{"entity":{"id":"paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021","kind":"paper","name":"Genomic analysis of circulating tumour DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms","aka":[],"tldr":"The largest blood-based study in advanced prostate cancer found detectable tumour DNA in nineteen men out of twenty, agreed with tissue on BRCA faults nine times out of ten, and found resistance changes tissue had missed.","summary":"Using plasma from 3,334 men with metastatic castration-resistant prostate cancer, including 1,674 screening samples from the TRITON2 and TRITON3 trials, the landscape of genomic alterations detectable in circulating tumour DNA was evaluated and compared with tissue-based profiling. Three thousand one hundred and twenty-nine men, 94%, had detectable circulating tumour DNA, at a median tumour fraction of 7.5%, and BRCA1 or BRCA2 was mutated in 295, 8.8%. In the concordance analysis, 72 of 837 men had BRCA1 or BRCA2 mutations detected in tissue, of which 67, 93%, were also identified in circulating tumour DNA, including 100% of the variants predicted to be germline. Circulating tumour DNA harboured some BRCA alterations not identified by tissue testing and was enriched for therapy resistance alterations as well as for possible clonal haematopoiesis mutations, for example in ATM and CHEK2. Potential androgen receptor resistance alterations were detected in 940 of 2,213 men, 42%, including amplifications, polyclonal and compound mutations, rearrangements and novel deletions in exon 8.","asOf":"2026-09-25","links":[{"label":"Tukachinsky et al., Clin Cancer Res 2021: circulating tumour DNA profiling in 3,334 men with advanced prostate cancer, including 1,674 TRITON screening samples","url":"https://doi.org/10.1158/1078-0432.CCR-20-4805"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33558422/"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc"],"sections":[],"technologies":["liquid-biopsy","cgp"],"targets":["brca","androgen-receptor","atm","chek2"],"drugs":[],"companies":[],"institutions":[],"pathways":["homologous-recombination-repair","ar-signaling","clonal-haematopoiesis","resistance-routes-map"],"terms":["ctdna","cfdna","liquid-biopsy","germline-vs-somatic","gbrca-mutation"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["clinical-cancer-research"],"dependsOn":[],"notes":[],"journal":"Clinical Cancer Research","year":2021,"doi":"10.1158/1078-0432.CCR-20-4805","pmid":"33558422","authors":"Tukachinsky H, Madison RW, Chung JH, et al.","paperType":"observational","findings":["Detectable circulating tumour DNA in 3,129 of 3,334 men, 94%, at a median tumour fraction of 7.5%.","BRCA1 or BRCA2 mutated in 295 men, 8.8%.","Ninety-three per cent concordance with tissue for BRCA mutations, including 100% of predicted germline variants.","Potential androgen receptor resistance alterations in 940 of 2,213 men, 42%.","Enrichment for possible clonal haematopoiesis mutations, notably in ATM and CHEK2."],"whatItMeans":"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.","caveats":["Half the cohort came from trial screening, so it is enriched for men being considered for a PARP inhibitor.","One commercial assay, so the performance is that assay's.","The clonal haematopoiesis mutations were inferred rather than confirmed against a paired blood control."],"changedPractice":true,"participants":3334},"route":"/key-papers/paper-tukachinsky-ctdna-3334-advanced-prostate-ccr-2021/","neighbours":{"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"chek2","kind":"target","name":"CHEK2","route":"/targets/chek2/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"clonal-haematopoiesis","kind":"pathway","name":"Clonal haematopoiesis (CHIP)","route":"/pathways/clonal-haematopoiesis/"},{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"term":[{"id":"cfdna","kind":"term","name":"Cell-free DNA (cfDNA)","route":"/terms/cfdna/"},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"gbrca-mutation","kind":"term","name":"Germline BRCA mutation (gBRCA)","route":"/terms/gbrca-mutation/"},{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"}],"journal":[{"id":"clinical-cancer-research","kind":"journal","name":"Clinical Cancer Research","route":"/journals/clinical-cancer-research/"}],"biomarker":[{"id":"ar-amplification","kind":"biomarker","name":"AR amplification (gene and upstream enhancer)","route":"/biomarkers/ar-amplification/"},{"id":"ar-ligand-binding-domain-mutation","kind":"biomarker","name":"AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L)","route":"/biomarkers/ar-ligand-binding-domain-mutation/"},{"id":"ctdna-tumour-fraction","kind":"biomarker","name":"Circulating tumour DNA fraction (and what a negative plasma result means)","route":"/biomarkers/ctdna-tumour-fraction/"},{"id":"brca-somatic","kind":"biomarker","name":"Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations","route":"/biomarkers/brca-somatic/"}]}}