November 30, 2023

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ASCO: Which metastatic/advanced cancers require genomic testing?

ASCO: Which metastatic/advanced cancers require genomic testing?


ASCO: Which metastatic/advanced cancers require genomic testing? This ASCO Guide is here!

An increasing number of therapies (targeted therapy, immunotherapy, etc.) are approved to treat cancers with specific genomic biomarkers. Next- generation gene sequencing (NGS) has been approved by the U.S. Food and Drug Administration (FDA) for a variety of tumor types as a routine pre-cancer treatment program.


ASCO: Which metastatic/advanced cancers require genomic testing?


In 2020 alone, the FDA approved 28 tumor-targeted therapies for patient populations defined by specific molecular biomarkers, and genomic sequencing results are now routinely used in many clinical trials to enroll patients.


However, results on when tumor genome sequencing should be undertaken, what type of testing should be performed, and how to interpret treatment choices are unclear.


Moreover, not all tumors have therapeutically targetable or driver gene alterations; nor do all tumors have driver gene alterations that warrant biomarker-related treatment sensitivity . Multigenic testing can also aid in treatment selection by identifying additional targets when there are few or no treatment options based on conventional genotypes.


To this end, ASCO convened a panel of experts to provide clinical guidance on the use of genome sequencing for treatment options for patients with metastatic or advanced solid tumors.



In what clinical situations should genomic testing be performed?

Genomic testing should be performed in patients with metastatic or advanced solid tumors with good general status in the following two clinical settings : 1. When there is a regulatory agency-approved cancer genomic biomarker-related therapy. 2. When there are contraindications or exclusions to treatments based on specific genomic biomarkers (Strength of recommendation: strong) .


Genomic testing should be performed on patients with metastatic or advanced solid tumors who have disease therapies associated with genomic biomarkers.


For example, patients with metastatic melanoma should be screened for the BRAFV600E mutation by genomic testing because RAF and MEK inhibitors are FDA-approved for this disease. Genomic testing should also be performed if there are well-defined markers of treatment resistance in patients with metastatic or advanced solid tumors.

For example, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab ) are ineffective in KRAS-mutated colorectal cancer (CRC) .



When should polygenic-based testing be performed when there is only one genomic biomarker or a small number of genomic biomarkers associated with regulatory approval of anticancer drugs?


For patients with metastatic or advanced solid tumors, genomic testing using multigene sequencing is preferred (Strength of Recommendation: Moderate) when the patient has access to regulatory agency-approved genomic biomarker-related therapies .


When more than one genomic biomarker is associated with a regulatory agency-approved therapy, a multigenome panel-based genomic assay should be used (strength of recommendation: strong) .


Although non-NGS-based companion diagnostics are approved for some targeted therapies, multigenome panel-based assays are the most efficient use of limited tumor biopsies to simultaneously detect multiple approved therapeutic targets.



What other important considerations are there in ordering genetic testing and interpreting genomic testing?


If genomic sequencing results are used for clinical management, this testing must be performed in an appropriately accredited laboratory (strength of recommendation: strong) .

In the United States, genome sequencing must be performed in a laboratory certified by the Clinical Laboratory Improvement Amendments (CLIA) . The agreement between CLIA laboratories using different assays was approximately 95%, which means that various qualified laboratory loci evaluating similar genomic regions are likely to identify the same variant.

Clinical decisions should include the known or predicted impact of a specific gene abnormality on protein expression or function, as well as clinical data on specific targeted drugs for that gene abnormality (Strength of Recommendation: Strong) .

Clinicians should not only be aware of the abnormal genes reported, but should also read functional annotations to clarify the impact of gene abnormalities on gene function and treatment sensitivity .

For patients with metastatic or advanced solid tumors for whom treatment for germline mutations is proposed, germline genetic testing in relation to approved treatments should be performed . It should not be limited by clinical criteria based on family history or for familial risk assessment. Patients with a pathogenic or likely pathogenic (P/LP) variant should receive genetic counseling to understand secondary cancer risk, possible inheritance of germline mutations in blood relatives, and differences between germline and somatic mutations (Recommended Strength: Strong) .


NOTE: Germline testing and genetic counseling may still be required for patients with a personal or family history suggestive of genetic predisposition, even if no germline alterations are identified when tumor genomes are sequenced using various sequencing panels.



