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Summary in Thirty Seconds
Since (Next Generation Sequencing) NGS first became commercially available, targeted therapy developments have increased dramatically. Yet some healthcare providers and insurers use Single-Gene Testing (SGT) before conducting NGS as standard practice.
Choosing NGS over SGT is a financially efficient and diagnostically effective strategy in many cases, as it identifies hundreds of actionable genetic alterations resulting in treatments targeted to specific biomarkers.
NGS is more cost-effective than SGT for people with advanced NSCLC and is related to additional life years gained.
Using SGT prior to NGS can result in tissue insufficiency and increased NGS DNA extraction failures. These findings have been confirmed in national and international studies.
NGS can be used to identify clinically actionable genomic alterations in most cancer types and can also be used to measure tumor mutational burden, identify resistance mutations, provide prognostic information, and connect patients with genomically matched clinical trials.
Single-Gene Testing versus Next Generation Sequencing
Testing for genetic alterations is now a critical component of selecting actionable targeted treatments and immunotherapies for people with cancer,[1] as well as for finding appropriate clinical trials. Testing can look for a specific and actionable genetic alteration where a therapy already exists (e.g., osimertinib for specific EGFR mutations in Non-Small Cell Lung Cancer [NSCLC] or one of three medications for NTRK fusions across a variety of cancers), or testing can look at a large panel of genetic alterations, searching for an actionable alteration amongst the numerous variants tested. Single-Gene Testing (SGT) looks for and pinpoints a specific alteration, while Next Generation Sequencing (NGS) identifies hundreds of actionable genetic alterations in cancer.[2],[3],[4] But questions have been raised about using SGT as a “gatekeeper” first step in the diagnostic process. Several studies conducted within the last 4 years compare NGS vs. SGT in a variety of ways and have found that conducting SGT as a standard first step before NGS is neither a financially efficient nor diagnostically effective strategy in many cases.
NSCLC US Studies
One study evaluated modeling outcomes using 89,000 hypothetical patients with newly diagnosed NSCLC and found each incremental 10% increase in NGS testing produced an average of 2,627 additional Life Years Gained (LYG), with an average cost savings per LYG of $75 US dollars. Using NGS for all testing at the current rate of 80% for NSCLC (any type of genetic testing) would result in an average additional 21,019 LYG and a cost per LYG of $599.[5]
Using NGS unsurprisingly improved the detection of actionable biomarkers by almost 75% in another research paper. NGS also increased the proportion of patients receiving biomarker-driven therapy by 12% while decreasing the proportion of patients who have actionable biomarker-driven cancer but received non–biomarker-targeting first-line treatment by 40%. While NGS cost $2,036 more than SGT per patient, the improved percentage of patients receiving guideline-recommended therapies ranged from 12%-68% depending on the scenario studied, and the percentage of patients receiving suboptimal treatment when receiving SGT rather than NGS ranged from 41%-72% depending on the scenario.[6]
Another study examined test results from 80 community oncology practices for 580 people with NSCLC. 29% of patients had at least one SGT ordered before receiving NGS, and the same FFPE tissue block was used in almost 90% of the cases. Comparing the SGT-then-NGS patients to the NGS-only patients revealed that prior negative SGT doubled subsequent cancellations of NGS Comprehensive Genome Profiling (CGP) testing for NSCLC due to tissue insufficiency and increased NGS DNA extraction failures. NGS detected variants with targeted treatment options in 51% of all cases. The study authors concluded that “SGT practice in the community oncology setting does not meet practice guideline recommendations and negatively impacts the potential benefit of subsequent CGP [using NGS] for NSCLC patients.”[7]
A 2022 study compared NGS to SGT for people with NSCLC and found that the mean time to targeted therapy was 2 weeks for NGS versus 6 weeks for PCR, with mean per patient costs of $4,932 for NGS and $6,605 for PCR. And while per-patient costs were higher for commercially insured versus Medicare-insured patients, NGS was still less costly than SGT.[8]
A US study of over 2,000 hypothetical Medicare-insured patients and 156 commercially insured patients with NSCLC found that the time to receive results and start treatment (including testing time and re-biopsy if needed) for NGS was almost 3 weeks faster than SGT. NGS also resulted in cost savings for both Medicare and commercial payers and increased the proportion of NGS-tested patients led to substantial cost savings.[9]
