{"entity":{"id":"paper-offin-rb1-tp53-transformation-risk-jto-2019","kind":"paper","name":"Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes","aka":[],"tldr":"Lung cancers with mutations in all three of the same genes make up only a twentieth of the targetable group, but they are the ones that turn into a different cancer, and they stop responding to treatment three times sooner than the rest.","summary":"Patients with EGFR, RB1 and TP53-mutant lung cancers identified by next-generation sequencing between 2014 and 2018 were compared with patients with untreated metastatic EGFR-mutant lung cancers lacking both RB1 and TP53 alterations. The triple-mutant group represented 43 of 863 EGFR-mutant lung cancers, 5%, but was uniquely at risk of transformation, 7 of 39, 18%, with no transformations among EGFR-mutant cancers without baseline TP53 and RB1 alterations. Irrespective of transformation, triple-mutant patients had a shorter time to EGFR inhibitor discontinuation than EGFR and TP53-mutant or EGFR-only cancers, 9.5 against 12.3 against 36.6 months. The triple-mutant population had a higher incidence of whole-genome doubling than non-small-cell lung cancer at large, 80% against 34%, further enriched in those that eventually became small-cell, and an APOBEC mutation signature was enriched in the cancers that transformed.","asOf":"2026-09-25","links":[{"label":"Offin et al., J Thorac Oncol 2019: concurrent RB1 and TP53 alterations and the risk of histological transformation in EGFR-mutant lung cancer","url":"https://doi.org/10.1016/j.jtho.2019.06.002"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31228622/"}],"tags":[],"related":[],"cancers":["nsclc","sclc"],"sections":[],"technologies":["cgp"],"targets":["egfr","rb1","tp53"],"drugs":[],"companies":[],"institutions":["mskcc"],"pathways":["lineage-plasticity-neuroendocrine","resistance-routes-map","clonal-evolution","mutagenesis-signatures"],"terms":["histologic-transformation","resistance","mutational-signature"],"trials":[],"people":["charles-rudin"],"bottlenecks":[],"keyPapers":[],"journals":["journal-of-thoracic-oncology"],"dependsOn":[],"notes":[],"journal":"Journal of Thoracic Oncology","year":2019,"doi":"10.1016/j.jtho.2019.06.002","pmid":"31228622","authors":"Offin M, Chan JM, Tenet M, et al.","paperType":"observational","findings":["Triple-mutant EGFR, RB1 and TP53 cancers are 5% of EGFR-mutant disease and account for the transformations.","Transformation occurred in 18% of the triple-mutant group and in none without baseline RB1 and TP53 loss.","Time to EGFR inhibitor discontinuation 9.5 against 36.6 months for EGFR-only cancers.","Whole-genome doubling in 80% of the triple-mutant group."],"whatItMeans":"It gives the sequencing report a prognostic reading that does not depend on a repeat biopsy: an EGFR-mutant cancer that also carries RB1 and TP53 alterations will stop responding sooner and should be watched for a change of histology.","caveats":["Single centre and retrospective.","Transformation is diagnosed only where a rebiopsy was taken, so the rate may be underestimated in both groups.","Whole-genome doubling estimates come from panel data."],"changedPractice":false,"participants":863},"route":"/key-papers/paper-offin-rb1-tp53-transformation-risk-jto-2019/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"histologic-transformation","kind":"term","name":"Histologic transformation","route":"/terms/histologic-transformation/"},{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"}],"person":[{"id":"charles-rudin","kind":"person","name":"Charles M. Rudin","route":"/people/charles-rudin/"}],"journal":[{"id":"journal-of-thoracic-oncology","kind":"journal","name":"Journal of Thoracic Oncology","route":"/journals/journal-of-thoracic-oncology/"}]}}