Getting the Full Story: The Importance of Ultra-Comprehensive Genomic Profiling in Advanced Cancer Therapy Selection

The drive to help physicians connect patients with their optimal treatment paths is behind the OncoExTra® test from Exact Sciences. This comprehensive genomic profiling test uncovered clinically actionable variants in 84% of patients with advanced solid tumors—and this number increases to over 90% in colorectal, lung, bladder, and breast cancers.^*1 To inform assessment and accuracy of each patient’s somatic mutations, given the complex tapestry of genetic ancestry in the US, it includes germline sequencing.¹ Germline results can also inform treatment decisions, such as homologous recombination repair (HRR) gene assessment to determine poly (ADP-ribose) polymerase (PARP) inhibitor eligibility. Germline assessment also ensures that physicians get high-quality results for tumor mutation burden (TMB).^1,2 As the list of targeted therapies continues to evolve, published guidelines shift toward broader genomic profiling, including germline and RNA assessment, and as insurance coverage grows (98% of patients have no out-of-pocket costs³), I expect this level of comprehensive testing to become standard. 

The importance of RNA testing 

DNA alone does not offer the full genomic picture for advanced cancer therapy selection, and physicians who rely on it exclusively may be missing key biomarker information. Although DNA identifies single nucleotide variants (SNVs), genetic insertions and deletions (INDELs), and copy number variants, RNA sequencing is often required to find transcript variants and structural variants such as gene fusions. By sequencing RNA up front, doctors can initiate therapy with the complete list of potential targeted therapies. This is more important than ever, as recent improvements in RNA sequencing have driven rapid evolution of targeted therapies for gene fusions.

RNA analysis brings so much value to clinical decision-making that the American Society of Clinical Oncology® (ASCO®) and the National Comprehensive Cancer Network® (NCCN®) have updated their guidelines for lung cancer to include broader testing with RNA sequencing.^4,5

To ensure that we detect candidates for new therapies, Exact Sciences has once again led the field in ultra-comprehensive genomic profiling by making clinical-grade RNA sequencing accessible to everyone with the OncoExTra test. The test includes whole-exome DNA sequencing and whole-transcriptome RNA sequencing.^† Now, instead of waiting before ordering RNA testing, doctors and patients can know the complete range of DNA- and RNA-guided choices for initial therapy while they save time by testing for all possibilities up front, rather than retesting later. Doctors can also select from a comprehensive menu to add immunohistochemistry (IHC)^‡ stains to the same report for thorough tumor classification. 

Benefits of inclusive germline data

We use germline subtraction to improve somatic variant detection and validate that a genomic variant is a somatic alteration and not a normal genetic variant attributable to the patient’s unique heredity. Unfortunately, not everyone’s heredity is reflected in normative databases, where many groups have historically been underrepresented.⁶ Lack of germline subtraction may reduce the accuracy of DNA sequencing results for many patients.²

To make germline testing more accurate and actionable, the OncoExTra test employs patient-matched tumor-normal sequencing, a comparison of the gene sequences of both somatic and germline DNA. This process accounts for real-world genetic diversity, identifying key variants while ruling out benign hereditary polymorphisms to potentially better identify immunotherapy candidates and limit false positives.¹ Physicians get the accurate molecular information they need about their patient’s unique tumor makeup, regardless of ethnicity or heritage.

Patient-matched tumor-normal sequencing is also beneficial for accurate evaluation of TMB (the total number of mutations in cancer cell DNA), which relies on whole-exome sequencing with germline subtraction. Most DNA tests are hotspot panels of about a million base pairs, rather than the 30 million base pairs in the full exome. Because the OncoExTra test does whole-exome sequencing and patient-matched tumor-normal profiling, it can exclude variants found in the germline sample to reduce overestimation of TMB, helping doctors avoid adverse effects or potential toxicity from immune checkpoint inhibitors.⁷

Preparing to make treatment decisions

We’ve finally reached a point where physicians can make vital treatment decisions based on the complete genomic profile. We can sequence the whole DNA exome, RNA transcriptome and the germline exome for germline subtraction, and then continue utilizing these results throughout the patient’s treatment. It is tailor-made for today’s changing therapeutic environment, covering all the genes oncologists need to make informed treatment decisions today and in the future.
 

*Clinically actionable variants are defined as variants that are associated with available therapies or clinical trial enrollment for a specific somatic variant identified in a patient’s tumor^1
† Whole-transcriptome with select variants reported in New York State
^‡ IHC testing not currently available in New York State
 

References:

1. White T, Szelinger S, LoBello J, et al. Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®. Oncotarget. 2021;12(8):726-739. Published 2021 Apr 13. doi:10.18632/oncotarget.27945

2. Asmann YW, Parikh K, Bergsagel PL, et al. Inflation of tumor mutation burden by tumor-only sequencing in under-represented groups. NPJ Precis Oncol. 2021;5(1):22. Published 2021 Mar 19. doi:10.1038/s41698-021-00164-5

3. Exact Sciences estimate is based on historical billing. This calculation includes patients with Medicare, Medicare Advantage, Medicaid, Managed Medicaid and commercial insurance and includes the cost of both NGS and IHC components as most commonly ordered by providers. Patient cost-sharing amounts, including deductibles and copays, will vary by plan and coverage type. Only your patient’s insurer can confirm if and how the OncoExTra® test will be covered.

4. Chakravarty D, Johnson A, Sklar J, et al. Somatic genomic testing in patients with metastatic or advanced cancer: ASCO provisional clinical opinion. Clin Oncol. 2022;40(11):1231-1258. doi:10.1200/jco.21.02767

5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.5.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed April 23, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

6. Sirugo G, Williams SM, Tishkoff SA. The missing diversity in human genetic studies [published correction appears in Cell. 2019;177(4):1080. doi: 10.1016/j.cell.2019.04.032]. Cell. 2019;177(1):26-31. doi:10.1016/j.cell.2019.02.048

7. Parikh K, Huether R, White K, et al. Tumor mutational burden from tumor-only sequencing compared with germline subtraction from paired tumor and normal specimens. JAMA Netw Open. 2020;3(2):e200202.


Rick Baehner, MD, is Chief Medical Officer of Precision Oncology at Exact Sciences and Clinical Professor of Pathology at University of California, San Francisco.
 

The OncoExTra test was developed, and the performance characteristics validated by Genomic Health, Inc., a wholly owned subsidiary of Exact Sciences Corporation following College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) regulations. The OncoExTra test is performed at the Genomic Health Phoenix clinical laboratory. Exact Sciences clinical laboratories are accredited by CAP, certified under CLIA regulations, and qualified to perform high-complexity clinical laboratory testing. This test has not been cleared or approved by the US Food and Drug Administration or other notified regulatory authority.

Benefits of Comprehensive DNA/RNA Sequencing With the OncoExTra Test¹

• Whole-exome DNA sequencing and whole-transcriptome RNA sequencing uncovered clinically actionable variants in 84% of patients with advanced solid tumors, including over 90% of colorectal, lung, bladder, and breast cancers¹
• With patient-matched tumor-normal sequencing, physicians get the accurate molecular information they need about their patient’s unique tumor makeup, regardless of ethnicity or heritage
• Accurate TMB assessment follows whole-exome sequencing of 30 million base pairs with germline subtraction—rather than hotspot panels—and delivers the results in an easy-to-interpret report for timely decision-making