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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.
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.
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.
Shares CHEK2, Circulating tumour DNA fraction (and what a negative plasma result means), Clonal haematopoiesis (CHIP), ATM.
Shares AR amplification (gene and upstream enhancer), Circulating tumour DNA fraction (and what a negative plasma result means), ATM, Cell-free DNA (cfDNA).
Shares Circulating tumour DNA fraction (and what a negative plasma result means), Cell-free DNA (cfDNA), Androgen receptor signalling, Androgen receptor.
Shares Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations, Cell-free DNA (cfDNA), Double-strand break repair: HR versus end joining, Resistance routes: how a blocked pathway comes back.
Shares CHEK2, ATM, Germline BRCA mutation (gBRCA), Double-strand break repair: HR versus end joining.
Shares AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L), Androgen receptor signalling, Resistance routes: how a blocked pathway comes back, Androgen receptor.
Shares CHEK2, ATM, Germline BRCA mutation (gBRCA), Double-strand break repair: HR versus end joining.
Shares Cell-free DNA (cfDNA), Clinical Cancer Research, Androgen receptor, Circulating tumour DNA (ctDNA).