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Androgen receptor signalling is prostate cancer's engine. Testosterone becomes DHT, binds the androgen receptor, and drives growth genes. Castration removes the fuel; newer pills block the receptor or the enzyme that makes fuel inside the tumour.
Testicular testosterone (and adrenal precursors converted intratumourally via CYP17A1) is reduced to DHT by 5α-reductase and binds AR, which translocates to the nucleus and drives PSA, TMPRSS2-ERG, and proliferation genes. GnRH agonists/antagonists shut testicular production; abiraterone blocks CYP17A1; enzalutamide, apalutamide, darolutamide block AR. Castration resistance arises via AR amplification, ligand-binding mutations, splice variants (AR-V7 lacks the ligand domain), glucocorticoid receptor substitution, and lineage plasticity to neuroendocrine phenotype.
Same key-and-lock idea as oestrogen: castration stops making keys, abiraterone shuts the tumour's own key factory, enzalutamide blocks the lock. AR-V7 is a lock with no keyhole that is permanently open.
It separates two explanations that are usually run together. Some of the difference in prostate cancer outcomes by race is in the tumour genome and persists when access to the same centre is held constant, and some of it tracks with income rather than with ancestry, so equalising access alone would not eliminate the gap.
It established plasma profiling as a routine alternative to tissue for the BRCA question in advanced prostate cancer, with a sensible rule attached: if plasma finds nothing actionable, go back to tissue. It also documents at scale both the extra resistance information plasma gives and the clonal haematopoiesis noise that comes with it.
It is the prospective test of the PI3K and androgen receptor feedback hypothesis in men, and it shows both halves of the answer: the biomarker-selected population benefits, and the benefit is small enough that the toxicity has to be weighed honestly.
It splits the alterations into two groups with different practical meanings. The repair defects are present at diagnosis at close to their castration-resistant prevalence, so testing early is worthwhile; AR, TP53 and RB1 changes accumulate later, so a diagnostic sample does not answer questions about the disease in front of you at relapse.
It fills the gap between the primary-tumour atlases and the castration-resistant series by describing the disease at the moment most treatment decisions are actually made, and it identifies SPOP as a favourable marker rather than a neutral one.
It is the most disciplined outcome analysis in this disease and its result is deflationary in a useful way: most of the alterations people quote as prognostic do not survive adjustment, and the one that does, RB1, is also the one that marks the route to neuroendocrine transformation.
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 turned a single-centre observation into a prospectively validated one and concluded that AR-V7-positive men should be offered alternatives to abiraterone and enzalutamide. It also quantified the honest limit: two assays for the same analyte disagree on nearly one sample in five.
Shares Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer, PROPHECY: prospective multicentre validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer, AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L), AR-V7 splice variant.
Shares The TMPRSS2-ERG rearrangement, ERG expression and prostate cancer outcomes: a cohort study and meta-analysis, Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer, Whole-genome and transcriptome sequencing of prostate cancer identifies new genetic alterations driving disease progression, TMPRSS2-ERG fusion (and the other ETS rearrangements).
Shares Differences in prostate cancer genomes by self-reported race, PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate, IPATential150: ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer, Reciprocal feedback regulation of PI3K and androgen receptor signalling in PTEN-deficient prostate cancer.
Shares Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer, Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer, PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate, Genomic correlates of clinical outcome in advanced prostate cancer.
Shares Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer, Differences in prostate cancer genomes by self-reported race, Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer, Genomic correlates of clinical outcome in advanced prostate cancer.
Shares The TMPRSS2-ERG rearrangement, ERG expression and prostate cancer outcomes: a cohort study and meta-analysis, Whole-genome and transcriptome sequencing of prostate cancer identifies new genetic alterations driving disease progression, TMPRSS2-ERG fusion (and the other ETS rearrangements), Integrative genomic profiling of human prostate cancer.
Shares Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer, Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer, PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate, Genomic correlates of clinical outcome in advanced prostate cancer.
Shares Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer, PROPHECY: prospective multicentre validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer, Reciprocal feedback regulation of PI3K and androgen receptor signalling in PTEN-deficient prostate cancer, Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling.