast cancer patients, specifically receiving anthracycline-based
chemotherapy. While the results of randomized trials are warranted, our
observations suggest that HIIT can be utilized in breast cancer patients receiving
anthracycline-based chemotherapy, with an appropriate measure of HIIT
prescription from a trained exercise physiologist.
46
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

CHAPTER IV: EFFECTS OF HIGH INTENSITY INTERVAL TRAINING ON
VASCULAR ENDOTHELIAL DYSFUNCTION IN BREAST CANCER PATIENTS
RECEIVING ANTHRACYCLINE-BASED CHEMOTHERAPY

ABSTRACT
Introduction Anthracycline is one of the most effective chemotherapeutic agents
to treat breast cancer yet may decrease vascular endothelial function and increase
vascular wall thickness in breast cancer patients. High intensity interval training
(HIIT) has been shown to improve vascular endothelial function compared to
moderate intensity exercise in patients with obesity and stroke. We sought to
determine the effects of an 8-week HIIT intervention on vascular endothelial
function, measured as brachial artery flow-mediated dilation (baFMD), and
vascular wall thickness measured by carotid intima media thickness (cIMT) in
breast cancer patients undergoing anthracycline-based chemotherapy.
Methods Thirty women were randomized to either HIIT or delayed groups (DEL).
The HIIT group participated in an 8-week HIIT intervention occurring 3 times per
week on a cycle ergometer. The DEL group was offered the HIIT intervention after
8 weeks. Outcomes were measured at week 0 and week 9. baFMD was measured
from the brachial artery diameter at baseline (D0) and 1min after cuff deflation
(D1); percent change was calculated by measuring brachial artery diameter 1min
after cuff deflation relative to the baseline [baFMD=(D1−D0)/D0×100]. The cIMT
was obtained from the posterior wall of common carotid artery 10mm below the
carotid bulb. The region of interest was identified at the intima and media on the far
47
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

wall of the vessel. Paired t-test and repeated measures ANCOVA were performed
to assess changes in vascular endothelial function and vascular wall thickness.
Results At baseline, the HIIT (n=15) and DEL (n=15) groups did not differ by
mean±SD of age (46.9±9.8 years), BMI (31.0±7.5kg/m
2
), and blood pressure
(116.1±11.8/72.3.9±5.6 mmHg). Post-exercise, baFMD significantly increased [4.3;
95% confidence interval (CI): (1.5, 7.0), P=0.005] in HIIT versus CON group. cIMT
did not significantly change [0.003, 95% CI: (-0.004, 0.009), P=0.40] in HIIT group,
while IMT significantly increased from baseline to post-intervention (0.009, 95% CI:
0.004, 0.010, P=0.003) in DEL group.
Conclusion HIIT improved vascular endothelial function and maintained wall
thickness in breast cancer patients undergoing anthracycline-based chemotherapy.
Larger randomized trials are needed to establish the optimal exercise strategy to
attenuate anthracycline-induced impairments on vascular endothelial function as
well as the underlying mechanisms involved.
Keywords vascular endothelial function, vascular wall thickness, high intensity
interval training, anthracycline-based chemotherapy, breast cancer patients.

48
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Introduction
Breast cancer mortality has been reduced by 20-30% over the last two decades
with the use of anthracycline-based chemotherapy (Zare et al., 2013), yet
anthracycline use is frequently accompanied by the toxic effects on the heart
(Nikitovic et al., 2014). Anthracyclines produce toxicity affecting the vascular
endothelial cells (Okur et al., 2016); these cells regulate the maintenance of blood
circulation and fluidity, vascular tone, coagulation, and inflammatory responses
(Mallat et al., 2017). Vascular endothelial dysfunction caused by anthracyclines is
related to the development of cardiovascular diseases including atherosclerosis
(Kalabova et al., 2011), hypertension, and heart failure (Murtagh et al., 2013). In
clinical settings, a previous study found that cardiomyopathy occurred in 9% of
2625 patients who received anthracycline-based chemotherapy for breast cancer
within the first few months (Cardinale et al., 2015). Importantly, vascular
endothelial function measured by brachial artery flow-mediated dilation (baFMD)
was significantly lower in patients with cardiomyopathy (Heffernan et al., 2010).
Further, in breast cancer or leukemia when anthracycline-based chemotherapy is
given, vascular endothelial function assessed by baFMD is significantly reduced (-
95%) when compared to patients who did not receive anthracycline-based
chemotherapy (P<0.05) (Vassilakopoulou et al., 2010). This nature of
chemotherapy-induced cardiovascular dysfunction provides a strong rationale for
the design and testing of intervention strategies to improve vascular function, and
ultimately the overall CVD mortality.
49
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Exercise is a well-known approach to improve vascular endothelial
dysfunction in healthy (McClean et al., 2015; Rossman et al., 2017; Stupin et al.,
2015), or clinical populations (Adams et al., 2015; Beck et al., 2013; Larsen et al.,
2015). In particular, high intensity interval training (HIIT) appears to be more
effective than moderate continuous intensity aerobic exercise for improving
vascular endothelial function among patients with heart failure (Adams et al.,
2015), and stroke (Boyne et al., 2015). HIIT is a novel exercise strategy that
maximizes exercise intensity by using bursts of concentrated effort alternated with
recovery periods, which allows clinical patients to perform high intensity exercise
due to the ‘on-off’ pattern of exercise. The “on” portion of HIIT typically involves 1-4
minutes performed at 80%-90% of peak power output (PPO) or maximum heart
rate (MHR), followed by the “off” period (1-3 minutes active break (10% PPO or 40-
50-60% of MHR) (Adams et al., 2015; Currie et al., 2015).This protective effect of
HIIT on vascular endothelial function has been mainly focused on patients with
CVD, regardless of etiology. However, this finding may be extended to breast
cancer patients since these group of patients share the similar underlying
pathophysiological mechanism of reduced nitric oxide caused by anthracyclines-
induced oxidative stress (Sterba et al., 2013a). Aside from studies in patients with
CVD, no studies have been conducted to date in clinical oncology settings to
confirm that HIIT offsets negative changes of vascular endothelial function during
anthracycline-based chemotherapy.
50
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

The purpose of this study was to determine the effects of an 8-week
supervised HIIT intervention on vascular endothelial function in early-stage breast
cancer patients receiving anthracycline-based chemotherapy. We hypothesized
that an 8-week HIIT intervention significantly increases baFMD in the HIIT group
compared to the delayed (DEL) group who did not participate in the HIIT
intervention. For the exploratory hypothesis, we explored whether an 8-week HIIT
intervention would maintain carotid intima media thickness (cIMT), a biomarker of
vascular wall thickness, in HIIT group compared to participants who did not
perform HIIT during 8 week anthracycline-based chemotherapy.

