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Molecular Tumor Genetic Testing – Adult – Ambulatory

Molecular Tumor Genetic Testing – Adult – Ambulatory - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Oncology


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Molecular Tumor Genetic Testing –
Adult – Ambulatory
Clinical Practice Guideline
Table of Contents
EXECUTIVE SUMMARY ................................................................................................ 3
SCOPE ............................................................................................................................ 4
METHODOLOGY ............................................................................................................ 5
INTRODUCTION ............................................................................................................. 6
RECOMMENDATIONS ................................................................................................... 6
Molecular Tumor Board Review ............................................................................... 6
Test Type ................................................................................................................. 6
When to Test ............................................................................................................ 6
Rationale for Comprehensive Profiling in Common Cancer Types .......................... 7
UW HEALTH IMPLEMENTATION................................................................................ 10
REFERENCES .............................................................................................................. 12
CPG Contact for Content:
Name: Mark Burkard, MD, PhD- Hematology/Oncology
Email Address: meburkard@medicine.wisc.edu
CPG Contact for Changes:
Name: Lindsey Spencer, MS- Center for Clinical Knowledge Management (CCKM)
Phone Number: (608) 890-6403
Email Address: lspencer2@uwhealth.org
Note: Active Table of Contents -- Click to follow link
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Coordinating Team Members:
Dustin Deming, MD- Hematology/Oncology
Joshua Lang, MD- Hematology/Oncology
Mark Albertini, MD- Hematology/Oncology
Anne Traynor, MD- Hematology/Oncology
Anwaar Saeed, MD- Hematology/Oncology
William Rehrauer, Ph.D. - Clinical Laboratories
Jennifer Laffin, Ph.D. - Wisconsin State Laboratory of Hygiene
Jill Kolesar, PharmD- School of Pharmacy
Kris Hahn, PharmD- Center for Clinical Knowledge Management (CCKM)
Review Individuals/Bodies:
Molecular Tumor Board (09/17/2015)
Committee Approvals/Dates:
Clinical Knowledge Management (CKM) Council (09/24/2015)
Release Date: September 2015
Next Review Date: September 2016
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Executive Summary
Guideline Overview
This guideline contains recommendations for the indications for genetic testing of
oncology tumors, and is heavily influenced by recommendations released by the
National Comprehensive Cancer Network (NCCN) as well as local expert opinion.
Key Practice Recommendations
1. It is recommended that patients with cancer gene mutation panel testing are referred
to the UWCCC/WON Molecular Tumor Board. (UW Health Low quality evidence, weak
recommendation)
2. Patients with colorectal cancer (UW Health Moderate quality evidence, weak recommendation),
non-small cell lung cancer (NCCN Category 2A), thyroid (UW Health Low quality evidence,
weak recommendation), or melanoma (UW Health Low quality evidence, weak recommendation)
should be tested upon initial diagnosis of advanced disease using a cancer gene
mutation panel.
3. Genomic testing using a cancer gene mutation panel may be considered in all other
patients with solid tumors who lack sufficient treatment options. (UW Health Low quality
evidence, weak recommendation)
Companion Documents
1. UW Health Lab Test Directory
2. cBioPortal Website
Pertinent UW Health Policies & Procedures
1. UWHC Policy 7.98- Entering Test Results Into UW Health Link (EPIC)
Patient Resources
1. My Cancer Genome
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Scope
Disease/Condition(s): Cancer
Clinical Specialty: Medical Oncology, Laboratory
Intended Users: Oncologists, Referring Oncologists (i.e., WON providers)
CPG objective(s):
To outline evidence-based recommendations for molecular tumor diagnostic testing in
patients with cancer which will support treatment decision-making using somatic test
results.
Target Population:
Adult patients 18 years or older with cancer (solid tumors).
Major Outcomes Considered:
1. Molecular genetic testing
Guideline Metrics:
1. Percentage of patients with panel testing who are referred to the UWCCC/WON
Molecular Tumor Board.
