# Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes

Source: https://onco.cc/key-papers/paper-offin-rb1-tp53-transformation-risk-jto-2019/  
OnCo record `paper-offin-rb1-tp53-transformation-risk-jto-2019` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Journal of Thoracic Oncology
- Year: 2019
- DOI: 10.1016/j.jtho.2019.06.002
- Authors: Offin M, Chan JM, Tenet M, et al.
- 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.
- What it means: 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.

## Sources

- Offin et al., J Thorac Oncol 2019: concurrent RB1 and TP53 alterations and the risk of histological transformation in EGFR-mutant lung cancer: https://doi.org/10.1016/j.jtho.2019.06.002
- PubMed: https://pubmed.ncbi.nlm.nih.gov/31228622/

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- terms: [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Mutational signature](https://onco.cc/terms/mutational-signature/)
- people: [Charles M. Rudin](https://onco.cc/people/charles-rudin/)
- journals: [Journal of Thoracic Oncology](https://onco.cc/journals/journal-of-thoracic-oncology/)

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