Methods
Participants/Consent. Eligible participants were 1) women >18 years of age
diagnosed (I-III) with a first primary invasive breast cancer; 2) planned receive
(neo)adjuvant anthracycline-based chemotherapy; 3) able to initiate exercise
program within 1 week of initiation of anthracycline-based chemotherapy; 4)
currently participate in less than 30 minutes of physical activity per week; 5)
nonsmokers (i.e., not smoking during previous 12 months); 6) willing to travel to the
exercise facility at USC; 7) able to provide physician clearance to participate in the
exercise program; 8) women of all racial and ethnic backgrounds will be included in
the study enrollment process. The exclusion criteria were: 1) history of chronic
disease including diabetes uncontrolled hypertension or thyroid disease; 2) weight
reduction > 10% within past 6 months; 3) metastatic disease; 4) overt CVD
51
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

(myocardial infarction, stroke, angina and etc.); 5) contra-indications to exercise; 6)
participation in regular exercise. Recruitment occurred between August 15
th
, 2017
and August 6
th
, 2018 from the USC Norris Comprehensive Cancer Center and Los
Angeles County Hospital. The protocol and informed consent were IRB-approved
(HS-15-00227) and registered (ClinicalTrials.gov: NCT02454777). A signed
informed consent was obtained from each participant. Participants were
randomized to the HIIT group or delayed (DEL) group following the completion of
baseline testing using concealed randomization lists.

Experimental Design. This pilot study compared HIIT group versus DEL group
baseline to post-intervention of 8-week changes in MMPs. Participants were
recruited from the breast cancer clinics at the Norris Comprehensive Cancer
Center and the Los Angeles County Medical Center. Following informed consent,
eligible participants completed baseline tests (week 0) test at the Integrative Center
for Oncology Research in Exercise (ICORE) within one week prior to the start of
the intervention. Participants randomized to the HIIT group visited the ICORE to
complete the exercise sessions for a total of 90 min of weekly exercise during the
8-week intervention period. Participants randomized to the DEL group were asked
to maintain their current level of physical activity, which was defined as less than
30 min of total exercise per week. All participants returned to the ICORE within 1
week following completion of the 8-week study period for post-intervention (week
52
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

9). To enhance participation, participants in the DEL group were offered the same
HIIT intervention following the 8-week study period.

Exercise Intervention. All exercise sessions took place at the Integrative Center
for Oncology Research (ICORE) in Exercise in the Division of Biokinesiology and
Physical Therapy at the University of Southern California (USC). Participants
received 3 supervised one-on-one exercise sessions/week. Participants assigned
to the HIIT group received supervised exercise sessions performed on a stationary
bike (Life Fitness 95 Elevation Series, Rosemont, IL). Exercise intensity was
individually prescribed for the HIIT group based on peak power output (PPO),
which was measured by a VO2max fitness testing performed on a stationary bike.
Each exercise session consisted of a 5-minute warm-up performed at 10% PPO,
followed by a 20 minute HIIT protocol. The HIIT protocol consisted of 7 bouts of 1
minute high intensity exercise (90% of PPO) followed by 2 minutes of active
recovery (10% of PPO). Participants were encouraged to complete each exercise
session with at least 24 hours of rest between each session and to complete
sessions on days when they did not receive anthracycline infusions. Power output,
heart rate, rating of perceived exertion (RPE; rated on the Borg scale of 6-20,
Appendix 4), and total minutes of exercise were documented for each session and
for each interval (Appendix 6). Participants were encouraged to make up any
missed sessions in the same week. Participants in the DEL group were asked to
maintain less than 30 minutes of total structured exercise per week during the 8
53
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

week study period. After the 8-weeks of intervention, the DEL group was provided
the same HIIT intervention.

Outcome measures
Vascular endothelial function. baFMD. Vascular endothelial function was
evaluated using baFMD following the cIMT exam while the participant was in the
supine position. A rapid inflation and deflation blood pressure cuff was positioned
on the unaffected arm from mastectomy or lumpectomy immediately distal to the
antecubital fossa to provide a stimulus to forearm ischemia, 1cm below the
antecubital fossa. If both arms were affected by surgery, the study oncologist
determined which arm to test. A 10-MHz multi-frequency linear array probe,
attached to a high-resolution ultrasound machine (GE LOGIQ e), was used to
image the brachial artery in the distal third of the upper arm. A single-lead ECG
recording was obtained concurrently during acquisition of brachial artery images.
The B-mode image of the brachial artery and Doppler images of flow are recorded
for 15sec at baseline (P0). Extra-vascular landmarks were identified and labeled to
assure that the imaged segment of the brachial was reproduced within and across
participants. After baseline images, the cuff was inflated to 250mmHg for 5
minutes. Following limb ischemia, there was a rapid increase in forearm blood flow,
which slowly returns to baseline values, and is termed reactive hyperemia.
Digitized images of brachial artery were captured continuously for 30 seconds
before cuff inflation and for 5 minutes following cuff release, to document the
54
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

endothelial-dependent vasodilator response. baFMD was calculated from the
brachial artery diameter at baseline (D0) and 1min after cuff deflation (D1). baFMD
is expressed as the percentage change of brachial artery diameter 1min after cuff
deflation relative to the baseline [baFMD = (D1−D0)/D0×100; D0= diameter at
baseline, D1=peak diameter after cuff deflation].

Vascular wall thickening. Vascular wall thickening was evaluated measuring
cIMT. Participants lied in the supine position on the plinth to assess the both
common carotid arteries (left and right) using B-mode ultrasound (GE LOGIQ e),
which directly scans carotid arteries. This was measured non-invasively after a 12-
hr fast and abstinence from alcohol, caffeine, and vitamins. The ultrasound scan
provided measures of lumen diameter, intima media thickness, and presence and
extent of plaques in millimeter. To measure cIMT, carotid bifurcation was detected
as a reference. Ultrasound caliper automatically detect the far wall along a 10mm
long section proximal to carotid bifurcation, where a bright-dark bright pattern
corresponding to the intima media adventitia layers of the vascular walls. By
means of auto detection of ultrasound caliper, we were able to reduce the
subjectivity of manual approaches and detect the cIMT throughout the artery
length, not only in a few points of cIMT, which leads to more precise results.

Covariate Assessments. Physical activity levels and dietary intake were
assessed through questionnaires. The International Physical Activity Questionnaire
55
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

(Appendix 1) has been validated in adults over the age of 18 with varying activity
levels across 12 countries (Van Holle et al., 2015), and was used to determine the
average current volume of activity over 1 week in metabolic equivalents (METs). In
addition, participants completed a 3-day dietary food log (Appendix 2) which
recorded food intake over 2 weekdays and 1 weekend day. A 3-day diet recall was
designed to get an accurate description of a typical daily diet. Participants were
asked to record all types of food and beverage and the amounts as accurate as
possible. Daily energy consumption (kilocalories) and daily macronutrient (g) intake
were assessed for each participant using Nutritionist Pro software (Axxya System,
Stafford, TX).

