ASCO 2024 workshop seeks to answer a burning question

“How do oncologists select the right genomic test and interpret it to most accurately inform patient treatment?”

With an ever expanding precision oncology landscape, standard of care treatments often change following the American Society of Clinical Oncology (ASCO) Annual Meeting. The Biofidelity team returned from another transformative ASCO and I wanted to share some of our observations, reflections and learnings.

Despite advances in targeted treatments, the field of genomic testing lingers behind with the heavy burden of interpretation placed squarely on practicing oncologists. Continuing on a theme that has woven through previous ASCOs, this year’s meeting kicked off with a “Genomics 101 for Oncologists” workshop. The objective was to help educate oncologists about the correct selection of broad gene panels and train them on genomic result interpretation and clinical utility. 

The workshop highlighted the currently available genomic testing tools and use cases for each depending on the clinical context and what needs to be tested including PCR, Sanger sequencing and next-generation sequencing (NGS). 

• Traditional Sanger sequencing is not very sensitive; however, it is still often used for single gene analysis in samples of high tumor purity. 
• Allele specific PCR is very specific and more sensitive then Sanger sequencing but has limited multiplexing capabilities. 
• For broad molecular profiling which is now recommended for several cancer types, NGS is touted as the solution that combines high sensitivity with comprehensive coverage of genes that are guideline recommended for testing.

The comprehensive coverage provided by NGS is accompanied by a high complexity of understanding test limitations and interpretation support. Multidisciplinary teams are needed to effectively order and interpret testing for precision oncology. In resource equipped settings, there is often a molecular tumor board to assist with genomic result interpretation. 

In simple words, a key question for oncologists is “How do you decide what to do with a genomic variant that was detected by NGS?”

To help answer that question, some of the key takeaways from the workshop were:

Not all tests are equal

Each NGS test has its own coverage of genes and assay limitations that are important for oncologists to understand. A targeted panel is often desirable compared to comprehensive pan-tumor panels that yield a lot of unactionable information that can be hard to interpret. For RNA based biomarkers, RNA-based NGS is preferable and an orthogonal testing strategy is encouraged. However, the required depth of sequencing and input nucleic acid required for RNA analysis by NGS can be prohibitive. Continued optimization of different testing methodologies is necessary to improve detection rates of both DNA and RNA biomarkers for NSCLC patient treatment.

Need to separate standard of care testing from investigational unactionable testing

Majority of current NGS-based tests detect variants in a target gene that is included in the panel rather than only therapeutically actionable variants. This leads to NGS-based testing yielding inconclusive results (in the form of variant(s) that are likely pathogenic, variants of uncertain significance (VUSs), and variants that are likely benign. VUSs can comprise up a high fraction of total variants identified by NGS and may be misinterpreted as causal, particularly by clinicians with less genomics experience. 

Liquid biopsy and Clonal Hematopoiesis of Indeterminate Potential (CHIP) variants

In the case of NGS-based testing of blood specimens, another byproduct is the detection of Clonal Hematopoiesis of Indeterminate Potential (CHIP) variants that are unrelated to the cancer of interest. CHIP variants are somatic mutations that represent an expansion of hematopoietic cells without an underlying malignancy and are often associated with increasing age, tobacco use, and prior therapies and can increase false-positives when using liquid biopsies. Paired white blood cell sequencing can help subtract CHIP variants but add costs to NGS. 

Somatic versus germline variants

Newer NGS assays also offer paired normal and tumor NGS with suspected/incidental germline findings to offer one test that can do it all. This is often undesirable as the somatic and germline variant calling algorithms are distinct with experts advocating use of distinct somatic tumor testing and germline testing panels. For hereditary cancer testing, there is not yet a good panel for both somatic and germline variant detection. Some of these NGS tests rely on an approximately 50% variant allele frequency as a major determinant for a variant being suspected germline, yet experts caution that the % VAF does not always obey that rule and can land anywhere in the 40-80% range depending on the sample. Most clinicians are  concerned about appropriate clinical decision making (including need for referral to medical geneticists) for  these suspected germline findings. Also, while there are laws like the Genetic Information Nondiscrimination (GINA) Act to protect patients, having incidental (and potentially)  unactionable genetic information as part of patient record was deemed unnecessary.

Variant understanding and verification

Due to complexity of variant reporting and interpretation, the experts urge oncologists to verify primary sources of data using different clinical variant interpretation databases such as OncoKb, CIVIC, COSMIC, Clingen, OMIM, GeneReviews, Clin var, Cbio portal, etc. While a useful work-around solution, it is a difficult task given current physician workload, burnout rates and training required to interpret this data. Another consideration with the excessive information that results from NGS testing is the cost of data storage increasing and still being untenable

Newer technologies that can process patient samples with sensitivity and specificity while reducing bioinformatics requirements are needed quickly so treatment decisions for patients can be expedited and real improvements be realized in the delivery of precision oncology to all. 

Our technology, Aspyre, is focused on actionable biomarkers and does not detect unactionable biomarkers such as VUSs and/or CHIP variants and may therefore reduce unnecessary follow-up and reduce patient distress. Additionally, due to the targeted testing for pre-determined actionable biomarkers using PCR-based methodologies, there is no need for specialized bioinformatics and genomic interpretation using multiplex PCR-based tests. Most PCR-based genomic analyses involve turnkey data analysis with no specialized bioinformatics required. 

Learn more here.

Written by Anjana Bhattacharya, PhD, Vice President of Strategic Marketing