Somatic Genomic Testing for Metastatic or Advanced Cancer

Publication Date: February 17, 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

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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.
  • Amplification: An increase in the number of gene copies within a cell beyond the expected two copies. Amplifications may be focal and limited to a specific gene or part of a broader, typically lower level, chromosomal gain.
  • Deletion: A decrease in the number of copies of a gene due to the loss of a single copy (heterozygous deletion) or both copies (homozygous deletion).
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.
  • Microsatellites: Highly polymorphic, short, tandem repeats of DNA nucleotides distributed throughout the human genome, prone to replication errors.
  • Microsatellite instability-high (MSI-H): The presence of a high level of mutations at the sequenced microsatellite loci.
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

...iagnosi...

...nal Clinical Opinions (PC...

...1: Multigene Panel-Based Genomic Seq...

...testing should be performed for patients wit...

PCO 1.2.1For patients with metastatic o...

...2Multigene panel-based genomic testing should be...

...enomic sequencing results are used to in...

...4Clinical decision-making should inc...

...ermline testing for genetic alterations...

...ction 2: Assessment of dMMR and/or MSI-H...

...us should be evaluated on patients with metastat...

...may influence the decision to use...

...ing for Gene Fusions and Exon Skipping Variants...

...ents with metastatic or advanced solid tumors, fu...

...O 3.2.1Neurotrophic tyrosine receptor kinase (N...

....2Testing for other fusions is recommended in...

...CO 3.3Testing for MET exon 14 skipping should be...

...4: Diseases with No Approved Disease-...

...nomic testing should be considered t...

....2For tumors with actionable genomic alterations w...

...bel and off-study use of genomic biomarker...

...ection 5: Elements to Consider While Revie...

...only testing versus matched tumor-normal testin...

Targeted sequencing approach: Multigene pan...

...ltigene panel-based sequencing reports...

Description of genomic alterations sho...

...: Additional Topics...


...ted Genetic Alterations Linked to FDA...


...eves that cancer clinical trials ar...