The metastatic spread of cancer is achieved by the hematogenous dissemination of circulating tumor cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, often assuming that CTCs are constantly shed from growing tumors or shed as a consequence of mechanical insults 1 . Here, we observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that the vast majority of spontaneous CTC intravasation events occur during the rest phase. Further, we demonstrate that rest-phase CTCs are highly metastasis-prone, while CTCs generated during active phase are devoid of metastatic ability. Mechanistically, single cell-resolution RNA sequencing analysis of CTCs reveals a dramatic upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Systemically, we find that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictate CTC generation dynamics, and as a consequence, that insulin directly promotes tumor cell proliferation in vivo, yet in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high proclivity to metastasize does not occur continuously but it is concentrated within the rest phase of the host, providing a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.3/24 Main Circulating tumor cells (CTCs) are pioneers of the metastatic cascade in several cancer types, including breast cancer 1 . The factors that regulate spontaneous CTC intravasation in physiological settings are poorly understood, and the general assumption is that CTCs are constantly generated from invasive cancerous tissues 2 , or generated upon mechanical cues such as surgery 3 or physical activity 4 . In patients and in mouse cancer models, the exact timing of the events that characterize metastatic cancer progression, as well as the principles that dictate CTC intravasation and their proclivity to metastasize are unclear. A better understanding of these processes may result in new approaches for cancer investigation and treatment. Circadian rhythm and CTC intravasationWe first sought to determine CTC abundance and composition in hospitalized women with progressive breast cancer that had no treatment or were temporarily off-treatment and that consented to donate blood during the active (10:00am) and rest (4:00am) phase of the same day, including a total of 30 patients (Fig. 1a). Of these, 21 patients were diagnosed with early breast cancer (no metastasis) and 9 were diagnosed with stage IV metastatic disease at the time of blood sampling (Supplementary Table 1). Strikingly, upon antigen-agnostic microfluidic capture of CTCs and confirmation via immunofluorescence staining 5 , we found the vast majority of CTCs (78.3%) in samples obtained at nighttime during rest phase, including single CTCs, CTC clusters and CTC-white blood cell (WBC) cl...

When implemented into clinical practice, the panel recommendations may improve safety and effectiveness of OPS. The attendees agreed that there is a need for prospective multicenter studies to optimize patient selection and for standardized criteria to qualify and accredit OPS training centers.

PurposeIndications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion.MethodsThe panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology.ResultsConsensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference.ConclusionsIn case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.Electronic supplementary materialThe online version of this article (10.1007/s10549-018-4937-1) contains supplementary material, which is available to authorized users.