New Dimensions in Comprehensive Genomic Testing

At the 2023 Clinical Pathways Congress and Cancer Care Business Exchange (CPC & CBEx) in Boston, Eric Severson, MD, PhD, MMSc, Labcorp Oncology, presented on genomic testing’s role in comprehensive oncology pathways. His presentation was titled “New Dimensions in Comprehensive Genomic Testing.”

Dr Severson began his presentation by breaking down different methodologies to detect biomarkers in patients: single gene assays, which look at each gene individually; hotspot panels, which sequence a smaller coding region of codons included on the panel; immunohistochemistry, which looks at protein expression within a tissue sample; and broad panel (comprehensive genomic profiling [CGP]), which is a next-generation sequencing (NGS) test that sequences a defined list of genes with at least 50 genes in total and may also include RNA testing.

According to Dr Severson, “Comprehensive genomic profiling of tumors is a powerful tool in oncology as it enables identification of biomarkers for diagnosis, targeted therapy selection, and clinical trial enrollment.” Patients with metastatic non–small cell lung cancer (NSCLC) that have oncogenic driver alterations have been found to have improved overall survival when treated with biomarker-matched tyrosine kinase inhibitors (TKIs). As such, NCCN and ASCO guidelines recommend this broad genomic profiling prior to systemic chemotherapy or immunotherapy.

However, there is an urgency to treat the patient, and because CGP takes longer than traditional testing, there has historically been a reliance on single gene tests (SGTs). And oftentimes in early treatment, there can be missed opportunities if targeted genomic alterations are missed on the SGTs for patients with NSCLC. There are also worse survival rates for patients that get chemotherapy upfront and then switch to targeted therapy compared to those who wait for comprehensive test results and receive TKI initially.

A common testing strategy for patients with NSCLC is to order an SGT at diagnosis. If the SGT results are negative or at recurrence of progression, CGP tests are then ordered. A limitation for single gene therapy in lung cancer is that there are nine of these actionable biomarkers. According to Dr Severson, it is impossible to identify all nine of these alterations with SGTs, and each SGT takes a lot of tissue from the patient. It is difficult to re-biopsy a patient for comprehensive testing, as there may be limited tissue available after the SGT. Although liquid biopsy is an option, it sometimes will not produce results.

A perspective observational study by Nesline et al investigated the impact of SGT on subsequent CGP success in community oncology for patients with advanced NSCLC (J Clin Oncol. 2023;41[suppl 16]:6506. doi:0.1200/JCO.2023.41.16_suppl.6506). The study consisted of 80 different providers that had ordered one or more SGTs at more than 80 community oncology practices. The providers generally ordered SGTs first (polymerase chain reaction [PCR] or fluorescent in situ hybridization [FISH]) and, if the SGT results were negative or at recurrence, they would order CGP tests (DNA sequencing or RNA sequencing).

The study found that out of 580 patients, 29% had one or more negative SGT prior to the ordering of CGP. Dr Severson had assumed that there would be a consistent set of ordered panels, but instead there were 25 different unique orders of different combinations. No patients had all successful tests for all seven biomarkers (ALK, EGFR, ROS1, BRAF, KRAS, RET, MET). As a result, for patients that had prior vs no prior SGT, cancellations of CGP orders occurred twice as much. In addition, DNA extraction failed more often for CGP orders in patients that had prior SGT.

Patients that had single testing previously ended up having fewer targetable alterations that were identified, and thus fewer of the patients got onto their appropriate targeted therapy. The turnaround time for receiving test results was also longer for those who received SGT prior to CGP (16 days) rather than those who had CGP prior to SGT (13 days). In addition, the findings showed that a higher percentage of patients who had no prior SGT had a turnaround time of less than two weeks (71% vs 38%).

“Precision oncology requires a stepwise approach to testing where you’re looking for patients with actionable biomarkers, matching the therapies so that you can efficiently improve their survival,” said Dr Severson. He added that the results of these tests should be delivered in a timely manner to ensure that physicians receive them on time to treat the patient with the targeted therapy. He also emphasized good “tissue stewardship” to properly preserve the tissue samples for testing.

Aggarwal et al, cited by Dr Severson, found that in patients with stage IV NSCLC, those who had comprehensive molecular genotyping upfront had higher overall survival compared to those with incomplete or no testing (22.1 months vs 11.6 months; P = 0.017), regardless of the testing modality (J Clin Oncol. 2022;40[suppl 16]:9022. doi:10.1200/JCO.2022.40.16_suppl.9022). “We want to make sure everyone has access to this type of testing because that’s important for equitable outcomes . . . If you can imagine, patients have double the survival [rates] with this type of testing—not having access to this type of testing is going to increase inequities,” Dr Severson concluded.