Statistical Analysis. Patient characteristics were analyzed by descriptive
statistics. Distribution of outcomes were evaluated and presented as mean (SD) for
continuous outcomes and frequency (%) for categorical outcomes. Comparisons of
baseline patient characteristics between groups were made using t-test or non-
parametric corollary for continuous outcomes and 
2
test for categorical outcomes.
Given the small sample size (N = 30), baseline confounders with a difference of p <
.25 were considered as additional covariates after testing for collinearity. For
outcome measures, the changes in cIMT and baFMD from baseline to week 9
were examined by a paired t-test (within treatment group) and two-way repeated
measures ANOVA (to compare between treatment groups), with a level of
significance set at p<0.05. Repeated measures ANOVA on the trial outcomes was
56
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

a 2 (group: HIIT, DEL) x 2 (time: pre-, post-intervention) analysis. Participant
baseline characteristics that were different across groups were included as
covariates in the statistical analyses. Specifically, a repeated measures ANCOVA
model was performed with treatment group and time (pre/post assessment) as
factors. Residual analyses were performed to test whether the assumptions of the
model were met. If the residuals did not meet the assumptions, data
transformations was performed. All analyses were performed with SPSS (v.22).

Results
The study CONSORT diagram is reported in the Chapter III (Figure 5). Briefly, we
assessed 58 women for eligibility of which 30 were randomized to the HIIT or DEL
group. Baseline characteristics were reported in Chapter III (Table 2) and were
similar across the two groups. On average, participants were 46.9± 9.8 years old
years old, Hispanic white (73%), with a BMI 31.0 7.5 kg/m
2
. Participants were
diagnosed primarily with stage II (30%) or III (63%) breast cancer and largely
treated with neoadjuvant chemotherapy (77%). High attendance of 82% (overall
average 46 of 48 sessions) was attained by the HIIT group. Adherence with HIIT,
and the average weekly minutes of exercise completion out of 90 min per week
was 95%. No adverse events were reported over the duration of the intervention.
baFMD outcomes are displayed in Table 4. At baseline, there were no
differences in diameters between groups (p= 0.87). Post-exercise, baFMD
significantly increased from baseline in the HIIT group (wk 0: 12.65±6.83%, wk 9:
57
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

16.93±4.06%; 33.8% increase) when compared to baseline and the DEL group
(P=0.005). In the DEL group, baFMD significantly decreased from baseline (wk 0:
13.21±4.06%, wk 9: 6.06±2.96%; 54.1% decrease, P<0.001). The Cohen’s d effect
size using the pooled standard deviation for the changes in baFMD was 0.63 (SD
of change=4.5).
cIMT outcomes are displayed in Table 4. At baseline, there were no
differences in cIMT between the two groups (p=0.52). No significant change in
cIMT [0.003, 95% CI: (-0.004, 0.009), P=0.40] was observed in the HIIT group
(0.591±0.089 to 0.589±0.092 mm; -0.7%) compared to the DEL group. However,
cIMT significantly increased from baseline to post intervention in the DEL group
(0.622±0.094 to 0.631±0.098 mm, P=0.003). The Cohen’s d effect size using the
pooled standard deviation for the changes in cIMT was 0.53 (SD of change=0.02).

58
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

Table 4. Mean differences on baFMD and CIMT between HIIT and DEL groups
across the 8 week intervention
Variable Baseline,
mean (SD)
Post-intervention,
mean (SD)
Between Group
Difference Post
intervention
Mean (SD) Mean (SD) P Mean (95% CI) P
baFMD (%)
HIIT group
DEL group

12.65 (6.83)
13.21(4.06)

16.93 (9.07)
6.06 (2.96)

0.005
*
<0.00
1*

10.87 (5.82,
15.92)

0.001
†

cIMT (mm)
HIIT group
DEL group

0.591 (0.084)
0.622 (0.091)

0.589 (0.098)
0.631 (0.111)

0.40
0.003
*

-0.04 (-0.11,
0.03)

0.23

Values are mean±SD. baFMD, brachial artery flow-mediated dilation; cIMT, carotid
intima media thickness; HIIT, high intensity interval training; DEL, delayed.
Significance values are reported from between group and between time points
repeated measures ANCOVA.
* P <0.05 baseline versus post intervention values
†P <0.05 group x time interaction

Discussion
A supervised 8 week HIIT intervention led to significant improvements in baFMD
and the maintenance of cIMT among breast cancer patients receiving
anthracycline-based chemotherapy. This is the first study to our knowledge to
significantly improve vascular endothelial function with a HIIT intervention in an
ethnically-diverse obese breast cancer patients during anthracycline-based
chemotherapy.
Despite this being a pilot study, our findings are promising given that
vascular endothelial function significantly improved (21.9%) in breast cancer
59
High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

