Next-generation sequencing (NGS) technologies are advancing, leading to reduced costs and quicker turnaround; thus, access to NGS platforms is increasing. However, at this time, genomic testing is not appropriate for all patients with cancer. Instead, application of genomic testing guided by current clinical principles falls into three basic clinical settings: hereditary screening, early stages and advanced stages (Figure 1). Furthermore, with the availability of many testing platforms, it is important to consider platforms/panels that are consistent with the clinical setting. The number of genes tested, types of alterations measured and type of sample needed will vary based on the goal for testing.
Figure 1. Nodes for genomic testing in clinical practice.
Hereditary genomic testing is performed when hereditary predisposition for cancer is suggested by family history and/or age of diagnosis.
- Approximately 5% to 10% of all cancers result from inheritance of a mutation.
- Asymptomatic patients with strong family history of cancer often proactively seek testing, usually through their primary care physician.
- Patients younger than 50 years of age who receive a diagnosis of cancer and who may or may not have a strong family history are strongly encouraged to have hereditary genomic testing performed.
Which testing platforms?
- Testing includes genes associated with cancer syndromes. Some of the most commonly detected cancer syndromes and genes associated with these diseases are shown in Table 1; however, at least 50 cancer syndromes have been described.
- Hereditary testing may include single gene tests or multigene cancer panels.
- Testing usually requires a single blood specimen, clinical questionnaire and results interpretation that follows American College of Medical Genetics guidelines. Positive results prompt services of genetic counseling, and follow-up may include recommendations for further testing in the family.
- For a list of commercially available platforms for hereditary testing, visit The Genetic Testing Registry at https://www.ncbi.nlm.nih.gov/gtr.
Table 1. List of common inherited cancer syndromes and associated genes.
Genomic testing for early stages of cancer is currently only routinely performed for breast cancer; however prognostic assays are being investigated for their role in many other cancer types.
- Genomic testing is used to identify more aggressive cases that have higher likelihood of recurrence and to guide selection of patients who would benefit most from adjuvant chemotherapy.
- Prognostic tools for risk stratification of early stages of cancer are currently only approved by the FDA for breast cancer.
Which testing platforms?
- Oncotype Dx (Genomic Health) is used for estrogen receptor–positive breast cancers and is covered by most insurance plans. This assay is used to determine which patients have a high risk for recurrence and, therefore, are predicted to benefit most from adjuvant chemotherapy.
- Mammaprint (Agendia), is FDA-approved and also covered by many insurance plans, is used in early-stage breast cancers regardless of estrogen receptor status to determine risk for recurrence and identification of patients who would benefit from adjuvant chemotherapy.
- Both breast prognostic assays use formalin-fixed paraffin-embedded tissue specimens for analysis.
- Patient selection tools that incorporate risk modeling based on genomic profiles are under investigation for early stages of several types of cancer, including melanoma, lung, colon and prostate cancers.
Genomic testing for advanced stages of disease is used to guide selection of targeted therapies, monitor response and identify clinical trials for refractory disease after standard of care has been exhausted.
- Genomic testing for targeted therapies considered standard of care is dependent on tumor type, and assessment of one or several genes may guide selection of appropriate therapy.
- As novel receptor tyrosine kinase inhibitors targeting acquired resistance mechanisms are becoming available, real-time monitoring for the appearance of resistance mutations through noninvasive techniques are being used to prompt switching of agents. This currently is only applicable for the treatment of epidermal growth factor receptor–mutated non–small cell lung cancer.
- Patients with cancers lacking targeted therapy options (eg, sarcoma, cancer of unknown primary) or patients whose targeted therapies lack predictive markers (eg, erlotinib for pancreatic cancer, cetuximab for head and neck cancer) are assayed by genomic tests only after failure of standard of care or when failure of standard of care is anticipated (eg, aggressive clinical behavior) to identify potential clinical trial options.
Which testing platforms?
- Most major academic medical centers and large community health care systems have standardized approaches to genomic testing that may include two tiers of testing. Upon diagnosis, internal pathology laboratory services may provide many of the necessary tests to guide standard of care for some of the most common cancer types (eg, HER-2–positive breast or gastric cancer, or ALK- or EGFR-positive lung cancer, etc.). The second tier of testing that is usually reserved to identify expanded clinical options would include a multigene panel approach and may be performed internally as well, or submitted systematically to a preferred commercial vendor.
- Depending on treatment goal, three main categories of genomic testing are available for guidance of therapy selection (Figure 2).
- Companion diagnostics are in vitro diagnostic tools that provide essential information for the safe and effective use of a corresponding therapeutic product, per the FDA’s definition. Used as enrichment tools (patients with positive results are enrolled) in the clinical trial, they are included in the drug’s labeling if co-approved by the FDA.
- The single-analyte approach assesses specific alterations (eg, mutations, amplifications, over-expression, rearrangement) in a specified gene or protein.
- Results are easily interpreted, and the patient is deemed as responder or nonresponder.
- Multigene NGS panels:
- Targeted sequencing/hotspot NGS panels
- Targeted sequencing panels usually include 30 to 50 genes and can detect multiple mutations within hotspot regions of genes (DNA only) associated with cancer.
- The panels are designed to detect alterations, single nucleotide variants (SNVs) and small insertions/deletions (indels) in therapeutically relevant genes.
- Comprehensive genomic profiling NGS panels
- Hundreds (300 to 500) of genes are assessed.
- The panels assess alterations in DNA and RNA (whole genome or whole exome).
- The panels allow for simultaneous detection of SNVs, indels, genomic copy number variations and rearrangements/fusions.
- Most data from comprehensive genomic profiling are exploratory, or for research purposes, or may lead to clinical trial options.
- Multidisciplinary teams consisting of clinicians, cancer biologists, clinical geneticists, basic scientists, biostatisticians, bioinformaticians and others may collectively analyze and interpret data and discuss cases through institutional molecular tumor boards that meet to guide direction for patient care.
- Several commercial assays have been validated in a Clinical Laboratory Improvement Amendments setting to detect therapeutically relevant genetic alterations and can be searched in The Genetic Testing Registry at https://www.ncbi.nlm.nih.gov/gtr.
Figure 2. Genomic testing in clinical practice.
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