Implementing Preemptive Pharmacogenomic Testing for Colorectal Cancer Patients in a Community Oncology Clinic

The goal of personalized medicine is to tailor therapies to an individual patient with a goal
of maximizing benefit and minimizing treatment related side effects. Inter-individual
variability in metabolic enzymes can have a significant impact on cancer therapies.
Pharmacogenomics (PGx) studies the interactions between drugs and genes, and pharmacogenomic
screening tests can assess for genetic variations among individuals to personalize medicine.
PGx testing identifies genes within an individual that may affect treatment, efficacy, and
toxicity of drugs. PGx screening prior to chemotherapy would help identify patients with
genetic polymorphisms that are at increased risk for drug toxicity and would benefit from
genetic-guided dosing, resulting in decreased risk of adverse events (AEs) related to the
chemotherapy. PGx testing is not routinely used in community-based oncology practices. The
cost of testing as well as lengthy waits for results have limited routine use of this
testing. Advances in testing have reached the point where routine preemptive testing could
benefit patients with newly diagnosed cancer.

PGx testing evaluating a large number of metabolic enzymes is now commercially available.
OneOme RightMed® is a privately owned company developed by doctors and scientists at Mayo
Clinic with a mission "to provide the most cost-effective, comprehensive, personalized,
pharmacogenomics analysis integrated into everyday clinical care." OneOme RightMed® currently
tests for 22 genes that impact over 340 drugs used in multiple fields of medicine, including
oncology. The drugs tested for by OneOme RightMed® were generated from practice guidelines
and the FDA's guidelines for genotyping, and drugs with published, clinical evidence
supporting genotyping. With developments in sequencing technology, comprehensive PGx testing
can now be completed for a modest cost. Testing is done using a prepackaged OneOme RightMed®
kit to collect a buccal swab. OneOme RightMed® PGx test uses a DNA Genotek ORAcollect OC-100
buccal swab kit to extract DNA, which is then analyzed through polymerase chain reaction
(PCR). The results are available in 10 or less calendar days to the provider and/or
pharmacist. The report provides "genotype-derived recommendations" with additional quick
references for medication dosing guidance.

Despite clear clinical implications, incorporation of PGx testing has historically been
challenging due to potential delay in initiation of therapy and uncertainty of clinical and
economic benefits. However, in the past decades, clinically actionable gene-drug
interactions, such as the polymorphisms discussed above, have been identified. Additionally,
the availability of high-quality genotyping in a timely manner with lower costs makes PGx
testing feasible. Pilot studies implementing PGx testing have been conducted at academic
centers.10,13-15 Though the knowledge gained from those studies enhanced their ability to
implement PGx testing, pilot studies implementing PGx testing in a community-based health
care setting in oncology treatment have not been conducted, to the best of our knowledge.
Therefore, our pilot study would evaluate the feasibility of implementing PGx testing in
routine oncology treatment at a community-based health care center. CRC is a common cancer
and the drugs used in treating CRC are affected by PGx. Thus, CRC represents an ideal
situation to evaluate the feasibility of routine preemptive PGx testing. While this study
represents an initial pilot feasibility study, our ultimate goal is to evaluate the benefits
of PGx in the community setting in regards to reduction of toxicity, improved cancer
outcomes, and cost savings.

Primary Objective

1. To determine if preemptive PGx testing is feasible in a community oncology clinic.

Secondary Objective

1. To gather pilot data on the proportion of Essentia Health patients with metabolic enzyme
alleles that could impact chemotherapy dosing.

2. To evaluate the impact of PGx guided chemotherapy dosing on toxicity.

3. To evaluate the cost-effectiveness of PGx testing in Essentia Health patients with
colorectal cancer.

Eligible patients will have a histological diagnosis of colorectal cancer. The intent of the
study is to enroll patients as quickly as possible once a decision has been made that a
patient is a candidate for chemotherapy for stage 2-4 colorectal cancer. While many patients
will be eligible for study participation at their initial consultation with medical oncology,
it is also anticipated that some patients may need additional testing prior to eligibility.
This would also include patients who have been followed in the medical oncology department
that develop a new malignancy or have a recurrence. Patients must be enrolled to the study
within 7 days of their initial consultation, or within 7 days of a physician visit, after any
additional tests or biopsies have been completed, when the patient is felt to be a suitable
candidate for chemotherapy. After obtaining informed consent from eligible patients, a
commercially available pharmacogenomics panel, the OneOme RightMed® pharmacogenomic test,
will be ordered. Patients will not be responsible for the cost of PGx testing. The study will
not prescribe any specific chemotherapy regimens. All decisions regarding the clinical care
of the patient will be made by the treating physician. Treatment will not be delayed to wait
for PGx results per study protocol, however the treating physician may elect to do so. When
PGx test results are available, results will be interpreted by the Oncology Lead Pharmacist
at Essentia Health, and recommendations will be made to the treating physician regarding
potential chemotherapy does adjustments. The treating physician will have the ultimate
decision as to whether chemotherapy dose adjustments are done as a result of PGx testing.
Patients will be seen by study staff prior to initiating chemotherapy, and after chemotherapy
cycles 1-3 to assess for toxicity and to determine if any dose modifications were done by the
treating physician.

Patient demographic data will be collected at baseline. Once patients start chemotherapy,
treatment toxicity data will be collected prior to chemotherapy and after cycles 1-3. For
patients receiving continuous chemotherapy such as infusional 5-FU or capecitabine concurrent
with radiation, a cycle will be defined as 2 weeks. Toxicity data will be collected following
Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Data will be collected for
common side effects associated with typical colorectal cancer chemotherapy regimens
including, leukopenia, neutropenia, anemia, thrombocytopenia, fatigue, nausea/vomiting,
diarrhea, mucositis, hand-foot syndrome, peripheral neuropathy, and abdominal pain. Other
toxicities identified by study staff will be collected as well. Chemotherapy dose
modifications made by the treating physician will be collected for chemotherapy cycles 1-3.

When PGx results are available, study staff will alert the Oncology Lead Pharmacist who will
evaluate the results and make recommendations to the treating physician regarding suggested
dose modification to the planned chemotherapy regimen. The primary assessment of the analysis
will focus on UGT1A1 and DPD.

In cases where the suggested dose modifications are unclear or the results are atypical, the
Lead Pharmacist will consult with OneOme RightMed® staff to determine appropriate
recommendations. The Lead Pharmacist will also review each patient's current medication list
and identify if there are any additional medication concerns related to evaluated genes other
than UGT1A1 and DPYD. Any identified additional concerns will be noted on the Results
Interpretation and Impact form. Once the form is complete, a copy will be forwarded to the
treating physician who will then complete the form to indicate whether any changes to the
planned chemotherapy regimen will be made.

Inclusion Criteria:

1. Histologically proven Stage 2-4 colon or rectal adenocarcinoma with an anticipated
need for chemotherapy, which may include neoadjuvant, adjuvant or palliative
treatment, and may include oral or intravenous chemotherapy.

2. Adequate organ function and performance status to receive chemotherapy as determined
by the treating physician.

3. Age ≥ 18 years.

4. Ability to understand and the willingness to sign a written informed consent
documented.

5. Patients must sign consent within 7 days of the physician visit for newly diagnosed or
recurrent colorectal cancer when a patient is initially felt to be a candidate for
chemotherapy.

Exclusion Criteria:

1. Patients received prior chemotherapy for colorectal cancer in the last 12 months.

2. Patients received prior OneOme RightMed® pharmacogenomic testing.