patients within a short time frame of 8 weeks during anthracycline-based
chemotherapy, and participants in the DEL group experienced worsened vascular
endothelial function (-54%). Our results align with those of Jones et al. (2013) who
reported that a 12-week of aerobic exercise intervention (cycle ergometer 30-45
min/session; progressively increased intensity of 60-100 VO2max) increased
baFMD (12%; P=0.07) in neoadjuvant breast cancer patients undergoing 12 weeks
of anthracycline-based chemotherapy (Jones et al., 2013). It is plausible that our
study resulted in a greater increase in baFMD due to the interval-training nature of
the exercise prescription, duration of exposure to anthracycline-based
chemotherapy and intervention, and ethnically diverse sample with higher
percentage of Hispanic patients in the present study. Further, it is possible that
higher or lower improvement in baFMD could have been identified if we chose
other types of HIIT protocols such as 4min high intensity:3min low intensity interval
protocol(Baguley et al., 2017; Ellingsen et al., 2017) or 1min high intensity:1 min
low intensity interval protocol (Kampshoff et al., 2015).
We have a higher percentage of Hispanic participants and this could have
influenced our results because different levels of baFMD have been reported in a
previous study (Kershaw et al., 2017). Kershaw et al. (2017) reported that baseline
baFMD is different in ethnic groups of Black (baFMD: 23%), Chinese (baFMD:
14.3%), Hispanic (baFMD: 25.9%), and White (baFMD: 36.8%) adults who were
aged 45-84 years in a total of 3,027 participants but no statistical analyses were
reported in terms of effects of ethnicity on baFMD (Kershaw et al., 2017). In
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relation to our study, there is limited evidence demonstrating the relationship
between Hispanic ethnicity and baFMD following an exercise intervention.
Therefore, future studies are necessary to reveal the relationship between ethnicity
and baFMD, particularly in conjunction with an exercise intervention and
anthracycline-based chemotherapy.
We found that baFMD was significantly reduced in the DEL group. This
finding is particularly important because previous studies assessing baFMD in
leukemia who received anthracycline-based chemotherapy have shown significant
impairments in baFMD following anthracycline-based chemotherapy (5.6±3.5% to
0.3±1.6; 95% decrease) (Vassilakopoulou et al., 2010). The less negative changes
of baFMD reported in the DEL group of our sample compared to the previous study
may partly be due to less duration of chemotherapy (8 weeks) compared to the 18
week of chemotherapy in the previous study, and the inclusion criteria of worse
clinical case since the previous study included 5 metastatic cancer patients out of
27 women.
We did not observe significant group by time interaction on cIMT following
the 8-week in the HIIT group. cIMT was maintained in the HIIT group following the
8-week anthracycline-based chemotherapy. This finding may be clinically important
in that cIMT did not worsen during anthracycline-based chemotherapy while cIMT
in the DEL group worsened (1.3%). No significant improvements in cIMT in the
HIIT group may be due to the short duration of the exercise intervention yet direct
comparisons to published literature are not possible since this is the first study to
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examine cIMT with an exercise intervention in breast cancer patients undergoing
chemotherapy. A meta-analysis with 371,970 patients of cIMT and CVD risk
revealed that a change of 0.1mm in cIMT increases future risk of myocardial
infarction 10-15% and stroke risk by 13-18% (Lorenz et al., 2007). While our study
did not observe the cIMT change of 0.1mm in our study participants, possibly due
to the short period of intervention, it is necessary to identify the long term effects of
anthracycline-based chemotherapy on cIMT in breast cancer patients.
While there is no direct evidence supporting the association between cIMT
and exercise in breast cancer, the effects of exercise on cIMT have been studied in
non-cancer populations. Park et al. (2017) reported a decrease in cIMT in obese
older women (65-77 years old) without a history of breast cancer following 6
months of aerobic and resistance (40-50 walking, 20-30 min resistance band
exercise; 5 days per week) (Park and Park, 2017b). Similarly, Byrkjeland et al.
(2016) reported that 12 month resistance and aerobic exercise (150 min weekly)
significantly decreased cIMT in patients with type 2 diabetes and coronary artery
disease (Byrkjeland et al., 2016). Notably, the duration of these two studies may
suggest that a minimum of 6-12 months of exercise would elicit a positive effect on
cIMT. Further, study participants in the previous studies did not undergo any
cancer treatment during the intervention, thus improvements in cIMT in cancer
patients may take longer to induce than non-cancer populations without a history of
cancer treatment.
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Strengths of this study include a focus on a single cardio-toxic
chemotherapy with a lower volume exercise intervention, diverse sample, and a
randomized controlled design. Particularly, our study participants were obese and
sedentary breast cancer patients, which may have induced higher significant
results than expected, due to the worse vascular endothelial function reported in
obese sedentary individuals. Although this study provides the first evidence of a
novel exercise approach targeting vascular endothelial function in breast cancer
patients undergoing anthracycline-based chemotherapy, we acknowledge
limitations in our design. We were not adequately powered to find statistically
significant improvements in the outcome measures. A possible mechanism to
improve baFMD may result from improved insulin sensitivity in addition to the
exercise. Since our patient population was obese, it is important to consider this
mechanism as a means for any observed improvements in vascular endothelial
function, as the exercise may have improved insulin resistance and subsequently
vascular endothelial function. Insulin resistance is the central mediator in
developing vascular endothelial dysfunction, and previous studies have shown that
HIIT improves vascular endothelial dysfunction in patients with type 2 diabetes
(Afousi et al., 2018; da Silva et al., 2016; Qiu et al., 2018).
In summary, the results of the current study underline the effects of HIIT on
vascular endothelial function in breast cancer patients undergoing anthracycline-
based chemotherapy. Given that anthracycline-based chemotherapy is typically
used in the (neo)adjuvant setting in breast cancer patients with a high survival
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Chemotherapy

expectancy emphasizes the need to elucidate all aspects of anthracycline-related
vascular endothelial function and to identify effective exercise interventions to
protect the endothelium against anthracycline-induced toxicity.

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Chemotherapy

CHAPTER V. EFFECTS OF HIGH INTENSITY INTERVAL TRAINING ON
MATRIX METALLOPROTEINASES IN BREAST CANCER PATIENTS WITH
RECEIVING ANTHRACYCLINE-BASED CHEMOTHERAPY

ABSTRACT
Introduction Anthracycline-based chemotherapy is one of the most commonly
used neoadjuvant or adjuvant chemotherapy for all stages of breast cancer, yet its
clinical use has been associated with vascular endothelial dysfunction.
Anthracyclines-induced overexpression of MMP-2 and MMP-9 is associated with
the development of atherosclerosis, hypertension and heart failure. While high
intensity interval training (HIIT) has been utilized to improve vascular endothelial
dysfunction measured by brachial artery flow-mediated dilation in patients with
breast cancer, it is unclear whether HIIT reduces MMP-2 and -9 levels in breast
cancer patients undergoing anthracycline based chemotherapy. The aim of this
study was to determine the effects of an 8-week HIIT intervention on ECM-
regulating enzymes in early stage breast cancer patients receiving anthracycline-
based chemotherapy.
Methods Thirty women were randomized to either HIIT or delayed groups (DEL).
The HIIT group participated in an 8-week HIIT intervention occurring 3 times per
week on a cycle ergometer. The DEL group was offered the HIIT intervention after
8 weeks. Outcomes were measured at week 0 and week 9. MMP-2 and -9 were
tested as a single batch at study completion and processed using the magplex
suspension bead array immuno-assays on a Luminex 100 Bioanalyzer (Luminex
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Chemotherapy

100, Luminex Corporation, Austin, Texas) according to the kit manufacturer’s
instructions (Milliplex ELISA kits, Millipore, MA).
Results: There was a significant within-group decrease in MMP-9 in the HIIT
group (-37.4%; P=0.01) while MMP-9 in the DEL group was not significantly
changed (-21.7%; P=0.10) following 8 weeks. Unexpectedly, a significant within-
group increase in MMP-2 was observed in both HIIT group (8.6%; P=0.007) and
the DEL group (12.6%; P=0.003).
Conclusion: HIIT significantly ameliorated levels of MMP-9 in breast cancer
patients undergoing anthracycline-based chemotherapy yet MMP-2 was
unexpectedly increased. Further investigations are required to understand the
underlying mechanisms of exercise-induced changes in ECM-regulating enzymes
in breast cancer patients undergoing anthracycline-based chemotherapy.

