Precision Medicine in Lung Cancer: How Comprehensive Testing Optimizes Patient Outcomes

August 01, 2024

Over the past two decades, the treatment of metastatic non-small cell lung cancer (NSCLC) has dramatically evolved with the introduction of targeted therapies and immunotherapy. These advancements require predictive molecular tests to determine which treatments are suitable for patients. Biomarker testing has become vital in lung cancer care, enabling personalized diagnosis and treatment by identifying specific genetic variants. This precision allows multidisciplinary cancer care teams to select the most effective therapies, reduce side effects, and improve patient outcomes. Despite its importance, adoption of comprehensive biomarker testing still needs to be improved. Experts recommend broad, panel-based molecular profiling, often using next-generation sequencing (NGS), to guide treatment decisions effectively, emphasizing the need for comprehensive testing to optimize therapy selection and improve outcomes.

The Neo Comprehensive^™–Solid Tumor Assay

Neo Comprehensive^™–Solid Tumor is a comprehensive genomic profiling (CGP) assay covering a broad range of relevant variations from DNA and RNA signatures.^1,2

The test profile includes 517 genes for single nucleotide variants (SNVs) and short insertions/deletions (InDels), 59 genes for copy number variations (CNVs), and 55 genes for known and novel fusions and splice variants. In addition, Neo Comprehensive^™–Solid Tumor assesses tumor mutational burden (TMB) from over 1.1 megabases of DNA sequences and microsatellite instability (MSI) status from 130 known homopolymer regions.³

Compared to similar assays, Neo Comprehensive^™–Solid Tumor assay has 208 more total genes for DNA aberrations and 19 more total genes for fusions and splice variants. Additionally, 235 of the genes assayed for DNA aberrations, and 32 of the genes assayed for fusions and splice variants are unique to the Neo Comprehensive^™–Solid Tumor assay.

The Benefit of Large Panel Comprehensive Testing

Comprehensive genomic profiling has been shown to identify predictive and prognostic biomarkers and drug resistance mechanisms using minimal clinical samples.^4,5

Using large panel NGS improves the detection of actionable biomarker genes by 74.4%, increases the proportion of patients receiving biomarker-driven targeted therapy by 11.9%, and decreases the proportion of patients with biomarker-positive disease receiving non–biomarker-driven chemotherapy treatment by 40.5%.⁶

NGS offers better diagnostic value and is more cost-effective than testing relevant genes individually through single gene testing.^7,8 Increasing the proportion of NGS-tested patients and using NGS testing upfront translates into substantial cost-savings and shorter time-to-testing results.⁶

Using RNA Sequencing for Optimal Fusion Detection

Neo Comprehensive^™–Solid Tumor detects fusions by RNA sequencing. Fusion detection using RNA sequencing can effectively identify gene fusions undetected when using DNA sequencing only.^9,10 Clinical guidelines recommend performing fusion detection via a broad, panel-based approach, such as NGS, and considering RNA-based NGS to maximize the detection of fusion events for patients that appear driver-negative by DNA NGS.¹¹ As a result, RNA NGS is the preferred method of fusion detection compared to DNA NGS, providing a sensitivity of nearly 100% and exceeding DNA-based NGS, which is estimated to be approximately 80%, carrying important implications for diagnostic, prognostic, and therapeutic indications.¹² A significant enrichment for fusions has been seen in variant driver negative samples with low TMB sequenced through DNA NGS only, highlighting the importance of prioritizing additional RNA sequencing.¹³ RNA sequencing increases the detection proportion of total and druggable fusions and expands the scope of druggable patients, reducing failure rates of missed fusion detections, and improving detection rates for treatment with targeted therapies compared to DNA NGS alone.^14,15 The combination of DNA and RNA as a multimodality molecular test for fusions is shown to increase the detection of driver variants by 5%.^10,16

An analysis of 6,009 tumors across 14 cancer types found that 7.2% of tumors expressed a gene fusion involving one of 19 actionable gene families/pathways targeted by an approved therapy.¹⁷

NTRK: In this analysis, three times as many actionable expressed NTRK fusions were detected with a targeted RNA-based hybridization approach (0.9%) compared with DNA-based testing (0.3%).^14,17NTRK fusions are rare and can be difficult to detect by DNA sequencing alone due to many partner genes and gene breakpoints occurring across large intronic regions.¹⁸

DNA is 81.1% sensitive compared to 100% sensitivity using RNA for NTRK fusion detection, and 30% of patients enrolled in an NTRK study by RNA were NTRK negative when sequenced by DNA.^12,19

METex14: In an analysis of 254 lung adenocarcinomas found to be negative for gene fusions and METex14 alterations by a DNA-based assay, previously undetected alterations were identified by RNA sequencing in 14% of cases.^13,20

NRG1: DNA sequencing cannot sufficiently detect the large intronic regions involved in rare NRG1 fusions to which the HER3 inhibitor seribantumab is indicated for the treatment of solid tumors with NRG1 fusions. This is in contrast to detecting NRG1 fusion effectively through RNA sequencing using an assay such as TSO500.¹²

The Use of Neo Comprehensive^™–Solid Tumor

The Neo Comprehensive^™–Solid Tumor profile is intended for use by qualified healthcare professionals in accordance with guidelines for cancer therapy, as well as providing guidance for clinical trial designs and biomarker discovery for solid-tumor cancers.

Patients with newly diagnosed, recurrent, or progressive solid-tumor disease; advanced cancer; or with unusual clinical presentation who need thorough coverage for clinical investigation are candidates for comprehensive testing.