NSCLC International Studies
A study of 1,000,000 hypothetical patients (based on historical data) with NSCLC in Canada determined that 38% of patients receiving NGS tested positive for a genetic alteration with a targeted therapy versus 26% tested with SGT. This led to a differential treatment initiation of 5.1 weeks for those tested with NGS versus 9.2 weeks with SGT. Each week of delayed care was estimated to cost 406 Canadian dollars (around $300).[10]
Research from Spain evaluated 9,734 hypothetical never-smoker patients with newly diagnosed advanced NSCLC and found that using NGS would provide 1,188 additional quality-adjusted life-years compared with SGT. (In Spain, the cost of NGS is approximately $150 more than SGT.) Additionally, if NGS was used instead of SGT, 1,873 more alterations would be detected, and 82 more patients with NSCLC could potentially be enrolled in clinical trials (based on typically low cancer clinical trial enrollment rates). Finally, estimated turnaround times for NGS results would be 10 working days, while SGT ranged from 6 to 15.5 days, depending on the gene sequenced.[11]
Italian research comparing NGS to SGT for people with either NSCLC or CRC found that in 15 out of 16 scenarios, cost savings were greater using NGS versus SGT. This study also suggested that hospitals could reduce sequencing costs by switching from SGT to NGS, especially as the number of patients undergoing NGS increases.[12] Similar results have been found in Asia, where first-line NGS was found to be more cost-effective than SGT.[13]
Reviews and Other Measures
A review of articles assessing the diagnostic and economic benefits of NGS versus SGT in NSCLC found turnaround times were longer for NGS versus SGT. However, NGS use results in more patients assigned to targeted therapy and increased life-year gains with costs at least neutral and possibly less than SGT in the long run.[14]
Another metric to evaluate diagnostic efficacy is Cost per Correctly Identified Patient (CCIP). A study comparing CCIP for NGS versus SGT found that CCIP was notably lower with NGS than sequential SGT for advanced/metastatic non-squamous non-small cell lung cancer (NSCLC), breast, colorectal, gastric cancers, and cholangiocarcinoma, and marginally lower for squamous NSCLC, pancreatic, and hepatic cancers. CCIP using SGT was better than NGS for prostate cancer. Thus, the cost to correctly identify clinically actionable genomic alterations was lower for NGS than sequential SGT in most cancer types.[15]
Other NGS Benefits and Uses and Rule-Outs
NGS has also been shown to identify resistance mutations that can be used to exclude treatments with little-to-no clinical benefit[16] and tumor heterogeneity[17], and it can be used to measure tumor mutational burden, which guides decisions regarding immunotherapy.[18] Broad NGS testing can also be used to better describe tumor biology, which then helps to identify potential areas of study for clinical trials or potential future therapies, as well as provide potentially prognostic information.[19]
A June 2023 study looked at when NGS is useful, not useful, and not necessary. Of the patients studied, 42% fell into the “NGS useful” category, and included patients with advanced NSCLC, colorectal cancer, and melanoma for initial therapy, those with advanced rare cancers, and those for whom clinical trials were ongoing (22% of all patients). 44% categorized in the “not useful” category included those with advanced cancers and no standard options (28% of all patients) and those with short expected lifetimes; the “not necessary” category (14%) included those with early-stage cancer undergoing definitive therapy and those for whom standard therapy was available without the need of genomic profiling.[20]
Summary
While individual genetic alterations may be uncommon or rare, research shows that approximately 50% of patients tested using NGS have an actionable genetic alteration across different cancer types.[21] Since NGS first became commercially available,[22] targeted therapy developments have increased notably. Between 2006 and 2018, seven times more patients were estimated to benefit from therapy targeting a specific genetic alteration.[23] NGS testing allows for screening of common and uncommon genetic alterations, and the latter are far less likely to be identified when using SGT. Matching patients with NGS has also been associated with the lowest total testing cost per patient (particularly as the number of patients tested increases) and the fastest time to the initiation of appropriate targeted therapy compared to SGT. Additionally, conducting SGT before NGS has been shown to result in delayed subsequent NGS testing secondary to tissue sample insufficiency and DNA extraction failures. Finally, conducting first-line NGS testing can identify patients for clinical trials, which may provide better treatment options than are currently clinically available.[24],[25]
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