INTRODUCTION
Anthracycline-based chemotherapy is one of the most commonly used
neoadjuvant or adjuvant chemotherapy for all stages of breast cancer, yet its
clinical use has been associated with vascular toxicity (Sawyer, 2013). The
vascular toxicity of anthracycline-based chemotherapy may be due to oxidative
stress which degrades the structure of the extracellular matrix (ECM) (Nikitovic et
al., 2014). The ECM surrounding vascular endothelial cells, also known as
endothelial ECM, is mainly regulated by enzymes called matrix metalloproteinases
(MMPs) (Ishihara et al., 2008; Vacek et al., 2015); the overexpression of certain
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MMPs (i.e., MMP-2 and -9) cause vascular endothelial dysfunction in patients with
coronary artery disease (Azevedo et al., 2014; Ceron and Luizon, 2016). Increased
levels of MMP-9 promotes plaque development in vasculature (Amin et al., 2016),
and elevated level of MMP-9 is associated with the development of
atherosclerosis, hypertension and heart failure (Kishimoto et al., 2017).
Particularly, anthracyclines increase the level of reactive oxygen species which
causes the overexpression MMP-2 and MMP-9 (Kandasamy et al., 2010; Kelly et
al., 2008; Nagareddy et al., 2012). The nature of anthracycline-induced alterations
in ECM-regulating enzymes provides a strong rationale for the design and testing
of intervention strategies (i.e., exercise) to improve vascular endothelial function,
and ultimately the overall cardiovascular disease (CVD) mortality in breast cancer
patients.
MMP-2 and -9 have been targeted with exercise interventions in patients
with CVD, type 2 diabetes, metabolic syndrome, and breast cancer. For instance,
previous studies have reported that a 16-week moderate-intensity brisk walking
program (150 min/week) significantly reduced MMP-9 in patients with type 2
diabetes (Kadoglou et al., 2010) or MMP-2 in cancer patients 10 years post-
surgery (Giganti et al., 2016). While there is evidence showing that moderate-
intensity aerobic exercise training may decrease MMP-2 and -9 levels in clinical
research settings, high intensity interval training (HIIT) has never been utilized, to
our knowledge, to reduce MMPs levels in any population. HIIT is an exercise
strategy that maximizes exercise intensity by using bursts of concentrated effort
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alternated with recovery periods (Cockcroft et al., 2015). HIIT allows clinical
patients to perform vigorous intensity exercise due to the ‘on-off’ pattern of
exercise. The “on” portion of HIIT typically involves 1-4 minutes performed at 80%-
90% of peak power output (PPO), followed by the “off” period (2-3 minutes active
break (10% PPO) (Adams et al., 2015). This strategy has been shown to be more
effective than moderate continuous intensity aerobic exercise for improving
endothelial function among individuals with stroke or coronary artery disease
(Boyne et al., 2015; Currie et al., 2015; Sawyer et al., 2014). It is plausible that
breast cancer patients undergoing anthracycline-based chemotherapy may
experience benefits of exercise due to the over-expression of MMPs caused by the
exposure to anthracyclines.
The aim of this study was to determine the effects of an 8-week HIIT
intervention on ECM-regulating enzymes in early stage breast cancer patients
receiving anthracycline-based chemotherapy. We hypothesized that an 8-week
HIIT intervention decreases circulating serum MMP-2 and -9 in the HIIT group
compared to the DEL group.

Methods
Participants/Consent. Eligible participants were 1) women >18 years of age
diagnosed (I-III) with a primary invasive breast cancer; 2) planned (neo)adjuvant
anthracycline chemotherapy; 3) able to initiate exercise program within 1 week of
initiation of anthracycline-based chemotherapy; 4) currently participate in less than
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30 minutes of physical activity per week; 5) nonsmokers (i.e. not smoking during
previous 12 months); 6) willing to travel to the exercise facility at the University of
Southern California (USC); 7) able to provide physician clearance to participate in
the exercise program; 8) speak English and Spanish as a primary language. The
exclusion criteria were: 1) history of chronic disease including diabetes
uncontrolled hypertension or thyroid disease; 2) weight reduction > 10% within past
6 months; 3) metastatic disease; 4) overt CVD (myocardial infarction, stroke,
angina and etc.); 5) contra-indications to exercise; 6) participation in regular
exercise. Recruitment occurred between August 15
th
, 2017 and August 6
th
, 2018
from the USC Norris Comprehensive Cancer Center and Los Angeles County
Hospital. The protocol and informed consent were IRB-approved (HS-15-00227)
and registered (ClinicalTrials.gov: NCT02454777). A signed informed consent was
obtained from each participant. Once the potential patient has signed the informed
consent and trial eligibility was confirmed, participants were randomly assigned by
computer-generated, investigator-blinded randomization assignments;
randomization was stratified by neoadjuvant versus adjuvant anthracyclines
treatment in a 1:1 allocation ratio by the clinical Investigation Support Office USC
Norris Comprehensive Cancer Center. Participants were randomized to the HIIT
group or delayed (DEL) group following the completion of baseline testing using
concealed randomization lists.

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Experimental Design. This pilot study compared HIIT group versus DEL group
baseline to post-intervention of 8-week changes in MMPs. Participants were
recruited from the breast cancer clinics at the Norris Comprehensive Cancer
Center and the Los Angeles County Medical Center. Following informed consent,
eligible participants completed baseline tests (week 0) test at the Integrative Center
for Oncology Research in Exercise (ICORE) within one week prior to the start of
the intervention. Participants randomized to the HIIT group visited the ICORE to
complete the exercise sessions for a total of 90 min of weekly exercise during the
8-week intervention period. Participants randomized to the DEL group were asked
to maintain their current level of physical activity, which was defined as less than
30 min of total exercise per week. All participants returned to the ICORE within 1
week following completion of the 8-week study period for post-intervention (week
9). To enhance participation, participants in the DEL group were offered the same
HIIT intervention following the 8-week study period.

Exercise Intervention. All supervised exercise sessions took place at the
Integrative Center for Oncology Research (ICORE) in Exercise in the Division of
Biokinesiology and Physical Therapy at the University of Southern California
(USC). Participants were asked to perform 3 supervised one-on-one exercise
sessions/week. Participants assigned to the HIIT group received supervised
exercise sessions performed on a stationary bike (Life Fitness 95 Elevation Series,
Rosemont, IL). Relative exercise intensity was individually prescribed for the HIIT
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Chemotherapy

group based on peak power output (PPO), which was measured by a VO2max
fitness testing performed on a stationary bike. Each exercise session consisted of
a 5-minute warm-up performed at 10% PPO, followed by a 20 minute HIIT
protocol. The HIIT protocol consisted of 7 bouts of 1 minute high intensity exercise
(90% of PPO) followed by 2 minutes of active recovery (10% of PPO). Participants
were encouraged to complete each exercise session with at least 24 hours of rest
between each session and to complete sessions on days when they did not
receive anthracycline infusions. Power output, heart rate, rating of perceived
exertion (RPE; rated on the Borg scale of 6-20, Appendix 4), and total minutes of
exercise were documented for each session and for each interval (Appendix 6).
Participants were encouraged to make up any missed sessions in the same week.
Participants in the DEL group were asked to maintain less than 30 minutes of total
structured exercise per week during the 8 week study period. After the 8-weeks of
intervention, the DEL group was provided the same HIIT intervention.

Outcome measures: MMP-2 and -9. A fasting venous blood sample was obtained
from each participant by a licensed phlebotomist. Obtained blood samples were
centrifuged at 3,000rpm for 10 minutes, and the serum portion was pipetted into
0.5 mL aliquots using a sterile pipette. Aliquots were stored at -80°C until further
processing. Participants in the HIIT group were requested to avoid any strenuous
physical activity for at least 48 h before blood sampling at baseline (week 0) and
post-intervention (week 9). MMP-2 and -9 were tested as a single batch at study
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completion and processed using the magplex suspension bead array immuno-
assays on a Luminex 100 Bioanalyzer (Luminex 100, Luminex Corporation, Austin,
Texas) according to the kit manufacturer’s instructions (Milliplex ELISA kits,
Millipore, MA) by the Metabolism Core Laboratory/Human Physiology laboratory of
the University of Alabama Birmingham. Specifically, 50 ml of each serum sample
were incubated with fluorokine-coloured microspheres coated with specific
antibodies, and analytes were allowed to bind to the specific antibody-coated
microspheres. Samples were then washed and incubated with biotinylated
antibodies and phycoerythrin-conjugated streptavidin. Finally, fluorescence were
detected using a flow cytometry technique (Luminex 100, Luminex Corporation,
Austin, Texas). All samples were assayed in triplicate wells (25 uL per well), and
the mean of these results was used. MMPs concentration was calculated by
reference to an eight-point spline fit curve.