The Neo Comprehensive^™ –Solid Tumor profile is appropriate for diagnostic, prognostic, and therapeutic assessment for patients with pan-tumor indications. It provides a wide-spectrum screening of genetic markers, including rare markers missed by cancer-specific profiles. The assay’s turnaround time of 8–10 days is used for quick assessment of therapeutic strategies, including:

Actionable information: Results useful for developing appropriate treatment strategies including key immuno-oncology markers and pertinent negative results impacting prognosis or therapy response.
Identification of therapeutic resistance: Results can help plan therapy based on potential resistance.
Simple reports: Comprehensive evaluation of patient results by leading medical and scientific experts provides relevant diagnostic, prognostic, and therapeutic information. The report format includes an easy-to-read table summarizing therapy and clinical trial options for patients.
Clinical trials identification: Results correlate to all open and recruiting clinical trials patients may qualify for based on their genomic alterations. Patients are identified for applicable clinical trials such as NCI-MATCH where a tumor gene testing lab is the only path to enrollment.

The advancements in treating metastatic NSCLC have revolutionized patient care, offering more personalized and effective therapeutic options. By embracing comprehensive biomarker testing and panel-based molecular profiling, we can ensure that patients receive appropriate and effective treatment to improve patient outcomes.

Don’t miss anything actionable with NeoGenomics’ largest pan-cancer CGP assay, Neo Comprehensive^™–Solid Tumor. For more information, visit the Neo Comprehensive^™–Solid Tumor website (https://neogenomics.com/diagnostic-services/specialty-testing/neo-comprehensive-solid-tumor).

Large Panel Testing Is Needed to Calculate TMB and MSI

TMB has recently emerged as a predictive immunotherapy biomarker for solid tumors.¹² Reference standards for TMB calculation state that an assay should sequence at least 1Mb genomic sequence, i.e. more than 300 genes, to calculate TMB. The Neo Comprehensive^™–Solid Tumor (TSO500) assay calculates TMB using 1.94 mb genomic content (517 genes). TMB scores are classified as high: ≥ 13.7 mut/mb, intermediate: ≥ 5.7 to < 13.7 mut/mb, and low: < 5.7 mut/mb. Similar assays that assess TMB with under 1.0 mb of DNA sequence increase the variability in TMB calls across clinical practice.²²

MSI status is an FDA-approved biomarker for the treatment selection of checkpoint inhibitor therapies for solid tumors.²³ MSI is scored in tumors by analyzing 130 MSI marker sites. More than 40 usable MSI sites are required to produce a score. A cutoff of 30% unstable MSI sites is used to define a status of MSI-stable (< 30%) versus MSI-high (≥ 30%), upon which prescribing decision can be based.

References

Illumina TruSight Oncology 500 and TruSight Oncology 500 High- Throughput data sheet.
NeoGenomics Pharma Services TSO500 Fact Sheet.
Illumina, Analysis of TMB and MSI Status with TruSight Oncology 500.
Sivapiragasam A., et al. Predictive Biomarkers for Immune Checkpoint Inhibitors in Metastatic Breast Cancer. Cancer Med. 10, 53-61 (2020).
Shang Y., et al. Comprehensive genomic profile of Chinese lung cancer patients and mutation characteristics of individuals resistant to icotinib/ gefitinib. Scientific Reports. 10, 20243 (2020).
Rosenthal SH, Gerasimova A, Ma C, et al. Analytical validation and performance characteristics of a 48-gene next-generation sequencing panel for detecting potentially actionable genomic alterations in myeloid neoplasms. PLoS One. 2021;16(4):e0243683. Published 2021 Apr 28. doi:10.1371/journal.pone.0243683
Pennell NA, Mutebi A, Zhou ZY, et al. Economic Impact of Next-Generation Sequencing Versus Single-Gene Testing to Detect Genomic Alterations in Metastatic Non-Small-Cell Lung Cancer Using a Decision Analytic Model. JCO Precis Oncol. 2019;3:1-9. doi:10.1200/PO.18.00356
Zou D, Ye W, Hess LM, et al. Diagnostic Value and Cost-Effectiveness of Next-Generation Sequencing-Based Testing for Treatment of Patients with Advanced/Metastatic Non-Squamous Non-Small-Cell Lung Cancer in the United States. J Mol Diagn. 2022;24(8):901-914. doi:10.1016/j.jmoldx.2022.04.010
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NCCN Guidelines® NCCN Version 7.2024 from June 26, 2024
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Benayed R, Offin M, Mullaney K, et al. High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden. Clin Cancer Res. 2019;25(15):4712-4722. doi:10.1158/1078-0432.CCR-19-0225
Westphalen CB, et al. NPJ Precis Oncol. 2021;5(1):69.
Li Y, Wang B, Wang C, et al. Genomic and Transcriptional Profiling of Chinese Melanoma Patients Enhanced Potentially Druggable Targets: A Multicenter Study. Cancers (Basel). 2022;15(1):283. Published 2022 Dec 31. doi:10.3390/cancers15010283
Moore DA, Benafif S, Poskitt B, et al. Optimising fusion detection through sequential DNA and RNA molecular profiling of non-small cell lung cancer. Lung Cancer. 2021;161:55-59. doi:10.1016/j.lungcan.2021.08.008
Lopez-Diaz FJ, et al. ASCO Annual Meeting, June 3-7, 2022. Abstract e18804.
https://www.illumina.com/company/news-center/feature-articles/rna-sequencing-critical-to-identifying-key-fusions-for-oncology-.html (https://www.illumina.com/company/news-center/feature-articles/rna-sequencing-critical-to-identifying-key-fusions-for-oncology-.html). AMP 2022, Illumina, two abstracts on TSO 500’s RNA fusion
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Stenzinger A., et al. Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions. Genes Chromosome. Cancer 58, 578-588 (2019).
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Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clinical Cancer Research 25, 3753–3758 (2019).

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