NATURE REVIEWS | CLINICAL ONCOLOGY ADVANCE ONLINE PUBLICATION | 1 Department of Medical Oncology (M.A., F .A.), INSERM Unit U981 (C.V., C.L.), Department of Biostatistics and Epidemiology (S.M.), Gustave Roussy and Université Paris Sud, 94800 Villejuif, France. Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, VIC 3002, Australia (S.L.). Department of Medical Oncology and INSERM U916, Institut Bergonié, 229 Cours de l’Argonne, 33000 Bordeaux, France (H.B.). Correspondence to: F.A. fandre@igr.fr Precision medicine for metastatic breast cancer—limitations and solutions Monica Arnedos, Cecile Vicier, Sherene Loi, Celine Lefebvre, Stefan Michiels, Herve Bonnefoi and Fabrice Andre Abstract | 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. Arnedos, M. et al. Nat. Rev. Clin. Oncol. advance online publication 21 July 2015; doi:10.1038/nrclinonc.2015.123 Introduction The discovery of the oestrogen receptor (ER) 1 and human epidermal growth factor receptor‑2 (HER2) 2 as therapeutic targets in patients with breast cancer has enabled treatment success in terms of patient out‑ comes with ER or HER2‑blocking therapies, 3,4 and set the stage for the development of stratified medicine. Furthermore, progress in cancer genomics research over the past few decades has reinforced the notion that cancer is driven by various genomics alterations. 5 As a result of different international initiatives such as The Cancer Genome Atlas (TCGA) or the International Cancer Genome Consortium (ICGC), the use of next‑ generation sequencing (NGS) has helped define the genomic landscape of early stage breast cancer. 6 These studies have revealed the high level of tumour hetero‑ geneity for each breast tumour that consists of several molecular subsets, which are driven by distinct molecu‑ lar alterations, indicating that tumours could be treated according to their individual molecular landscape. Despite the exciting potential for personalized medicine, ER and HER2 are currently the only targetable molecu‑ lar alterations with confirmed predictive and prognostic value. 3,4 Other targeted therapies, such as mTOR and CDK4/6 inhibitors, have been approved on the basis of their efficacy in subgroup populations, but no predic‑ tive biomarkers have been found. 7,8 In this Review, we discuss the potential applications of genomics to improve the management of metastatic breast cancer (MBC), and consider the challenges that precision medicine must overcome before it can be widely implemented in the clinic—most notably, those challenges that relate to the remarkable cellular complexity of this type of cancer. Genomic landscape of breast cancer Analysis of the molecular features of early stage breast cancer using NGS has led to the description of the genomic landscape of this disease. 6 This research has confirmed that TP53 and PIK3CA mutations are the most frequent genomic alterations overall in all intrinsic subtypes (28% for both genes). Amplifications in ERBB2, FGFR1 and CCND1 follow in frequency, being observed in 10–20% of all breast cancer subtypes. Additional alterations are less frequent, but could be highly clinically relevant, including PTEN mutations and deletions, and AKT1, RB1 BRCA1 or BRCA2 mutations. Sequencing analyses have uncovered mutations in other genes of interest that might have some clinical relevance in breast cancer, including KRAS, APC, NF1, SKT11, MAP2K4, MAP3K1 and AKT2. 6 A similar genomic study focused on patients with triple‑negative breast cancer (TNBC) revealed a more heterogeneous molecular profile, with some tumours having just a few molecular alterations whereas others harboured hundreds of alterations. 9 Competing interests F.A. receives honourarium and has a research contract with AstraZeneca and Novartis. M.A. receives honourarium from Novartis. The other authors declare no competing interests. REVIEWS © 2015 Macmillan Publishers Limited. All rights reserved