  Citation: Obi, N.; Werner, S.; Thelen, F.; Becher, H.; Pantel, K. Metastatic Breast Cancer Recurrence after Bone Fractures. Cancers 2022, 14, 601. https://doi.org/10.3390/ cancers14030601 Academic Editor: Fernando Schmitt Received: 10 December 2021 Accepted: 21 January 2022 Published: 25 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Article Metastatic Breast Cancer Recurrence after Bone Fractures Nadia Obi 1,† , Stefan Werner 2,3,† , Frank Thelen 4 , Heiko Becher 1 and Klaus Pantel 2, * 1 Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; n.obi@uke.de (N.O.); h.becher@uke.de (H.B.) 2 Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; st.werner@uke.de 3 Mildred-Scheel-Nachwuchszentrum HaTRiCs4, Universitäres Cancer Center Hamburg, 20246 Hamburg, Germany 4 Analytics & Insights, Techniker Krankenkasse, Bramfelder Str. 140, 22305 Hamburg, Germany; Frank.Thelen@tk.de * Correspondence: pantel@uke.de † These authors contributed equally to the study. Simple Summary: Bone fractures bear potential risk to promote metastatic relapse in breast cancer. We conducted a population-based cohort study of 84,300 breast cancer patients diagnosed between January 2015 and November 2019. Bone fracture after breast cancer diagnosis was associated with an increased metastasis risk. Fractures may pose an increased risk to developing metastasis. Potential clinical implications for cancer patients are in support of fall prevention programs. Abstract: Experimental studies suggest that bone fractures result in the release of cytokines and cells that might promote metastasis. Obtaining observational data on bone fractures after breast cancer diagnoses related to distant breast cancer recurrence could help to provide first epidemiological evidence for a metastasis-promoting effect of bone fractures. We used data from the largest German statutory health insurance fund (Techniker Krankenkasse, Hamburg, Germany) in a population-based cohort study of breast cancer patients with ICD-10 C50 codes documented between January 2015 and November 2019. The risk of metastasis overall, regional, distant non-bone or bone metastasis related to a fracture was modeled by an adjusted discrete time-to-event analysis with time-dependent exposure. Of 154,000 breast cancer patients, 84,300 fulfilled the inclusion criteria and had a follow-up time of more than half a year. During follow-up, fractures were diagnosed in 13,579 (16.1%) patients. Metastases occurred in 7047 (8.4%) patients; thereof 1544 had affected regional lymph nodes only and 5503 distant metastases. Fractures demonstrated a statistically significant association with subsequent metastasis overall (adjusted HR 1.12, 95% CI 1.04, 1.20). The highest risk for metastasis was observed in patients with subsequent bone metastasis (adjusted HR 1.18, 95% CI 1.05, 1.34), followed by distant non-bone metastasis (adjusted HR 1.16, 95% CI 1.07, 1.26) and lymph node metastasis (adjusted HR 1.08, 95% CI 0.97, 1.21). Keywords: metastasis; breast cancer; risk of relapse; bone fractures; administrative data 1. Introduction Breast cancer is the most commonly diagnosed cancer in women (2.1 million new cases in 2018) and the leading cause of cancer death in women globally (627,000 deaths in 2018) [1]. Metastasis—the spread of tumor cells to distant sites and outgrowth into secondary lesions— is the main cause of cancer-related death in breast cancer and most cancer-related deaths (83% in estrogen receptor (ER)-positive and 87% in ER-negative tumors) happen after distant metastasis formation [2]. Recurrence can occur years after diagnosis and surgical resection of the primary tumor and affects the regional lymph nodes and/or distant organs, such as bone, liver, lungs or brain. In this regard, ER-negative tumors relapse frequently early after diagnosis but the relapse frequency progressively declines over Cancers 2022, 14, 601. https://doi.org/10.3390/cancers14030601 https://www.mdpi.com/journal/cancers