Somatic Genomic Testing for Metastatic or Advanced Cancer
Publication Date: February 16, 2022
Key Points
Key Points
- An increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers.
- All cancers with regulatory-approved biomarkers that guide therapy choice should undergo genomic sequencing.
- Multi-gene panel testing should be conducted whenever more than one genomic biomarker is linked to a regulatory agency-approved therapy in the patient’s disease.
- Multi-gene panel testing is also beneficial when considering immunotherapies with genomic biomarker-linked site-agnostic approvals and to identify additional targets when there are few or no genotype-based therapy approvals for the patient’s disease.
- Clinicians should consider the functional impact of the targeted alteration and the expected efficacy of genomic biomarker-linked-options relative to other treatments during treatment planning.
- Clinical trials are encouraged.
- Genomic sequencing should be performed within a certified laboratory.
Table 1. Select Definitions of Commonly Used Terms in Precision Oncology
| Term | Definition |
|---|---|
| Biomarker | A biological marker that can be detected and measured by a validated test to diagnose or treat disease, including genes, genomic alterations, ribonucleic acid (RNA) transcripts, proteins, post-translationally modified forms of proteins, and signatures of combinations of the aforementioned biomarkers. |
| Circulating tumor DNA (ctDNA) | Tumor deoxyribonucleic acid (DNA) shed into the plasma. |
| Clonal | Tumor cells derived from the division of a common ancestral tumor cell. |
| Copy number variation (CNV) | Deviation from the expected two copies of a gene within a cell.
|
| Fusion | A novel gene product that is created from two previously separate and independent genes. |
| Genomic alteration | Alteration of a gene from its original wildtype (normal) status through mutation, CNV, or rearrangement. |
| Genomic instability | A high frequency of mutations within the tumor’s genome, which may be caused by loss of expression or function of proteins that direct DNA repair and/or are involved in mitotic checkpoints. |
| Genomic instability score (GIS) | A measurement of genomic instability that reflects homologous recombination deficiency. The companion diagnostic for niraparib utilizes a GIS, which measures the presence of telomeric allelic imbalance (TAI), loss of heterozygosity (LOH), and large-scale state transitions (LST) i.e., large structural variants |
| Genomic biomarker-linked therapy | Therapy selected to target specific genomic alterations detected within the tumor. This includes targeted therapy designed to inhibit gain-of-function mutations in oncogenes, loss-of-function mutations in tumor suppressors, or other pathways sensitive to specific therapies due to the presence of a genomic alteration. |
| Germline | Mutations (variants) that are present within the egg and sperm that united to form the zygote from which an individual develops and are thus heritable. Inherited germline mutations are present within both tumor and normal samples sequenced. |
| Homologous recombination deficiency (HRD) | Cells that cannot efficiently repair damaged DNA via homologous recombination. The companion diagnostic for niraparib defines HRD-positive as detection of deleterious or suspected deleterious mutations within BRCA1 or BRCA2 or a positive GIS. |
| Immunotherapy | A type of therapy that activates the body's immune system to target cancer cells. |
| Intertumoral heterogeneity | The evolution of tumor cells over time so that the genomic profile differs between the primary and the metastatic sites and/or amongst multiple metastatic lesions. |
| Intratumoral heterogeneity (ITH) | Within the same tumor, different populations of cells within distinct spatial regions have unique genomic alterations. |
| Multigene panel | A next-generation sequencing (NGS) test that sequences a defined list of genes with at least 50 genes in total. |
| Mutation | A change in the nucleotide sequence encoding for a gene. |
| Mutational signature | Combination of mutations that are characteristic of a specific mutagenesis process leading to or contributing to the disease. |
| Minimal residual disease (MRD) | The presence of tumor cells that have spread from the primary tumor but are not detectable by imaging. |
| Microsatellite instability (MSI) | The presence of nucleotide insertions or deletions at microsatellite loci, which indicates a deficiency in the mismatch repair machinery that normally corrects these errors.
|
| Mismatch repair deficiency (dMMR) | The loss of function or expression of one or more of the components of the dMMR (typically PMS2, MLH1, MSH2, and MSH6) that recognize mismatches within DNA as a result of injury and initiate the repair process. |
| LOH | The loss of the wildtype allele of a gene that was previously in a heterozygous state due to a germline or somatic mutation. LOH can occur at a single gene or as a genome-wide event due to defective DNA repair and be indicative of homologous recombination deficiency. |
| NGS | A technology that performs massively parallel DNA sequencing to detect genomic alterations. |
| Pathogenic or likely pathogenic (P/LP) variants | Variants known or suspected to be causative of disease. |
| Precision oncology | The use of molecular biomarkers to aid in the diagnosis, prognosis, or treatment of cancer. |
| Somatic | Mutations that only occur within somatic cells and not within reproductive cells. In cancer, somatic mutations are found within the tumor and not within normal, non-tumor samples. DNA from both tumor and non-tumor sites must be sequenced to definitively ascertain if a mutation is somatic. |
| Therapeutically actionable alteration | A genomic alteration predicted to confer sensitivity or resistance to an available therapy (FDA-approved or investigational). These alterations are typically functionally significant, in that they confer a change in the property of the encoded protein that promotes tumorigenesis but may also affect drug binding and inhibition without affecting the activity of the protein. |
| Tumor mutation burden (TMB) | A measurement of the number of somatic mutations per megabase of DNA sequenced. |
| Variant allele fraction (VAF) | The fraction of alleles sequenced within a single tumor sample that contain the genomic alteration of interest. |
Diagnosis
...gnosis...
...isional Clinical Opinions (PCOs)...
Section 1: Multigene Panel-Based Genomic S...
...ic testing should be performed for...
PCO 1.2.1For patients with metastatic or a...
...Multigene panel-based genomic testi...
...O 1.3If the genomic sequencing results are u...
...decision-making should incorporate: The known...
...ne testing for genetic alterations linked t...
...on 2: Assessment of dMMR and/or MSI-H Status,...
....1dMMR status should be evaluated on patients w...
...TMB may influence the decision to use immunot...
...ection 3: Testing for Gene Fusions and Exon Sk...
PCO 3.1In patients with metastatic or advance...
...rotrophic tyrosine receptor kinase (...
...3.2.2Testing for other fusions is recommen...
...ing for MET exon 14 skipping should be...
...Diseases with No Approved Disease-Specif...
...O 4.1Genomic testing should be considered t...
PCO 4.2For tumors with actionable genomic alterati...
...4.3Off-label and off-study use of genomic biom...
...5: Elements to Consider While Reviewing Gen...
Tumor only testing versus matched tumor-nor...
Targeted sequencing approach: Multigene p...
...nes tested: Multigene panel-based sequen...
...tion of genomic alterations should include:...
...ction 6: Additional Topics...
...cted Genetic Alterations Linked to FDA Approvals...
...es that cancer clinical trials are...