Statistical analyses Baseline participant characteristics were analyzed by
descriptive statistics. Distribution of outcomes were evaluated and presented as
mean (SD) for continuous outcomes and frequency (%) for categorical outcomes.
Comparisons of baseline participant characteristics between groups were made
using t-test or non-parametric corollary for continuous outcomes and 
2
test for
categorical outcomes. Given the small sample size (N = 30), baseline confounders
with a difference of P<0.10 were considered as additional covariates after testing
for collinearity. For outcome measures, the changes in MMPs from baseline to
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Chemotherapy

week 9 (within group difference) were examined by a paired t-test and two-way
repeated measures ANOVA (between group difference), with a level of significance
set at P<0.05. Repeated measures ANOVA on the trial outcomes was a 2 (group:
HIIT, DEL) x 2 (time: baseline, post-intervention) analysis. Participant baseline
characteristics that were different across groups were included as covariates in the
statistical analyses. Specifically, a repeated measures ANCOVA model was
performed with treatment group and time (baseline/post-intervention) as factors.
Cohen’s d effect size for the changes in MMPs was calculated using the difference
in means from baseline and post-intervention and the pooled standard deviations.
Specifically, a repeated measures ANCOVA model were performed with treatment
group and time (pre/post assessment) as factors. All analyses were performed with
SPSS (v.22).

Results
The study CONSORT diagram is presented in the chapter 3 (Figure 5). Briefly, we
assessed 58 women for eligibility of which 30 were randomized to the HIIT or DEL
group. Baseline characteristics are reported in the Table 2, and were similar across
the two groups. On average, participants were 46.9±9.8 years old years old,
Hispanic white (73%), with a BMI 31.0±7.5 kg/m2. Participants were diagnosed
primarily with stage II (30%) or III (63%) breast cancer and largely treated with
neoadjuvant chemotherapy (77%). High attendance of 82.3% (overall average 19.2
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Chemotherapy

of 24 sessions) was attained by the HIIT group. No adverse events were reported
over the duration of the intervention.
MMPs outcomes are displayed in Table 5. At baseline there were no
differences in MMPs (-1, -2, -7, -9 and -10) between the two groups. Post-
intervention, there was no significant group (HIIT vs DEL) x time (Pre vs Post)
interaction on MMP-2 (P=0.53) and -9 (P=0.28). Unexpectedly, a significant within-
group increase in MMP-2 was observed in both HIIT group (8.6%; P=0.007) and
the DEL group (12.6%; P=0.003). However, there was a significant within-group
decrease in MMP-9 in the HIIT group (-37.4%; P=0.01) while MMP-9 in the DEL
group was not significantly changed (-21.7%; P=0.10) following 8 weeks. The
Cohen’s d effects size using the pooled standard deviation for the change in MMP-
9 was 0.17.

Table 5. Comparison of MMP-2 and -9 between HIIT and DEL groups
Variable Baseline,
mean (SD)
Post-intervention Between Group
Difference Post
intervention
Mean (SD) Mean (SD) P Mean (95% CI) P
MMP-9 (ng/ml)
HIIT
DEL

104.3 (51.9)
115.5 (47.2)

65.2 (69.1)
90.4 (67.9)

0.01*
0.10
-46.4 (-80.4 to
12.4)
0.65
MMP-2 (ng/ml)
HIIT
DEL

76.6 (11.2)
69.0 (8.9)

83.2 (13.1)
77.6 (11.1)

0.007*
0.003*
6.5 (2.1 to 10.9) 0.53
HIIT, high intensity interval training; DEL, delayed; MMP, matrix metalloproteinases
*P value denotes significant change in outcome measure at the p<0.05 level by
paired t-test comparing changes in the HIIT group from baseline to post-
intervention, and in the DEL group from baseline to post-intervention
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Discussion
Our results demonstrate for the first time that an exercise intervention, specifically
HIIT, can alter ECM-regulating enzymes in cancer patients. The 8-week HIIT
intervention significantly reduced MMP-9 levels in breast cancer patients
undergoing anthracycline-based chemotherapy yet increased MMP-2 level. To our
knowledge, this is the first study to demonstrate significant exercise-related
amelioration of MMP-9 in cancer patients undergoing anthracycline-based
chemotherapy.
The reduction in MMP-9 resulting from our HIIT intervention is similar to
previous exercise studies in non-cancer and cancer populations. To date, one
exercise intervention led to reductions in serum MMP-9 level (Kadoglou et al.,
2010). Kadoglou et al. (2010) reported a significant decrease in serum MMP-9 after
a 16-week supervised endurance training (30-60 min of brisk walking; 4
days/week) in patients with type 2 diabetes (Kadoglou et al., 2010). To our
knowledge, only one study has been conducted to examine the effect of exercise
on MMPs in breast cancer survivors who completed cancer treatment (10 years
post-surgery) (Giganti et al., 2016). Breast cancer patients who regularly
participated in exercise (30 min treadmill plus 20 min strength training; 3 times a
week) had significantly lower MMP-9 levels compared to breast cancer patients
who did not participate in the exercise intervention, however the latter group lacked
a baseline measure of MMPs. Although it is difficult to compare our findings with
the previous studies due to different exercise protocols and disease status (i.e.
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Chemotherapy

