54 Discussion The MBC Alliance analyzed the MBC research landscape, including 224 clinical trials actively recruiting MBC patients and 2281 funded grants totaling $1.07 billion US. Using the hallmarks of cancer[5] and the steps in metastasis[6] as frameworks, we were able to identify well supported areas as well as some neglected areas in MBC research. For example, no targeted therapy trials were identified for 3 of the 10 hallmarks of cancer: enabling replicative immortality, tumor- promoting inflammation, and deregulating cellular energetics. Furthermore, few MBC research grants were focused on understanding some of the steps of metastasis, including intravasation and circulation, immune escape, arrest and extravasation, and metabolic deregulation. In addition, we found that MBC research is underfunded, accounting for only 7% of the breast cancer funding identified in our analysis from 2000 to 2013. Interviews with experts in the field suggested that laboratory models that appropriately mimic the steps of metastasis need to be refined and standardized across laboratories and that more laboratories need to access and study metastatic tissue in comparison to primary tumors. These suggestions were supported in the published literature [15-17] . Experts also called for updates in clinical trials for MBC, including new trial designs with time-to-new metastasis as an endpoint, and the need for multicenter, collaborative phase II trials [17, 18] . Through our analysis, we found that there are 118 unique drugs or drug combinations being studied in 169 clinical trials of targeted therapies that address 7 of the 10 hallmarks of cancer currently being tested. Of note, more than 40% of the targeted therapy trials are in the latter stages of development (17 phase III, 54 phase II), which suggests they are nearing clinical applicability. MBC appears to be well studied in clinical trials in comparison to other cancers; as of August 2014, the numbers of active trials included 376 trials for any breast cancer, 57 trials for metastatic small-cell lung cancer, 220 trials for metastatic non–small cell lung cancer, and 116 trials for metastatic pancreatic cancer. However, it should be noted that clinical trials for breast cancer nearly always start in the MBC setting before being tested in early settings. The Alliance believes that categorizing MBC clinical trials according to the hallmarks of cancer is important for MBC research, especially since the simplistic view of a “war” on cancer and the hope for a single “magic bullet” treatment has evolved—combination therapy is now routine [19, 20] . A multipronged approach is essential, because cancer is a dynamic, heterogeneous system with a complex network of interrelations that vary between and across cells as well as over time within each cell[19, 21] . For example, it is now clear that cancers can initially resist the targeting of a hallmark by activating other cellular mechanisms within that hallmark. A second pattern of resistance is to rely on other hallmark capabilities to overcome deficiencies; for example, a cancer could resist angiogenesis inhibitors by becoming more invasive and metastatic[22-24] . Thus, the use of categorization schemes, such as the hallmarks of cancer, can provide strategic guidance for clinical approaches that will target multiple hallmarks simultaneously and avoid these common mechanisms of therapeutic resistance. Several KOLs noted that it is challenging to recruit patients to MBC trials and it can thus take a long time to complete accrual (e.g., 2 years to recruit 600 MBC patients)[17, 25] . Although one barrier is the low percentage of cancer patients that participate in clinical trials in general, this can be mitigated. Groups in the United Kingdom faced a similarly low rate of enrollment into cancer trials and increased the rate from approximately 4% to 12% of cancer patients within just a few years through a coordinated and managed approach to clinical research and by integrating research networks with community cancer service networks in their socialized