What is the role of multigenome panel-based tumor genome sequencing for mismatch repair (dMMR) and/or high microsatellite instability (MSI-H) detection?


dMMR should be evaluated in patients with metastatic or advanced solid tumors eligible for immunotherapy. There are a variety of approaches, including the use of large multi-genome panel-based assays to assess MSI. When making this decision, consider the prevalence of dMMR/MSI-H status in a single tumor type (Strength of Recommendation: Strong) .



What is the role of multi-genome panel-based tumor genome sequencing in tumor mutational burden (TMB) detection?


When TMB may influence the decision to use immunotherapy, a large multigenome panel or whole-exome analysis of a validated TMB assay should be used (strength of recommendation: strong) .

TMB refers to the number of somatic mutations per megabase of DNA sequenced and usually varies by tumor type. There is literature showing that high TMB can predict patient response to immune checkpoint inhibitors.



When should a patient be tested for fusions?

For patients with metastatic or advanced solid tumors, a fusion trial should be performed if an approved fusion- targeted drug is available (strength of recommendation: strong) .


When should patients be tested for fusions outside of an approved disease?

Due to the pan-tumor nature of NTRK fusions, NTRK fusion testing should be performed in all patients with metastatic or advanced solid tumors who may receive TRK inhibitor therapy (Strength Recommendation: Strong) . If no driver gene abnormality is found in the large genome panel, additional fusion testing is recommended (strength of recommendation: moderate) .


When should patients be tested for exon skipping mutations?

MET exon 14 skipping mutation testing should be performed in patients with all types of NSCLC (Strength of recommendation: strong) .

The MET gene encodes a receptor tyrosine kinase that induces downstream signaling through the RAS or RAF and phosphoinositide 3-kinase pathways. MET abnormalities caused by splice site alterations result in loss of exon 14 of the MET transcript. These splice site alterations may be due to point mutations, insertions or deletions that disrupt the donor or acceptor splice sites for MET precursor RNA splicing, or due to whole-exon deletions.

The MET juxtamembrane domain containing the E3 ubiquitin ligase Casitasb lineage lymphoma (CBL) binding site (Y1003) is deleted due to exon 14 skipping , impairing MET ubiquitination, increasing MET protein stability and MET signaling. MET exon 14 skipping is a targetable genetic abnormality in NSCLC, and the FDA approved the MET inhibitors Capmatinib and Tepotinib. 2.7% of NSCLC patients have MET exon skipping mutations, which often occur in older patients.



How should multigene testing be performed in tumors without approved disease-specific biomarkers?

For patients with metastatic or advanced solid tumors without an approved genomic biomarker-related therapy, genomic testing should be considered to identify potential therapy (Strength of Recommendation: Moderate) .

In the absence of an approved indication, on what evidence should clinicians recommend treatment based on genetic testing results?

Patients with activated genes and no approved therapy are encouraged to participate in the clinical trial option (strength of recommendation: strong) .

Off-label use of approved genomic biomarker-linked therapies in other diseases is not recommended when there is an opportunity to participate in a clinical trial, or when there is no clinical evidence of meaningful efficacy (strength of recommendation: strong) .




What factors should be considered when interpreting genetic test results?

When interpreting genomic test results, consider the tests performed, including the reliability of the laboratory. To best assist clinical decision-making, genomic testing reporting should cover certain essential elements such as reporting specifications and brief descriptions in the joint consensus recommendation of the Society for Molecular Pathology, ASCO, and College of American Pathologists.



Other Mentoring Programs

The ASCO group provides assays for circulating cell-free DNA (cfDNA) ; minimal residual disease assays; pharmacogenomic biomarkers; detection of cancers of unknown primary (CUP) ; homologous recombination deficiency (HRD) assays; NGS diagnosis and prognosis value; inter- and intra-tumor heterogeneity (ITH) ; assessment of genomic covariation; and guidance on the rationale for repeat genetic testing.


✩ This article is for reference only by professionals such as medical and health care professionals




Chakravarty Debyani, Johnson Amber, Sklar Jeffrey, et al. Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol, 2022, undefined: JCO2102767

ASCO: Which metastatic/advanced cancers require genomic testing?

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