FOXO1 fusion status and IRS group (rhabdomyosarcoma)

What is measured: the presence of a PAX3::FOXO1 or PAX7::FOXO1 fusion, and the extent of disease at surgery. How: FISH with a FOXO1 break-apart probe or RT-PCR and RNA sequencing for the fusion; PAX3::FOXO1 is found in about 60 percent of alveolar rhabdomyosarcomas and carries the worse outlook, PAX7::FOXO1 in about 20 percent, and the fusion-negative fifth behaves like embryonal disease; sequencing also finds MYOD1 L122R (spindle cell and sclerosing tumours, very poor), TP53 mutation (poor), RAS pathway mutations in embryonal disease and DICER1 in a few. The IRS clinical group records what surgery left behind (I complete resection, II microscopic residual or involved nodes, III gross residual or biopsy only, IV metastases) and the TNM stage records site (favourable: orbit, non-parameningeal head and neck, non-bladder and non-prostate genitourinary, biliary), size and nodes; age under 1 or over 10 is unfavourable. What a result changes: fusion-positive localised disease is treated as intermediate risk whatever the histology, with vincristine, actinomycin and cyclophosphamide plus irinotecan in COG trials and maintenance vinorelbine and cyclophosphamide from the RMS 2005 trial; fusion-negative low-risk disease gets shorter therapy with less alkylator; the European FaR-RMS trial stratifies by fusion rather than histology; radiotherapy dose follows the group; MYOD1-mutant tumours join the very high-risk arm. Where it matters: rhabdomyosarcoma.