Improving Molecular Oncology by Making Results Available to Patients

Abstract

During the past 15 years, genomic analysis for selection of molecularly guided targeted therapy has become standard of care for a wide range of advanced solid tumors including non-small cell lung cancer (NSCLC) (eg, EGFR, ALK, ROS1), colorectal cancer (eg, KRAS, BRAF), breast cancer (eg, PIK3CA), and urothelial carcinoma (eg, FGFR2/3), with emerging targets being studied across a range of cancers. This has led to a growing array of available targeted therapies and a parallel increase in the number and diversity of molecular diagnostic tests to help with treatment selection. Tumor sequencing not only helps to inform which treatments are likely to be effective but also point to which therapies should not be used (eg, EGFR antibodies in KRAS-mutant colon cancer, immune checkpoint inhibitors in EGFR or ALK-positive NSCLC).Are we delivering on the promise of molecularly guided targeted therapy in our day-to-day practice? We can learn from focusing on advanced NSCLC, where genotyping should be well established given its established role for more than a decade and where recent real-world data demonstrate that we are falling short. First, too small a proportion of appropriate patients are receiving standard-of-care biomarker evaluation. 1 Furthermore, real-world evidence now reveals that even when testing is performed, the results are not appropriately informing therapy selection. In a recent report of the paired clinical and genomic data from Flatiron Health and Foundation Medicine, 2 which included 4064 patients with NSCLC (86.7% with advanced NSCLC at the time of analysis), of 737 patients with EGFR mutations or ALK rearrangements detected in their lung cancer, only 480 (65%) received biomarker-driven therapy at any point in their treatment. In patients harboring any biomarker recommended by the National Comprehensive Cancer Network as a current standard of care or emerging target, 3 only 48% received a targeted therapy over the course of their treatment.These results are clearly disappointing, and some may view them with skepticism. However, these data are corroborated by a report of testing and treatment patterns among 1203 patients with advanced NSCLC from 5 cancer practices, as captured in the Integra Connect database. 1 Among the patients with a targetable EGFR, ALK, ROS1, or BRAF molecular alteration detected, the available evidence demonstrated that only 45% received the appropriate targeted therapy. Among those patients who received an immune checkpoint inhibitor prior to receiving biomarker-driven therapy, most had the results of molecular testing back before initiating systemic therapy, suggesting there was a missed opportunity to treat these patients with appropriate targeted therapies.

Beyond finding druggable targets and tumor mutational burden: to measure heterogeneity by ctDNA

“…With the advances in molecular oncology, genomic analysis for selection of molecularly guided therapy has become standard of care for various advanced solid tumors (1,2). Tumor sequencing not only helps to inform which druggable targets are likely to be effective [e.g., EGFR-TKI in EGFR-mutant non-small cell lung cancer (NSCLC)] but also provides many promising biomarkers in guiding cancer immunotherapy [e.g., tumor mutational burden (TMB) and microsatellite instability (MSI)].…”