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When a lung adenocarcinoma escapes targeted therapy by turning into a different cell type, usually small-cell.
Histologic transformation is the escape of a lung adenocarcinoma from targeted therapy by changing cell type, most often into small-cell lung cancer and sometimes into squamous carcinoma. It accounts for a minority of resistance to EGFR tyrosine kinase inhibitors, is more likely when RB1 and TP53 are lost at baseline, and is also seen after ALK and KRAS inhibitors. It is not detectable by ctDNA genotyping, so it requires a repeat tissue biopsy, after which treatment switches to platinum-etoposide. The term connects to the resistance bottleneck, the resistance-routes map, the lineage plasticity pathway and the hallmark of unlocking phenotypic plasticity. Transformation is also described in follicular lymphoma, peripheral T-cell lymphoma and Waldenström macroglobulinaemia.
In plain words · A growth receptor that is mutated in some lung cancers and overproduced in others; the first great success of targeted pills.
Showing the target this term concerns: EGFR.
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
It is the right shape of answer for a transition that is epigenetic rather than genetic, and it could in principle spare the biopsy that is currently the only way to make this diagnosis.
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.
It is the practical guide to what to do after transformation: treat it as small-cell lung cancer with platinum and etoposide, expect central nervous system disease, and do not expect a checkpoint inhibitor to help.
It gives the field a vocabulary for the states between androgen receptor-driven adenocarcinoma and small cell carcinoma, which matters because those in-between tumours are the ones most likely to be mismanaged as ordinary castration-resistant disease.
It shows that leaving androgen receptor dependence does not have to mean becoming neuroendocrine, and it names a treatable pathway for a group of men whose tumours would otherwise be described only by what they lack.
It made transformation predictable from the first biopsy, using two stains that most pathology laboratories can already run, which is the practical way to know which patients need close watching and early rebiopsy.
It turned neuroendocrine transformation from a pathological curiosity into a mechanism with a genotype and a candidate intervention, and it is the reason EZH2 inhibitors are in prostate cancer trials at all.
A mechanism for the most feared form of treatment resistance in prostate cancer, and the reason combined TP53 and RB1 loss is worth knowing about before a man starts an androgen receptor drug rather than after his biopsy comes back neuroendocrine. Reversibility in the laboratory is also an argument that the switch is a target and not just a prognosis.
Shares Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer, Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance, Neuroendocrine differentiation in prostate cancer, SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer.
Shares Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance, SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer, Neuroendocrine and small-cell prostate cancer, Lineage plasticity & neuroendocrine transformation.
Shares Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares RB1, Lineage plasticity & neuroendocrine transformation, Drug resistance (primary and acquired), Metastatic castration-resistant prostate cancer.
Shares Neuroendocrine differentiation in prostate cancer, SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired).
Shares Hallmark (2022): unlocking phenotypic plasticity, Cancer stem cells & phenotypic plasticity, Extrapulmonary neuroendocrine carcinoma, Neuroendocrine and small-cell prostate cancer.
Shares Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Acquired resistance to every therapy, EGFR-mutated non-small-cell lung cancer.
Shares Proposed morphologic classification of prostate cancer with neuroendocrine differentiation, Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer, Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling, Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers.