2013 was another high year for breast cancer research. (range ~90 – 60 0 Breast cancers were enriched for mutations in and or explained later) that are absent or present at very low frequencies in main breast malignancy (e.g. in rare subclones) supporting the need for study of metastases. TCGA and other large projects have struggled to address the extent of genomic intra-tumor heterogeneity (ITH). Sequencing of unique tumor regions and single cells has revealed tremendous ITH; however determining the extent and clinical significance of ITH is usually hampered by the difficulty in obtaining repeated tissue biopsies. A stylish alternative is examination of circulating malignancy DNA in plasma (circulating-free DNA or cfDNA) the so called ‘liquid biopsy’. 2013 saw two reports on longitudinal analysis of whole exome and genome sequencing of cfDNA in breast cancer patients. Whole exome sequencing on cfDNA collected over 1-2 years from patients with advanced breast cancer showed AMG 548 that mutations in liquid biopsies arose or increased in frequency coincident with development of clinical therapeutic resistance3. In one patient treatment with tamoxifen and trastuzumab was followed by an increase in truncation of MED1 an estrogen receptor co-activator known to be involved in tamoxifen resistance. Subsequent treatment of the patient with lapatinib and capecitabine was AMG 548 followed by an increase in a splicing mutation in GAS6 the ligand for AXL which has been shown to cause resistance to lapatinib3. Dawson et al.4 used whole exome and whole genome sequencing of cfDNA to design patient-specific assays for longitudinal monitoring. cfDNA was detected in 29/30 (97%) patients with advanced breast cancer whereas elevated CA15-3 and circulating tumor cells were only detected in 78 and 87% respectively. Importantly an increase in cfDNA was noted months before confirmation of progression by CT scan. These studies as well as LIN28 antibody others highlight the potential power of using cfDNA to monitor disease burden and progression and hopefully identify targets to treat the disease and prevent the molecular development of drug resistance. Perhaps the best surprise in breast malignancy genetics/genomics in 2013 was the identification of estrogen AMG AMG 548 548 receptor alpha (ER in only 2 out of 825 main breast cancers (0.2%). The scenery changed dramatically when the analysis was shifted from main breast malignancy to biopsies of advanced hormone-resistant disease. In a herculean AMG 548 effort designed to sequence and characterize patient-derived xenografts Ellis et al.5 recognized somatic mutations in advanced breast cancers that were obtained from patients who were refractory to anti-hormonal therapy. This obtaining was substantiated in two subsequent studies. Robinson et al.6 recognized somatic mutations in 6 out of 11 (55%) patients with advanced breast cancer. Toy et al.7 recognized mutations in 9 out of 36 (25%) ER+ advanced breast cancers as well as 5/44 (11%) derived from participants in the BOLERO-2 clinical trial. Importantly these mutations were found almost exclusively in advanced ER+ breast cancers particularly after treatment with an aromatase inhibitor rather than an antiestrogen. The somatic mutations clustered in the ligand binding domain name of ER and structure-function studies showed these mutations switch receptor conformation and result in ligand-independent activity. Together these studies open up a new avenue for studying hormone action and developing new therapies in ER+ advanced breast cancer such as inhibitors which specifically target mutant ER. The use of massively parallel sequencing to personalize genomic-directed breast malignancy therapy is rapidly becoming a fact. However AMG 548 the quantity of approved “targeted” drugs remains small and the path to their clinical development and screening is unacceptably long. Last year the FDA provided guidelines for the use of pathologic total response (pCR) as an endpoint to support accelerated approval of new brokers in the setting of neoadjuvant treatment of high-risk early-stage breast malignancy. In 2013 Pertuzumab (Perjeta Genentech) was the first agent to receive such approval for neoadjuvant treatment of early stage HER-2-overexpressing breast malignancy (http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm370393.htm) It is hoped that the use of pCR as an endpoint will accelerate the development of new therapeutics needed to tackle the diverse array of somatic.