The American Society of Clinical Oncology (ASCO) Annual Meeting 2023 kicked off with informative sessions including a “Genomics 101 for Oncologists” workshop that shed light on the current state of biomarker testing and the gaps therein. The currently available molecular testing tools highlighted were: PCR, Sanger sequencing and next-generation sequencing (NGS) depending on the clinical context and what needs to be tested. 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 can improve sensitivity over Sanger sequencing but has limited multiplexing capabilities and thus is quite restricted when multiple genes and biomarkers need to be detected, e.g. in metastatic non-small cell lung cancer (NSCLC) patients.
Notably, a large fraction of NSCLC patients present when the disease has already metastasized making time to treatment extremely critical for overall survival. There are numerous FDA-approved first-line targeted therapies now available for these patients but only if they can get timely biomarker testing. Some clinicians suggested PCR molecular reflex testing at diagnosis for these patients so they can be put on treatment as fast as possible. In an effort to improve the turnaround time of NGS-based biomarker testing, there have been efforts by academic medical centers and larger centers to provide NGS in a patient proximal setting such as local labs. However, so far, bringing testing closer to the patient has been exclusive to resource-equipped settings and is further hampered by the high cost of NGS data storage, bioinformatics and lack of standardization in variant interpretation, leaving many patients out.
NGS is currently the most commonly used method for biomarker testing but it comes with heavy costs to patients who are already dealing with financial toxicity. The cost aspect is further exacerbated by long turnaround times, complicated and lengthy non patient-friendly reports, even with targeted panels. Comprehensive genomic profiling (CGP) assays that are commercially available often yield a lot of unactionable information such as off-label therapies and Variants of Uncertain Significance (VUSs) that are not useful for treatment decision planning. Even if actionable clinical trial results are reported in some CGP reports, clinicians quoted going down a long windy path of figuring out options for their patients in terms of eligibility and geographic location.
Furthermore, as variant interpretation evolves in response to newer clinical study readouts, a lot of unactionable variants detected over time can become actionable, presenting ethical and logistic dilemmas on how to communicate the new clinical significance of pathogenicity to existing patients who were tested previously. 95% of the information presented in lengthy NGS reports was therefore cited as not useful and clinicians are urged to not solely rely on these but also verify primary sources of data using different clinical variant interpretation databases such as OncoKB, CIVIC, COSMIC, Clingen, etc. While a useful work-around solution, it is a tall ask given the current physician workload and burnout rates.
Newer NGS assays offer paired normal and tumor NGS with suspected germline findings in an effort to offer one test that can do it all. Yet, most clinicians voiced concerns about being able to do anything regarding these suspected germline findings. 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. Germline testing and pre-test counseling aspects in cases of suspected germline findings are quite elaborate and separate workflows with implications of cascade testing in the patient’s family.
While resource-equipped settings such as academic medical centers report increased use of NGS for biomarker testing often funded by alternative means, the MYLUNG pragmatic study reported contemporary (Dec’2020- Sep’2022) community-wide biomarker testing rates for both early-stage (ES) and metastatic NSCLC (mNSCLC) patients enrolled from 12 community practices (69 sites) across The US Oncology Network. It is sobering that there are still wide gaps in biomarker testing rates prior to treatment initiation, 64% of ES and 83% of mNSCLC pts had at least one molecular biomarker result; and 37% of mNSCLC pts had results for all nine biomarkers that are recommended for testing in the metastatic setting currently. NGS-based testing was conducted in 37% and 57% of the ES and mNSCLC cohorts respectively. Reasons for not testing included: barriers to ordering (42%, 25%), insufficient tissue (18%, 18%), clinical deterioration/crisis (5%, 12%), and other reasons (37%, 49%), respectively.
Barriers to ordering are commonly both financial and due to limited tissue for testing, which is a known issue in NSCLC patients. Oftentimes, clinical samples from patients can be mucinous, of low sample purity and poor diagnostic yield with current technologies unable to provide satisfactory biomarker testing results. Newer technologies that can process such samples while reducing bioinformatic requirements are needed as upfront as possible so treatment decisions for patients can be expedited and real improvements be realized in the delivery of precision oncology to all.
Written by Anjana Bhattacharya, PhD, Vice President of Strategic Marketing
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