A report issued by the European Society of Medical Oncology (ESMO) on the use of multigene next-generation sequencing (NGS) to characterize 8 types of metastatic, solid tumors associated with the greatest number of cancer-related deaths worldwide, represents the first guidance provided by a scientific society on this topic in the setting of routine clinical practice. These recommendations were published in Annals of Oncology.
Recent advances in high-throughput NGS technology have made it possible to quickly sequence a large number of genes at relatively low cost. Nevertheless, questions remain regarding the clinical utility of these assays in characterizing tumor types in a variety of clinical settings, and whether this method can substitute for other types of tests currently in use.
To address these questions, the ESMO Precision Medicine Working Group ranked known potentially pathogenic alterations in 8 types of solid tumors according to the evidence demonstrating that they are actionable molecular targets of particular types of targeted therapy.
This method, called the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT), was then applied to each alteration within each cancer type of interest to provide 1 of 4 rankings:
- Level 1: clinical trial data validating match between alteration and drug in cancer type of interest
- Level 2: data from phase 1/2 trials or retrospective analyses of randomized trials associating alteration with responses to drug in cancer type of interest
- Level 3: clinical trial data validating match between alteration and drug in another cancer type, but not the cancer type of interest
- Level 4: preclinical data suggesting association between alteration and drug
Based on the ESCAT rankings as well as the prevalence of each alteration, the use of tumor multigene NGS profiling was designated as appropriate for use in daily clinical practice, at clinical research centers, and/or within the context of specific considerations for the individual patients, with the latter recommendation taking into account the potential for the patient to be an exceptional responder to a particular type of targeted therapy.
Specifically, tumor multigene NGS was recommended by the ESMO group for the detection of level 1 alterations in daily clinical practice in the setting of nonsquamous lung adenocarcinoma and prostate cancer, and for consideration in the setting of cholangiocarcinoma. Plasma multigene NGS was also considered appropriate in the setting of nonsquamous lung adenocarcinoma.
“In these [tumors], large multigene panels could be used if they add acceptable extra cost compared with small panels,” the authors of these recommendations commented.
In addition, the use of tumor multigene NGS in daily clinical practice as a substitute for a polymerase chain reaction (PCR)-based assay to characterize microsatellite status in the setting of colon cancer, somatic BRCA1/2 mutations in the setting of ovarian cancer, and the tumor mutational burden (TMB) in a number of other cancer types, including cervical cancers, well- and moderately-differentiated neuroendocrine tumors, salivary cancers, thyroid cancers and vulvar cancers, was also sanctioned by the ESMO Working Group, with the latter recommendation based on the recent approval of the programmed cell death-1 inhibitor, pembrolizumab, in the setting of high TMB.2
In contrast, the ESMO Working Group recommended against the use of multigene NGS profiling in daily clinical practice for the characterization of squamous cell lung cancer, breast cancer, hepatocellular carcinoma, gastric cancer, and pancreatic cancer. Specifically, it was recommended that identification of alterations in specific gene targets in these tumors, such as NTRK fusions,be performed using cheaper standard tests.
Other recommendations regarding multigene NGS profiling were the importance of using rigorous, standardized protocols to ensure assay validation, as well as its more widespread use at clinical research centers to identify patients suitable for clinical trials related to targeted therapy and also to prospectively capture data on these patients.
In summarizing these recommendations from the ESMO Precision Medicine Working Group, the authors noted that they “will need to be updated on a regular basis as new data emerges for novel therapies across [tumor] types.”
- Mosele F, Remon J, Mateo J, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol. Published online August 24, 2020. doi:S0923-7534(20)39971-3
- The ASCO Post. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. Published August 10, 2020. Accessed August 31, 2020.