2. Number of patients with advanced colorectal cancer, non-small cell lung cancer,
thyroid, or melanoma tested upon initial diagnosis using a cancer gene mutation
panel.
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Methodology
Methods Used to Collect/Select the Evidence:
Electronic database searches (i.e., PUBMED) were conducted by the Center for Clinical
Knowledge Management and workgroup members to collect evidence for review. Expert
opinion, clinical experience, and regard for patient safety/experience were also
considered during discussions of the evidence.
Methods Used to Formulate the Recommendations:
The interdisciplinary workgroup members agreed to adopt recommendations developed
by external organizations, and arrived at a consensus through discussion of the
literature evidence and expert/institutional experiences.
Methods Used to Assess the Quality and Strength of the
Evidence/Recommendations:
Recommendations developed by external organizations, such as the National Cancer
Center Network (NCCN), maintained the evidence grades assigned within the original
document and were adopted for use at UW Health.
Internally developed recommendations during the workgroup meetings were evaluated
using the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) algorithm (Figure 1) to establish evidence grades for each individual piece of
literature and/or recommendation.
Figure 1. GRADE Algorithm
Rating Scheme for the Strength of the Evidence/Recommendations:
See Appendix A for the various rating schemes used within this document.
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Introduction
Advances in technology have enabled routine molecular testing of tumors, which may
provide guidance in treatment decisions for some of the most common and deadly
malignancies. This guideline provides recommendations for genetic testing in common
cancer types and education on the UWCCC/WON Molecular Tumor Board.
Recommendations
Molecular Tumor Board Review
It is recommended that patients with cancer gene mutation panel testing are referred to
the UWCCC/WON (University of Wisconsin-Madison Carbone Cancer
Center/Wisconsin Oncology Network) Molecular Tumor Board. (UW Health Low quality
evidence, weak recommendation) Regional affiliates or outreach facilities may consider
submitting cases to the UWCCC/WON Molecular Tumor Board based upon a
discussion of the risks and benefits with their patients. (UW Health Very low quality evidence,
weak recommendation)
Test Type
Cancer gene mutation panel test results must be available prior to case presentation at
the UWCCC/WON Molecular Tumor Board. (UW Health Very low quality evidence, strong
recommendation) Benefits to ordering a panel over sequential individual tests include
increasing efficiency (e.g., cost effective) and improving patient care (e.g., avoiding
lengthy turnaround time for sequential test results and exhaustion of tissue which
requires the patient to undergo an additional biopsy). When using a multi-gene panel
clinically actionable mutations which drive treatment decisions are more likely to be
identified with the first test ordered. In addition, markers with promising utility may be
identified which may direct additional lines of therapy or clinical trial participation; clinical
trials are routinely recommended as standard management for many patients with
cancer. (NCCN Evidence Category 2A)
Individual tests or additional genomic testing may be completed when the genetic
mutation of interest is not captured within the panel. Genetic mutations may be captured
by another type of testing that is standard of care (e.g. HER2 amplification and EML4-
ALK translocation detected by FISH) or based upon the characteristics specific to the
case (e.g., SNP array comparative genomic hybridization or whole exome sequencing).
Ordering providers should be cognizant of the cancer gene mutation panel
specifications and are encouraged to reference the UW Health Lab Test Directory or
regional affiliates or outreach facilities should contact the Wisconsin State Laboratory of
Hygiene via the following website for additional details.
When to Test
Patients with colorectal cancer (UW Health Moderate quality evidence, weak recommendation),
non-small cell lung cancer (NCCN Category 2A), thyroid (UW Health Low quality evidence, weak
recommendation), or melanoma (UW Health Low quality evidence, weak recommendation) should
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be tested upon initial diagnosis of advanced disease using a cancer gene mutation
panel. Genomic testing using a cancer gene mutation panel may be considered in all
other patients with solid tumors who lack sufficient treatment options. (UW Health Low
quality evidence, weak recommendation)
Rationale for Comprehensive Profiling in Common Cancer Types
Determining each patient’s mutation status allows clinicians to make better therapy
selection decisions, including eligibility for clinical trials. The following recommendations
for genetic testing by cancer type are not exhaustive, but function to provide guidance
related to the mutations in common cancer types. This listing will be continuously
updated to reflect evolving evidence in this field.