breast cancer vs type 2 diabetes), HIIT in our study resulted in significant decrease
in MMP-9 with a lower volume of exercise (90 min vs 150 min per week) over fewer
number of weeks (8 vs 16 weeks). Further, it is important to note that higher or
lower improvements in MMP-2 and -9 may have been identified if we chose other
types of HIIT protocols such as a 4min high intensity:3min low intensity interval
protocol (Baguley et al., 2017; Ellingsen et al., 2017) or 1min high intensity:1 min
low intensity interval protocol (Kampshoff et al., 2015). Physiologically, HIIT-
induced improvements in vascular endothelial function are mainly due to elevated
shear stress which decreases oxidative stress (Gurovich et al., 2011; Scharf et al.,
2015). The elevated shear stress may be maintained longer when longer duration
of high intensity is performed (Afousi et al., 2018). Collectively, this mechanism
may offset anthracycline-induced vascular endothelial dysfunction at higher level
than shorter duration of HIIT protocol. However, there is no direct evidence
comparing between different types of HIIT protocols on MMP levels. Future studies
are warranted to identify the optimal HIIT protocols to ameliorate negative impact
of anthracycline-based chemotherapy on MMPs in breast cancer patients.
While we hypothesized that HIIT would reduce MMP-2 levels in breast
cancer patients undergoing anthracycline-based chemotherapy, MMP-2 levels
were significantly increased in the HIIT group as well as DEL group following 8
weeks. Increased MMP-2 and -9 levels are expected due to the nature of
anthracycline-based chemotherapy (Ivanova et al., 2012b; Potacova et al., 2006).
As MMP-2 levels were not improved by an 8-week HIIT intervention, it is plausible
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that the exercise intervention was not adequate to offset the negative influence of
anthracycline-based chemotherapy on this enzyme. This finding is consistent with
a previous finding of Kadoglou et al. (2010) (Kadoglou et al., 2010) in that exercise
training did not alter MMP-2 level in type 2 diabetics. In addition, Donley et al.
(2014) showed that an 8-week aerobic exercise training (3 times/week, 60 min per
day, 60-85% heart rate reserve) in patients with metabolic syndrome did not result
in changes in MMP-2 (Donley et al., 2014). Therefore, exercise may not be an
effective non-pharmacologic strategy to target MMP-2. However, it is difficult to
generalize these findings due to the variability within the exercise protocols and
clinical cohorts involved. Perhaps, exercise training including HIIT, moderate
intensity aerobic exercise, or strength plus aerobic exercise may not influence the
activity of MMP-2 level in 8-16 weeks. Future studies are needed to examine
whether a longer duration of exercise training alters MMP-2 level in breast cancer
patients who completed anthracycline-based chemotherapy.
Potential biologic mechanisms exist that may explain our findings. Exercise
reduces pro-inflammatory cytokines, which, although not measured, may have
occurred in our study. Previous studies reported that MMP-9 was reduced in
conjunction with tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and
intercellular adhesion molecule-1 (ICAM-1), with no change in MMP-2 (Ma et al.,
2009; Ohta et al., 2017). Evidence derived from a mouse model indicates that
MMP-9 expression is elevated during inflammation (Manicone and McGuire, 2008;
Oh et al., 2006), suggesting that the pro-inflammatory cytokines may increase
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Chemotherapy

MMP synthesis (Reihmane et al., 2013). It is possible that pro-inflammatory
cytokines in the ECM were reduced by exercise, which subsequently reduced
MMP-9 levels. Future investigations are warranted to assess exercise-induced
changes in inflammation and ECM-regulating enzymes to understand mechanism
by which exercise influences MMP levels.
The strengths of our study included: 1) direct one-on-one supervision of all
exercise sessions, 2) high adherence of 82.3%; previous studies investigating
MMPs did not report the adherence to exercise (Donley et al., 2014; Giganti et al.,
2016; Kadoglou et al., 2010); 3) focus on a single chemotherapeutic agent so the
effects of exercise on MMPs with chemotherapy can be clearly understood.
Despite these strengths, we acknowledge the following limitations. Since this study
was designed as a pilot study, the small sample size is notable. Compared to the
sample size (n=22-50) reported in the previous reports on the effects of exercise
on MMPs, our study sample size (n=30) was in the similar range of those studies
(Donley et al., 2014; Giganti et al., 2016; Kadoglou et al., 2010). Since our patient
population was mostly obese who may be insulin resistant, it is possible that our
findings may be the result of improvements in insulin sensitivity (Unal et al., 2009).
In conclusion, HIIT significantly ameliorated levels of MMP-9 in breast
cancer patients undergoing anthracycline-based chemotherapy yet MMP-2 was
unexpectedly increased. Further investigations are required to understand the
underlying mechanisms of exercise-induced changes in ECM-regulating enzymes
in breast cancer patients undergoing anthracycline–based chemotherapy.
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Chemotherapy

CHAPTER VI: SUMMARY AND CONCLUSIONS

Anthracycline-based chemotherapy, a primary cancer treatment for all stages of
breast cancer, is associated with adverse effects on numerous vascular function
measures, including baFMD, cIMT, and MMPs. Due to these adverse effects,
women receiving anthracycline-based chemotherapy may be at greater risk for
future cardiovascular events. It is evidenced that exercise interventions improve
these parameters of vascular function in patients with CVD, but this area is
relatively unexplored in women receiving anthracycline-based chemotherapy.
Aerobic exercise has been acknowledged as a key strategy in improving baFMD
and cIMT in clinical settings. However, a growing body of evidence supports HIIT,
a method of aerobic exercise that may elicit greater benefits on vascular
endothelial function. Because the effect of HIIT on vascular endothelial function in
breast cancer patients undergoing anthracycline-based chemotherapy is not well
understood, a mechanistic understanding of the signaling pathways underlying
vascular endothelial function in response to HIIT may unveil novel approaches to
reducing complications of anthracycline-based chemotherapy.
The purpose of this dissertation was to evaluate the feasibility and the
effects of an 8-week HIIT intervention on vascular endothelial function in breast
cancer patients undergoing anthracycline-based chemotherapy. This study was the
first study to employ a HIIT intervention which specifically incorporated high
intensity into an exercise intervention while undergoing anthracycline-based
chemotherapy. The first aim was conducted to examine if implementing HIIT in
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Chemotherapy

breast cancer patients was feasible while undergoing anthracycline-based
chemotherapy, where an average of weekly minutes attended and sessions of
exercise completed were measured. The second aim evaluated outcomes related
to vascular function, where changes in baFMD, and cIMT were examined. The
third aim investigated changes in ECM-regulating enzymes by measuring serum
blood markers MMP-2 and -9.
Results for the first aim demonstrated that implementing an 8-week HIIT
intervention is feasible, as hypothesized, while undergoing anthracycline-based
chemotherapy. In particular, the mean adherence to sessions attended out of 24
sessions was 82.3%. The adherence to HIIT was higher than other previous
studies reported 68-72% of adherence to exercise during chemotherapy. Overall,
80% (12 of 15) of HIIT participants met both criteria: 19.2±2.1 (mean±SD) of 24
sessions were attended, and an average of 78±5.1 (mean±SD) of 90 weekly
minutes of exercise were completed over 8 weeks with no adverse events. This
study was the first to evaluate the feasibility of HIIT prescribed by individual’s PPO
in breast cancer patients. Utilizing PPO is important since breast cancer patients
have varying resting/maximal heart rates and heart rate recovery during
chemotherapy (within subject variability), utilizing heart rate to prescribe intensity
does not ensure that participants will be exercising at a high intensity. As our study
cohort successfully performed a HIIT intervention prescribed by PPO, HIIT
prescribed by PPO is a useful method for prescribing/performing HIIT in breast
cancer patients undergoing anthracycline-based chemotherapy. PPO may be a
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
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more valid method of prescribing intensity in this population because it is a direct
measure of the rate of external work performed.
In concordance with our hypothesis, findings from the second aim
demonstrated that an 8-week HIIT intervention was effective at improving vascular
endothelial function measured by baFMD. This is the first study to our knowledge
to significantly improve vascular endothelial function with a HIIT intervention
involved in ethnic minority sample of obese breast cancer patients receiving
anthracycline-based chemotherapy. Another important finding was that baFMD
was significantly reduced in the DEL group who maintained their sedentary
lifestyle. This emphasizes the importance of an exercise intervention which may
prevent vascular endothelial dysfunction during anthracycline-based
chemotherapy. Our results align with a previous study which reported that a 12-
week of aerobic exercise intervention increased baFMD in neoadjuvant breast
cancer patients undergoing 12 weeks of anthracycline-based chemotherapy (Jones
et al., 2013). It is plausible that our study resulted in a greater increase in baFMD
due to the interval-training nature of the exercise prescription, duration of exposure
to anthracycline-based chemotherapy and intervention, and diverse sample in the
present study. The mechanisms were likely to offset anthracycline-induced
oxidative stress by a HIIT intervention. However, future studies are necessary to
identify the molecular signaling pathways related to the role of exercise in
regulating oxidative stress and vascular endothelial function during anthracycline-
based chemotherapy.
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

