By analysing an intraindividual molecular diversity of metastatic prostate cancer, the researchers discovered that although exceptions exist, evaluation of a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumours within an individual, and thus may be useful for selection of treatments on the basis of predicted molecular vulnerabilities. The study results are published in the Nature Medicine.
The mainstay of initial therapy for metastatic prostate cancer, which has remained essentially unchanged for more than 50 years, relies on the suppression of circulating levels of testosterone, and consequently, suppression of the androgen receptor (AR) signalling programme in prostate cancer cells. This therapy, which was conceptually one of the first precision medicine approaches to cancer treatment, is highly effective. However, at the time of disease progression, metastatic castration resistant prostate cancers exhibit a spectrum of recurrent molecular aberrations, some of which are predicted to confer susceptibility to targeted therapeutics.
In general, tumour heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasised.
To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, the researchers analysed multiple tumours from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization and RNA transcript profiling, and compared the genomic diversity within and between individuals.
In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of AR activity and cell cycle activity.
The AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment response durations to carboplatin than did men without defects in genes encoding DNA repair proteins.
Comprehensive molecular assessments of prostate cancer have identified numerous recurrent genomic and epigenomic aberrations in genes that are implicated in driving cancer development, of which a substantial fraction have clinical implications for directing treatment. These findings provide a rationale for tumour sequencing to identify the facets of tumour biology that prioritise and individualise therapeutics. However, deep sequencing of tumour genomes has also identified mutational heterogeneity, particularly within primary tumours. Branching evolution and the co-existence of multiple cancer lineages occur in a spectrum of carcinomas and have implications with respect to accurately sampling tumours and also for evolutionary mechanisms that may rapidly promote treatment resistance.
Kumar A, Coleman I, Morrissey C, et al.Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nature Medicine 2016; Published online 29 February. doi:10.1038/nm.4053