Breast Cancer
Along with estrogen receptor (ER) and progesterone receptor (PR), the determination of
human epidermal growth factor 2 (HER2) tumor statuses is recommended for all newly
diagnosed invasive breast cancers and for first recurrences of breast cancer whenever
possible.1,2 (NCCN Evidence Category 2A)
Due to the growing list of emerging targeted agents for genetic alterations within breast
cancer, broad molecular profiling is recommended. The additional mutations listed in the
table below have shown promising utility in guiding therapy selection.3-9 (UW Health Low
quality evidence, weak recommendation)
Table 1. Genetic Mutations in Breast Cancer
HER2 (ERBB2)
ER (ESR1)
PR (PGR)
AKT1
AR
CDH1
FGFR1
FGFR2
PIK3CA
PTEN
TP53
Colorectal Cancer
All patients with metastatic colorectal cancer should have their tumor tissue genotyped
for RAS mutations (KRAS and NRAS).1,10 (NCCN Evidence Category 2A) Testing may be
performed on the primary colorectal cancers and/or the metastasis.10 (NCCN Evidence
Category 2A) If KRAS non-mutated, consider testing for BRAF mutation.1 (NCCN Evidence
Category 2A)
Due to the growing list of emerging targeted agents for genetic alterations within
colorectal cancer, broad molecular profiling is recommended. The additional mutations
listed in the table below have shown promising utility in guiding therapy selection.3,11,12
(UW Health Low quality evidence, weak recommendation)
Table 2. Genetic Mutations in Colorectal Cancer
KRAS
NRAS
BRAF
AKT1
PIK3CA
PTEN
SMAD4
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Lung Cancer
All patients with recurrent or metastatic non-small cell lung cancer (NSCLC) should be
tested for ALK gene rearrangements and EGFR mutations.1,13 (NCCN Evidence Category 1)
EGFR and ALK testing in early stage disease (stage I, II, or III) is encouraged.14 Testing
in early stage disease allows for the availability of molecular information if recurrence
should occur.15 KRAS mutations in lung adenocarcinomas are mutually exclusive with
EGFR and ALK. It is not recommended that KRAS mutation be used as a sole
determinant of EGFR tyrosine kinase inhibitor therapy selection.15
Due to the growing list of emerging targeted agents for genetic alterations within
NSCLC, broad molecular profiling is recommended.13 Some of the genetic alterations
with the strongest evidence are BRAF V600E mutation, MET amplification, and ROS1
rearrangements.13 (NCCN Evidence Category 2A) In addition, other disease-relevant genes
providing information on available targeted agents include HER2 mutations and RET
rearrangements.13 (NCCN Evidence Category 2B) The additional mutations listed in the table
below have shown promising utility in guiding therapy selection.16-22 (UW Health Low quality
evidence, weak recommendation)
Table 3. Genetic Mutations in NSCLC
ALK
EGFR
KRAS
AKT1
BRAF
CCND1
CCND2
CCND3
CDK4
DDR2
ERBB2 (HER2)
FGFR1
MEK1
MET
NRAS
NTRK1
PIK3CA
PTEN
RET
ROS1
Melanoma
All patients with recurrent or advanced melanoma should be tested for BRAF mutation
status.23,24 (UW Health High quality evidence, strong recommendation) Targeted therapy
significantly improves overall survival in previously untreated patients with metastatic
melanoma with BRAF V600E or V600K mutations. Melanomas that arise on mucosal,
acral, or chronic sun damaged skin should be assessed for KIT mutations.25 (UW Health
Low quality evidence, weak recommendation) All patients with recurrent or advanced
melanoma being considered for routine treatment or clinical trials should receive
mutational analysis.23 (NCCN Evidence Category 2A) Due to the growing list of emerging
targeted agents for genetic alterations within melanoma, broad molecular profiling is
recommended. The additional mutations listed in the table below have shown promising
utility in guiding therapy selection.26-29 (UW Health Low quality evidence, weak recommendation)
Table 4. Genetic Mutations in Melanoma
BRAF
KIT
CTNNB1
GNA11
GNAQ
MEK1 (MAP2K1)
NF1
NRAS
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Thyroid Cancer
Molecular diagnostic testing can be done to assist in management decisions on
cytologically indeterminate thyroid nodules.32 (NCCN Category 2B) Both point mutations
(BRAF and N/K/H-RAS) and rearrangements (RET/PTC and PAX8/PPARγ) are
commonly associated with thyroid cancer.32,33
Due to the growing list of emerging targeted agents for genetic alterations within thyroid
cancer, broad molecular profiling is recommended. The mutations and rearrangements
listed in the table below have shown promising utility in guiding therapy selection.34 (UW
Health Low quality evidence, weak recommendation)
Table 5. Genetic Mutations in Thyroid Cancer
BRAF
HRAS
KRAS
NRAS
PI3KCA
PTEN
P53
RET/PTC
PAX8/PPARγ
Tumors of the Central Nervous System
Gliomas are the most common tumors of the central nervous system (CNS).
Astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas are the major
histologic types of human gliomas; histologic differentiation among these tumors can be
difficult. It has been shown that specific genetic alterations, such as deletions of the
short arm of chromosome 1(1p) and long arm of chromosome 19 (19q), methylation of
the MGMT (O[6]-methylguanine-DNA methyltransferase) promoter and certain
mutations in the IDH1 and IDH2 (nicotinamide adenine dinucleotide phosphate (NADP)-
dependent isocitrate dehydrogenases 1 and 2) genes are highly associated with specific
morphologic types of gliomas.33-35 In addition, specific genetic alterations seem to
predict prognosis (survival), as well as response to specific chemotherapeutic and
radiotherapeutic regimens, irrespective of tumor morphology.35-37 (UW Health Low quality
evidence, weak recommendation)
Table 6. Genetic Mutations in CNS Tumors
1p 19q deletions
MGMT promoter methylation
IDH1/IDH2 mutations
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UW Health Implementation
Potential Benefits:
Following these guidelines should lead to standardized tumor genotyping by providers.
The results from appropriate molecular testing can aid in the selection of optimal
treatment regimens, which may result in improved cancer patient outcomes.
Potential Harms:
None identified.
Implementation Plan/Tools
1. Guideline will be housed on U-Connect in a dedicated folder for CPGs and linked on
a webpage associated with the lab portal.
2. Release of the guideline will be advertised in the Clinical Knowledge Management
Corner within the Best Practice newsletter.
3. Education and communication will be provided at Oncology DOWGs and
Chemotherapy Council.
4. Reference link will be added the Cancer Gene Mutation Panel EAP [HCCANPNL].
Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and
treatment of patients. This Clinical Practice Guideline outlines the preferred approach
for most patients. It is not intended to replace a clinician’s judgment or to establish a
protocol for all patients. It is understood that some patients will not fit the clinical
condition contemplated by a guideline and that a guideline will rarely establish the only
appropriate approach to a problem.
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Appendix A. Rating Schemes for the Strength of Evidence/Recommendations
Grading of Recommendations Assessment, Development and Evaluation (GRADE)
GRADE Ranking of Evidence
High We are confident that the effect in the study reflects the actual effect.
Moderate We are quite confident that the effect in the study is close to the true effect, but it is also
possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.
GRADE Ratings for Recommendations
Strong for using/Strong against using The net benefit of the treatment is clear, patient values and
circumstances are unlikely to affect the decision.
Weak for using/ Weak against using The evidence is weak or the balance of positive and
negative effects is vague.
National Comprehensive Cancer Network (NCCN)
NCCN Categories of Evidence and Consensus
Category
1
Based upon high-level evidence, there is uniform NCCN consensus that the intervention is
appropriate.
2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
3 Based upon any level of evidence, there is major NCCN disagreement that the intervention
is appropriate.
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Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 09/2015CCKM@uwhealth.org