We examined cIMT as an exploratory aim and found that an 8-week HIIT
intervention maintained cIMT during the course of anthracycline-based
chemotherapy. This finding is particularly important in that cIMT did not worsen
during anthracycline-based chemotherapy in the HIIT group while cIMT worsened
(1.3%) in the DEL group. Although direct comparisons to published literature are
not possible since this is the first study to examine cIMT with an exercise
intervention in breast cancer patients undergoing chemotherapy, other clinical
exercise studies suggested that a minimum of 6-12 months of exercise would elicit
a positive effect on cIMT (Park and Park, 2017a); therefore, it is plausible that our
8-week intervention was not long enough to induce improvements in cIMT in
cancer patients undergoing chemotherapy.
Findings from the third aim showed that, as hypothesized, MMP-9 was
reduced in response to 8 weeks of HIIT. Unexpectedly, MMP-2 was elevated in
both HIIT group and DEL groups following the 8-week study duration. This finding
is consistent with a previous finding of a previous study in that exercise training did
not alter MMP-2 level in type 2 diabetes (Kadoglou et al., 2010). Therefore,
exercise may not be an effective non-pharmacologic strategy to target MMP-2.
However, it is difficult to generalize these findings due to the variability within the
exercise protocols and clinical cohorts involved. There are possible biologic
pathways by which MMPs are altered following an exercise intervention in breast
cancer patients undergoing anthracycline-based chemotherapy. Potentially, MMP-
9 level is mediated by inflammation and exercise-induced reductions in
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High Intensity Interval Training and Breast Cancer Anthracycline-Based
Chemotherapy

inflammation may have driven the reduction in MMP-9. Pro-inflammatory cytokines
in the ECM may have been reduced by exercise, which subsequently reduced
MMP-9 levels. Future investigations are warranted to assess exercise-induced
changes in inflammation and ECM-regulating enzymes to understand mechanism
by which exercise influences MMP levels.
In conclusion, this dissertation provided evidence that an 8-week HIIT
intervention designed for women with breast cancer receiving anthracycline-based
chemotherapy is feasible, and can improve vascular endothelial function. This
research employed novel approaches, including the use of a HIIT model using
PPO to accurately prescribe aerobic exercise intensity. This study was also the first
to investigate molecular biomarkers regulating vascular endothelial function in
breast cancer patients undergoing anthracycline-based chemotherapy. The
findings from this study demonstrate that HIIT can be employed to improve a range
of health outcomes such as vascular endothelial function in breast cancer patients,
particularly undergoing anthracycline-based chemotherapy. This study contributes
to the growing body of evidence in the field of cancer rehabilitation, and has the
potential to impact cancer survivorship by providing a specific strategy to offset
vascular dysfunction worsened by anthracycline-based chemotherapy, thereby
reducing the risk of cardiovascular disease mortality later in life.

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Chemotherapy

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APPENDIX

A.1 International Physical Activity Questionnaire

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APPENDIX A.2 3 day Diet Recall Form

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APPENDIX A.3 High intensity interval training for breast cancer patients
during Anthracycline Use

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APPENDIX A.4 Rating of Perceived Exertion: Borg RPE Scale

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APPENDIX A.5 Cycle Ergometer Test

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APPENDIX A.6 Weekly high intensity interval training log

Abstract (if available)

Abstract Breast cancer patients were at greater risk for cardiovascular disease (CVD) mortality, compared to age-matched women without breast cancer. CVD mortality was two times higher among breast cancer patients who receive chemotherapy. Specifically, anthracycline-based chemotherapy was of particular concern due to the impairment of vascular endothelial function and vascular wall thickness, as well as dysregulation of extracellular matrix (ECM) in vasculature induced by increased oxidative stress caused by anthracycline-based chemotherapy. One strategy to offset these impairments was a form of exercise referred to as high-intensity interval training (HIIT) which improved vascular endothelial function by decreasing the level of oxidative stress, the main cause of the anthracycline-induced vascular complication. The purpose of this study was to assess the feasibility of implementing and conducting an 8-week HIIT in breast cancer patients undergoing anthracycline-based chemotherapy. Further, we determined the effects of an 8-week HIIT on vascular endothelial function, vascular wall thickness and the ECM-regulating enzymes in breast cancer patients undergoing anthracycline-based chemotherapy. We designed a pilot study to include 30 breast cancer patients undergoing anthracycline-based chemotherapy. Following informed consent and baseline measures, participants were randomized to either the HIIT group or the delayed (DEL) group. ❧ Chapter 3 was design to determine the feasibility of HIIT in breast cancer patients undergoing anthracycline-based chemotherapy. Thirty women initiating anthracycline-based chemotherapy were randomized to either the HIIT or delayed (DEL) groups. The HIIT group participated in an 8-week HIIT intervention occurring 3 times weekly. Adherence measures used to define feasibility were calculated for each participant by computing (1) the average weekly minutes of HIIT over 8 weeks and (2) the number of sessions attended and multiplied by 100 (percentage of sessions). The HIIT intervention was considered feasible if more than 50% of participants completed both an average of 70% of weekly minutes (63/90 minutes) and attended 70% exercise sessions (17/24 sessions). Feasibility was demonstrated by: 12 of 15 participants met both feasibility criteria average weekly minutes of exercise completed was 78±5.1 out of 90 min and 19.2±2.1 out of 24 sessions (82.3%). ❧ Chapter 4 was conducted to demonstrate the effects of HIIT on vascular endothelial function and vascular wall thickness in breast cancer patients undergoing anthracycline-based chemotherapy. The HIIT group participated in an 8-week HIIT intervention occurring 3 times per week on a cycle ergometer. The DEL group was offered the HIIT intervention after 8 weeks. Outcomes were measured at week 0 and week 9. baFMD was measured from the brachial artery diameter at baseline (D0) and 1min after cuff deﬂation (D1)

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Creator Lee, Kyuwan (author)

Core Title High intensity interval training for breast cancer patients receiving anthracycline-based chemotherapy

School School of Dentistry

Degree Doctor of Philosophy

Degree Program Biokinesiology

Publication Date 03/11/2019

Defense Date 01/10/2019

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag anthracycline-based chemotherapy,breast cancer patients,high intensity interval training,OAI-PMH Harvest

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Advisor Dieli-Conwright, Christina (committee chair), Mack, Wendy (committee member), Mortimer, Joanne (committee member), Salem, George (committee member), Sattler, Fred (committee member)

Creator Email kulee2533@gmail.com,kyuwanle@usc.edu

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