Lethal breast cancer.

The successful first full genomic sequencing of a basal breast cancer has been accomplished, with both the primary cancer as well as a brain metastasis having been fully analyzed. Among the lessons learned is that the lethal breast cancer cells, those with the ability to penetrate and colonize the central nervous system, were present as a subset of cells in the primary cancer at diagnosis, one of many subclones in the genomically heterogeneous primary.1 The importance of tumor heterogeneity has been further elucidated by studies in early breast cancer where small pockets of HER2-amplfied cells, focally HER2-amplified clones, can be surrounded by a majority of HER2-normal cells; adjuvant trastuzumab appears to improve disease-free survival in the treatment of patients with these cancers, underscoring the need to eradicate the most lethal subclone of cells.2 Norton and Massague’s concept of tumor self-seeding speaks to this heterogeneity in postulating that metastatic cells that leave the primary cancer may return to it again having acquired heightened mesenchymal capacity that further drives tumor-stroma interactions that in turn promote more lethal metastases.3,4 One of the more riveting works to be published in recent years provides insights into the molecular and chemical mechanisms underlying the primary cancer’s successful orchestration of the establishment of micrometastases.5 The primary cancer’s elaboration of vascular endothelial growth factor (VEGF)-A in the case of a boneseeking breast cancer xenograft, or of both VEGF-A and fibroblast growth factor (FGF) in the case of a to-be-widely-metastatic melanoma, led to mobilization of VEGF receptor (VEGFR)-1–expressing bone marrow vascular progenitor cells that migrated to the preordained metastatic sites, attaching to fibronectin on the tissue fibroblasts that had been upregulated in response to the tumors’ cytokines. The vascular progenitors created the stromal premetastatic niche that the circulating tumor cells were then able to bind to in the distant sites to establish micrometastases. The surprising and central role that breast cancer cytokines play in supporting and directing metastases has also been elegantly described in the context of tumor cell lymphatic infiltration.6 The ligand CCL21 is secreted by lymphatic endothelial cells within highly invasive primary breast cancers that express the receptor for CCL21, CCR7. The increased interstitial flow of lymph fluid to the lymphatics from the inflammatory-like primary tumor sets up a gradient of CCL21 that pied-pipers the CCR7-expressing tumor cells into the nearby lymphatic vessels. CCL21 also attracts dendritic cells, which also express CCR7, as well as naive T lymphocytes into the lymph node, where the young T cells are tolerized to the cancer cells. Interestingly, the cytokine VEGF-C that is expressed by the lymphatic-seeking breast cancer cells enhances CCL21 production by lymphatic endothelial cells while also stimulating the VEGFR-3–mediated migratory invasiveness of the VEGFR-3–expressing tumor cells. In this Clinical Breast Cancer supplement, leaders in breast cancer translational research explore a variety of diagnostic and therapeutic strategies aimed at understanding, detecting, and eradicating the lethal subpopulations of breast cancer cells. HER2-amplified breast cancer, while once one of the most deadly subtypes, is now associated with a generally favorable outcome with adjuvant trastuzumab/ chemotherapy (and endocrine therapy in estrogen receptor–positive disease), especially for the smaller, presumably less heterogeneous early-stage cancers. Much remains to be done in the quest to cure some of the HER2-amplified subtypes that are impervious to HER2-directed therapy such as the pleomorphic lobular apocrine cancers that coexpress androgen receptors7 and those that are an admixture of HER2 and basal breast cancers.8 The discovery that some HER2-driven breast cancers elude trastuzumab’s inhibition of HER2 signaling by co-opting other HER family receptors and related networks has led to the clinical development of multiple other therapeutic agents that cooperate with trastuzumab to prevent the outgrowth of resistant clones.9 The ongoing and planned studies of HER2-directed therapies such as pertuzumab, neratinib, lapatinib, and bevacizumab in early breast cancer use combinations of HER2 signaling inhibitors designed to eradicate heterogeneous clones within these cancers. In this supplement, Isaacs et al discuss our current ability to identify patients with breast cancers that have developed metastatic potential and who therefore require systemic therapies. Several promising prognostic and predictive diagnostic assays such as the Oncotype DX Recurrence Score and the MammaPrint 70-gene profile are undergoing prospective evaluation of their clinical utility within large adjuvant trials. The results of these studies will likely lead to much greater clarity about which patients have breast cancers with lethal capacity, which patients have micrometastatic disease best managed as a chronic condition, and which patients have virulent disease that requires aggressive therapy. Coupling the predictive insights gained from multigene analyses with rapid preoperative clinical interrogation of agents that have been designed to interrupt the adaptive mechanisms that resist our current therapies Introduction