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European Working Group Develops System to Classify Tumor Genomic Alterations

NEW YORK (GenomeWeb) – The European Society for Medical Oncology Translational Research and Precision Medicine Working Group has developed a system for classifying molecular alterations found in patients' tumors.

The system, described today in a publication in the Annals of Oncology, classifies alterations based on their relevance as markers for matching patients with targeted treatment, including both treatments that have regulatory approval and those that are still in clinical trials.

"For the first time, ESMO has created the tools to make it clear what data are needed for a mutation to be considered actionable and how this may change in response to new clinical data," Joaquin Mateo, lead author of the paper and principal investigator of the Prostate Cancer Translational Research Group at the Vall d'Hebron Institute of Oncology in Spain, said in a statement. "The scale focuses on the clinical evidence for matching tumor mutations with the drugs we have in our clinics and gives us a common vocabulary for communication between clinicians, and for explaining potential treatment benefits to patients."

In the study, the team described five classes of targetable mutations. Tier I mutations are targets that can be used in routine clinical decisions such as HER2 amplifications in breast cancer and EGFR in non-small cell lung cancer. Tier II mutations are investigational targets for which evidence exists that patients would benefit from a targeted therapy, but for which additional data is still needed. The group considers alterations within the PTEN pathway, including PIK3CA and AKT1 mutations to fall within this category. Tier III mutations are those for which clinical benefit has been demonstrated in other tumor types but not the tumor type of the patient tested, including BRAF mutations in cancers other than melanoma. Tier IV mutations are those for which there is only preclinical evidence. And Tier V mutations are those for which there is evidence that they could be beneficial as co-targets. These include PIK3CA mutations in breast cancer.

The ESMO classification system is similar to the classification system described last year by a team led by the Association for Molecular Pathology. And, the ESMO team noted that other efforts have been made to standardize how cancer variants are reported and used to guide targeted therapies, including by the University of Texas MD Anderson Cancer Center and the Memorial Sloan Kettering Cancer Center.

However, the ESMO researchers cautioned in their new paper that the various classification systems are only "partially overlapping" and "none of them have been broadly implemented in clinical practice." In addition, the authors noted that the various systems give top tier designation to variants with regulatory approval status in the groups' respective geographic regions, which "introduces bias in the context of global cancer research."

By contrast, the ESMO team gave variants the highest classification — Tier I-A — if randomized prospective clinical trials have demonstrated "clinically meaningful improvement of a survival endpoint," rather than basing the designation on a specific regulatory approval.