CYCling Lynch Patients for Exercise and Prevention: CYCLE-P

If you agree to take part in this study, you will be asked screening questions to complete
the eligibility requirement and if you are eligible you will have the following study visits.

Study Visits:

Visit 1 (Day 0):

- You will have a lower GI endoscopy (flexible sigmoidoscopy or colonoscopy). During an
endoscopy, you will be mildly sedated and a thin, flexible tube (called an endoscope)
will be inserted inside the anus and rectum. Tissue samples will also be collected
during this procedure. Up to 15 normal tissue biopsies will be taken during these
procedures for biomarker testing, including genetic biomarkers. Biomarkers are found in
the blood/tissue and may be related to the disease and the impact of exercise on the
disease. If the doctor finds any abnormal tissue in your bowel during the procedure,
they will be counted and removed. You will sign a separate consent for this procedure
which will describe it in more detail, including its risks.

- Blood (about 1 teaspoon) and urine will be collected for biomarker testing.

- Your gums will be rubbed with a cotton swab to collect a sample of bacteria in your
mouth.

- You will be asked to collect a stool sample at home either before you are prepped for
your endoscopy or within 1 month (+/- 10 days) after your colonoscopy when you resume
your usual bowel movements (normal bowel habits). The study staff will give you detailed
instructions how to collect and then mail the stool sample. You will be given a stool
collection kit and mailer in order to ship the stool sample back to the MD Anderson. If
you consented over the phone and collected the stool sample before your endoscopy prep
visit, the stool kit will be collected at this visit.

Visit 2 (Day 15):

- You will have a cardiopulmonary exercise test (CPET) to check your lung function. The
CPET checks how well your lungs are working by measuring how much oxygen and carbon
dioxide your lungs take in and release when you breathe. To perform this test, you will
be asked to bicycle at increasingly higher resistance until you reach a point that you
can no longer exercise. You will be breathing into the machine while you cycle. This
test will take about 30 minutes to complete. The study doctor and an exercise
physiologist will be present for each CPET and available to respond to any complication.

- You will have an EKG to check your heart function.

- You will complete a questionnaire about your demographics, health history, and physical
activity.

Cycling Classes and FITBIT:

Starting at Day 15 of the study, you will enroll in 3 cycling classes every week (for a total
of 12 cycling classes each month). You will continue with these classes for up to 1 year.
These cycling classes can be done at any fitness center in your local community. You will not
be responsible for the cost of these cycling classes. You may choose any cycling class at any
location you prefer.

You will be given a FITBIT to wear while you attend cycling classes. You are encouraged to
wear the FITBIT during the day as well, but this is not required. The FITBIT will record your
exercise frequency and intensity. The exercise physiologist will tell you how to use it, if
you have any questions. The FITBIT will be yours to keep. Data from your FITBIT will be
linked to your medical record.

After Day 15, you will be contacted, either phone or email, every 2 weeks by the study staff
and asked about your FITBIT and FITBIT data and your exercise schedule. The exercise
physiologist will discuss any barriers to exercise you may be having and/or answer any
questions you may have related to physical activity, including the cycling classes.

Visit 3 (between Day 300-360):

- You will have an endoscopy as described above in Visit 1.

- Blood (about 1 teaspoon) and urine will be collected for biomarker testing.

- Your gums will be rubbed with a cotton swab to collect a sample of bacteria in your
mouth.

- You will be asked to collect a stool sample at home either before you are prepped for
your endoscopy or within 1 month (+/- 10 days) after your colonoscopy when you resume
your usual bowel movements (normal bowel habits). The study staff will give you detailed
instructions how to collect and then mail the stool sample. You will be given a stool
collection kit and mailer in order to ship the stool sample back to the MD Anderson. If
you consented over the phone and collected the stool sample before your endoscopy prep
visit, the stool kit will be collected at this visit.

Visit 4 (within 30 days after Visit 3):

- You will have a CPET to check your heart and lung function.

- You will also complete the questionnaires about your demographics, health history, and
physical activity.

Length of Study:

Your active participation in this study will be over after Visit 4. If you continue to use
the FITBIT after your participation in this study is over, the data will not be viewed,
collected, or entered into your medical record.

Inclusion Criteria:

1. Participants must have Lynch syndrome defined as meeting any of the following: (1)
Mutation-Positive Lynch syndrome: carriers or obligate carriers (by pedigree) of a
pathogenic mutation in one of the DNA mismatch repair (MMR) genes (i.e. MLH1,
MSH2/EPCAM, MSH6, or PMS2) or (2) Mutation-Negative Lynch syndrome: patients with a
personal history of a non-sporadic MMR deficient premalignant lesion (i.e. polyp) or a
non-sporadic MMR deficient malignant tumor (where non-sporadic MMR deficient is
defined by: microsatellite-instability high by either immunohistochemistry or MSI
testing or both, but no evidence of MLH1 promoter methylation in cases with loss of
both MLH1 and PMS2, and/or no evidence of BRAF mutation in cases with loss of both
MLH1 and PMS2) but germline MMR genetic testing showed either a variant of unknown
significance or mutation negative result or had declined germline MMR genetic testing.

2. Participants must not have evidence of active/recurrent malignant disease for a
minimum of 6 months.

3. Participants must be at least 6 months from any prior cancer-directed treatment (such
as surgical resection, chemotherapy, immunotherapy, hormonal therapy or radiation).

4. Participants must have endoscopically accessible distal colon and/or rectal mucosa
(i.e. participants must have at least part of the descending/sigmoid colon and/or
rectum intact).

5. Participants must consent to two standard of care lower GI endoscopy (flexible
sigmoidoscopy or colonoscopy) with biopsies that will be 12 months (+/-21 days) apart.

6. Ability to understand and the willingness to sign a written informed consent document.

7. Must have normal cardiopulmonary exercise test prior to exercise participation.

Exclusion Criteria:

1. Individuals who are status post total proctocolectomy (i.e. removal of all colon and
rectum).

2. Individuals with history of myocardial infarction, stroke, coronary-artery bypass
draft, invasive coronary revascularization, arrhythmia requiring treatment such as
atrial fibrillation, congestive heart failure, peripheral vascular disease, pulmonary
embolism, or deep venous thrombosis.

3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, uncontrolled hypertension, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements.

4. Individuals with a history of diabetes, hypertension, or have smoked cigarettes in the
last 12 months.

5. Individuals who are unable to participate in cycling due to musculoskeletal
limitations.

6. Individuals who are unable to identify cycling classes in their community for
exercise.

7. Individuals less than 18 years of age and more than 50 years of age.