New Study: Biomarker Identification for Targeted Therapies in 10K Tumor Samples

Data reveal several key capabilities of the OncoExTra test that contribute to that high percentage of actionable alterations. For example, it can match biomarkers for a range of therapies, including those that are off-label, cancer-agnostic, or in clinical trials. RNA analysis reveals actionable fusions that DNA analysis alone may miss. Another key capability—and a highlight of the study—is the test’s ability to detect key biomarkers at very low variant allele frequency.

Knowing all the options at the start

The case for choosing ultra-comprehensive genomic profiling over smaller fixed panels is now widely known. It offers doctors a more complete picture with information they need to make treatment decisions, including detecting RNA fusions, right from the start. It also eliminates the need for running sequential DNA and RNA tests, each of which diminishes the supply of tissue for testing. Importantly, comprehensive genomic profiling goes beyond biomarkers that are traditionally evaluated for specific tumor types to include appropriate off-label FDA-approved therapies, clinical trials, and cancer-agnostic therapies that are FDA-approved for a given biomarker, regardless of the cancer type.

In this first large-scale retrospective look at the OncoExTra test database, including 11,091 solid tumor samples from 10,768 patients, these advantages were clear:

• On- and off-label FDA-approved therapies – The test identified biomarkers associated with on-label FDA-approved therapies in 29.2% of samples, and it identified biomarkers for off-label therapies in 28.0% of samples. The results reflect therapies available at the time of testing.
• Therapeutically relevant RNA fusions – Analysis identified clinically relevant RNA fusion biomarkers in 7.5% of samples. Of these, 30.9% of fusions approved for matched therapies were found in the RNA only, highlighting the importance of RNA sequencing for fusion detection.

These results encompass 31 distinct tumor types, the most common of which were breast, colorectal, prostate, non-small cell lung, and epithelial ovarian cancer (56% of all samples). Single nucleotide variants were the most frequent therapeutically actionable alteration, present in 85.3% of samples.

Performance highlight: Low 1% limit of detection

In personalized medicine, where treatment hinges on the ability of ultra-comprehensive genomic profiling to identify key biomarkers, a test’s sensitivity to detect those biomarkers at very low levels is crucial. Authors of Exact Sciences’ retrospective tumor analysis were pleased to find that the OncoExTra test’s sensitivity allowed it to identify biomarkers at levels as low as 1%—biomarkers that would not be identified with less sensitive tests.

The quantity of a given biomarker, or variant allele frequency (VAF), is high in some tumor samples and low in others. There are many reasons for this finding, such as variants only occurring in some of a patient’s cancer cells (tumor heterogeneity), sample degradation, and the excised tumor sample containing a higher percentage of healthy cells vs. cancer cells (low tumor fraction).

Data show how the OncoExTra test’s ability to detect biomarkers in low-VAF samples translates into more targeted therapy options for oncologists and patients.

• Making a difference in treatment
  • Because the OncoExTra test can identify validated hotspot biomarkers at low VAF, patients had 15.8% more clinically relevant results, including 10.9% more results that qualified patients for an FDA-approved matched therapy.
• Detecting very low-VAF biomarkers
  • 9.8% of detected hotspot alterations associated with an on- or off label FDA-approved matched therapy were detected at a VAF below 5%.
  • In HR+/HER2- breast cancer, 8.7% of detected hotspot alterations associated with an on-label therapy were detected at a VAF below 5%. In CRC and NSCLC, 4.2% and 3.6% were detected below 5% VAF, respectively.

These results show the real-world impact of overcoming some biological and technical limitations of this type of testing. We can now detect low-VAF biomarkers through a next-generation sequencing assay and get the answers that oncologists and their patients need. Oncologists can feel less uncertainty about whether a negative result means something was missed and can get the full picture from ultra-comprehensive genomic profiling.

Opening doors to treating advanced cancers

For patients with advanced cancers, detecting key biomarkers is essential to providing the best options for therapy. Broad-based testing of DNA and RNA with a low limit of detection is essential for helping find eligible therapies for these patients today, as well as in the future as the list of therapies continues to grow.

1. De La O JP, Hoag JR, Deem AK, et al. Comprehensive genomic profiling of over 10,000 advanced solid tumors. PubMed. 2025;16:587-603. doi:10.18632/oncotarget.28757

Jean Paul De La O is Senior Principal Medical Affairs Director at Exact Sciences.

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.