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In a minority of men, prostate cancer escapes hormone drugs by becoming a different kind of cell that no longer needs the androgen receptor. By the time a biopsy shows it, the treatment options are almost gone. The genetic changes that allow the switch are detectable years earlier, and nobody is looking for them.
Mu and Ku showed in 2017 that combined loss of TP53 and RB1 function enables prostate cancer cells to shift from androgen receptor-dependent luminal cells to androgen receptor-independent basal-like cells, mediated by SOX2, and that restoring the tumour suppressors reverses it in the laboratory. Beltran had already shown that neuroendocrine prostate cancer arises by divergent clonal evolution from the same tumour rather than as a separate disease. Aggarwal found treatment-emergent small-cell neuroendocrine carcinoma in 17 percent of metastatic biopsies in a prospective cohort. Chung found RB1 alteration enriched in metastatic over primary samples.
The enabling lesions are therefore known, detectable in circulating tumour DNA, and present before the phenotype changes. What is missing is any protocol that uses them. A man with combined TP53 and RB1 loss who is started on a third androgen receptor-directed line is being given a treatment his tumour is predisposed to escape by the one route that leads nowhere. The proposal is a two-part programme: serial circulating tumour DNA genotyping for TP53 and RB1 status, plus a plasma transcriptional readout of neuroendocrine identity, in men starting an androgen receptor pathway inhibitor for castration-resistant disease; and a randomised test of whether men who convert should switch to platinum-based chemotherapy or a neuroendocrine-directed agent at conversion rather than at biopsy-proven transformation.
UK and NHS specifics (the National Screening Committee position, NICE technology appraisals and their recommendation numbers, Cancer Drugs Fund status, magnetic resonance imaging and radiotherapy capacity, National Prostate Cancer Audit indicators and trial access) belong on the UK and NHS page for prostate cancer and are not restated here.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
What a prostate cancer sequencing report looks like in practice, and the numerical basis for two clinical rules: do not expect checkpoint immunotherapy to work unless the tumour is mismatch repair deficient, and do not treat a CDK12 alteration as if it were a BRCA alteration.
Biopsy of progressing lesions, especially with low PSA or visceral spread, is recommended to detect neuroendocrine transformation and switch to platinum-based therapy or trials.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
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.
Treatment-emergent neuroendocrine prostate cancer is understood as lineage plasticity under androgen receptor blockade; EZH2, DLL3 and Aurora kinase are the targets under investigation.
Shares Destroy the truncated androgen receptor that hormone drugs cannot touch, SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer, Neuroendocrine differentiation in prostate cancer, Abiraterone acetate and the tag prostate-evidence.
Shares Tumour heterogeneity and clonal evolution, Castration-resistant prostate cancer (CRPC), Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch, Androgen receptor and the tag prostate-evidence.
Shares Castration-resistant prostate cancer (CRPC), The undruggable drivers, Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch, Androgen receptor and the tag prostate-evidence.
Shares Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours, Next-generation sequencing (NGS), Castration-resistant prostate cancer (CRPC), Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch and the tag prostate-evidence.
Shares Abiraterone acetate, Enzalutamide, Castration-resistant prostate cancer (CRPC), Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch and the tag prostate-evidence.
Shares Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours, Abiraterone acetate, Enzalutamide, Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch and the tag prostate-evidence.
Shares Next-generation sequencing (NGS), The undruggable drivers, Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch, Androgen receptor and the tag prostate-evidence.
Shares Enzalutamide, Castration-resistant prostate cancer (CRPC), Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch, Androgen receptor and the tag prostate-evidence.