Cancer chromosomal instability (CIN) results from dynamic changes to chromosome number and structure. The resulting diversity in somatic copy number alterations (SCNA) may provide the variation necessary for cancer evolution. Multi-sample phasing and SCNA analysis of 1421 samples from 394 tumours across 24 cancer types revealed ongoing CIN resulting in pervasive SCNA heterogeneity. Parallel evolutionary events, causing disruption to the same genes, such as BCL9, ARNT/HIF1B, TERT and MYC, within separate subclones were present in 35% of tumours. Most recurrent losses occurred prior to whole genome doubling (WGD), a clonal event in 48% of tumours. However, loss of heterozygosity at the human leukocyte antigen locus and loss of 8p to a single haploid copy recurred at significant subclonal frequencies, even in WGD tumours, likely reflecting ongoing karyotype remodeling. Focal amplifications affecting 1q21 (BCL9, ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal and exhibited an illusion of clonality within single samples. Analysis of an independent series of 1024 metastatic samples revealed enrichment for 14 focal SCNAs in metastatic samples, including late gains of 8q24.1 (MYC) in clear cell renal carcinoma and 11q13.3 (CCND1) in HER2-positive breast cancer. CIN may enable ongoing selection of SCNAs, manifested as ordered events, often occurring in parallel, throughout tumour evolution.

The development of precision medicine for the management of metastatic breast cancer is an appealing concept; however, major scientific and logistical challenges hinder its implementation in the clinic. The identification of driver mutational events remains the biggest challenge, because, with the few exceptions of ER, HER2, PIK3CA and AKT1, no validated oncogenic drivers of breast cancer exist. The development of bioinformatic tools to help identify driver mutations, together with assessment of pathway activation and dependency should help resolve this issue in the future. The occurrence of secondary resistance, such as ESR1 mutations, following endocrine therapy poses a further challenge. Ultra-deep sequencing and monitoring of circulating tumour DNA (ctDNA) could permit early detection of the genetic events underlying resistance and inform on combination therapy approaches. Beside these scientific challenges, logistical and operational issues are a major limitation to the development of precision medicine. For example, the low incidence of most candidate genomic alterations hinders randomized trials, as the number of patients to be screened would be too high. We discuss these limitations and the solutions, which include scaling-up the number of patients screened for identifying a genomic alteration, the clustering of genomic alterations into pathways, and the development of personalized medicine trials.