Recommendations, Insights on Use of Comprehensive Genomic Profiling in Oncology

A discussion at the National Comprehensive Cancer Network 2021 Virtual Congress: Biomarkers in Solid Tumors addressed the advantages and considerations for broad and targeted genomic profiling in oncology.

Kicking off the National Comprehensive Cancer Network (NCCN) 2021 Virtual Congress: Biomarkers in Solid Tumor, co-chair Jennifer Morrissette, PhD, Abramson Cancer Center at the University of Pennsylvania, discussed considerations for use of genomic profiling in cancer, particularly how understanding the differences in capabilities and limitations of tissue vs liquid biopsies can be key in deciding which tests to order and perform for patients with solid tumors.

With all cancers having a genetic component, consisting of an accumulation of mutations in genes that regulate cell division, survival, invasion, or other hallmarks of cancer, detecting these driver mutations helps to personalize therapy choice and monitor for residual disease, noted Morrissette.

In addition, she added that genetic testing of solid tumors can help to answer important clinical questions, such as whether the variant is somatic or germline, if the variant is associated with cancer predisposition, and if there are any variants associated with risk of therapy toxicity.

However, there are various types of genetic abnormalities in solid tumors beyond driver mutations (eg, oncogenes, tumor suppressor genes), including chromosomal abnormalities, mutational processes, and tumor heterogeneity. And detecting these abnormalities depend on the test design and validation process utilized.

“An important consideration when you're thinking about ordering molecular testing for solid tumors is what specimen you're going to be submitting for solid tumor testing,” Morrissette explained. “In our laboratory, for solid tumors we have validated for fine needle aspiration [FNA]/pleural fluids and FFPE [formalin-fixed, paraffin-embedded tissue] samples.”

There were several advantages and considerations regarding the use of both solid tumor tests, as well as for liquid biopsy tests:

  • Advantages of FNA: less likely to be degraded, fast, and may be enriched in tumor cells
  • Considerations for FNA: not always available, small specimen, validation dependent, paucicellular, and pleural fluids can be degraded
  • Advantages of FFPE: common for all tumors, well characterized, enrichment enables broad application of sequencing for all tumor samples
  • Considerations for FFPE: possibility of formalin artifact, especially for archival specimens, as well as degraded RNA, cold ischemic time, and small specimens
  • Advantages/considerations for liquid biopsy: non-invasive, broad testing in specialized tubes, in which timing could be critical dependent on the type of tube used and how quickly it gets to the appropriate laboratory

When choosing the appropriate genetic testing for patients with solid tumors, Morrissette said the first question clinicians are trying to decide is whether to go big or small, in other words using single gene or broad panels.

These options also have their respective advantages and disadvantages. Targeted mutation analysis, such as polymerase chain reaction (PCR), was noted to be usually lower in cost and faster, but limited in scope and may miss other clinically useful alterations; whereas comprehensive genomic profiling (CGP), such as next-generation sequencing (NGS), was indicated to provide consolidation of sequential testing results, but is slower and subject to variable coverage based on the specific laboratory analyzing the data.

“If you send NGS tests to 5 different laboratories, they might cover different genes, but they also might cover different abnormalities….The other thing to remember is that most laboratories only sequence the tumor—about 90% of laboratories only sequence the tumor and about 10% of laboratories do match tumor normal sequencing.”

Moreover, other considerations listed by Morrissette on the use of CGP included if there are any potentially targetable mutations in the tumor type, the type of abnormalities captured, the minimum input of nucleic acid, the minimum tumor percentage for the assay, and whether sequencing from both DNA and RNA is warranted.

If conducting tests like NGS, clinicians will be able to identify a targetable mutation or rearrangement and subsequently initiate biomarker-guided therapy, Morrissette said. And if a targetable mutation is not identified, the broad profiling approach can still determine mutations associated with resistance to therapy and mutational patterns/signatures that may be associated with exposures (eg, smoking or UV light), which can itself be a potential target.

Another factor to consider was the detection of oncogenic gene fusions, which are common in patients with solid tumors and occur across a spectrum of tumor types. Notably, these gene fusions are caused by genomic rearrangements and can drive both the development and the progression of cancer, indicating that a rearrangement that may not have been identified at diagnosis may be present at recurrence.

“When you think about your 2 genes rearranging—you've got gene A and gene B—you have breakage events and these breakage events usually occur within introns….introns tend to contain a lot more repetitive sequences so they can be difficult to map. And so RNA is often a consideration for being used as a template.

“You're going to have more copies of the RNA than DNA so you should be able to potentially capture the fusion from a lower input tumor sample.”

Regarding liquid biopsy testing, its use can be leveraged to detect actionable mutations in the blood and can prove useful when samples from the primary tumor are insufficient or inaccessible.


Although, detection of mutations does not always mean that the mutations are from the known tumor, she highlighted. And if analysis of a liquid biopsy does not detect an actual mutation, confirmation using tissue testing has been strongly considered by both American Society of Clinical Oncology and Association of Moleculare Pathology guidelines.

In the added Q&A, Morrissette said reimbursement of genomic testing can prove an issue and depends on what laboratory clinicians send samples to and what providers or insurers encompass.

“Should these be reimbursed? Yes," she said. "How well they are reimbursed is going to depend on a lot of factors and it's something that many of the professional organizations are very interested in addressing.”