Abstract Introduction: The BOLERO-2 study showed significant doubling of PFS benefit with the addition of EVE to EXE in postmenopausal women with hormone receptor–positive advanced breast cancer progressing after non-steroidal aromatase inhibitor (NSAI) therapy. The BOLERO-2 bone sub study indicated an immediate positive influence of EVE on bone health after 6 and 12 weeks of treatment. To further investigate the longer term effect of mTOR inhibition on bone health, we included this exploratory objective in the phase IIIb, multi-center, open label study 4EVER for postmenopausal women with hormone receptor positive advanced breast cancer treated with EVE +EXE. Methods: From May 2012 to November 2012 bone biomarker samples of 247 postmenopausal women with metastatic or locally advanced, hormone receptor positive, HER2 negative breast cancer refractory to NSAI were collected within this phase IIIb study. Here, we report the results of the planned exploratory analysis of biomarkers of bone turnover. The objective of the exploratory biomarker analysis of bone resorption and formation was to assess the effect of EVE on changes of biomarker levels of bone metabolism (CTX, P-I-NP, osteocalcin, vitamin D, testosterone, estradiol, DHEAS, SHBG, PTH,TSH and FSH) from day 1 to weeks 4, 12 and 24 to confirm potential protective effects of EVE on bone via inhibition of bone osteoclast resorption. Descriptive statistics were used to summarize the single bone resorption markers by visit and difference to baseline. Results: Trial data base lock will occur in late June 2014, therefore, the final biomarker analysis of bone resorption and formation and their influence on ORR, PFS and safety will be presented at SABCS 2014. The preliminary analysis on the changes of bone marker levels from baseline to week 24 included 247 patients. The measured changes from baseline to week 24 in biomarker levels revealed increasing levels of testosterone, DHEAS and FSH, while SHBG and PTH were significantly decreased from baseline to week 24. The combination of EVE to EXE resulted in stabilization of bone health as documented by a decrease of absolute P-I-NP levels at week 24 compared to baseline as well as a stabilization of bone resorption as measured by CTX. Conclusion: Our first preliminary results (data cut off 15 Nov 2013) on the changes in bone marker levels supported the hypothesis of EVE having direct impact on bone health, suggesting a decrease of bone turnover and a reversal of the increase in bone resorption associated with aromatase inhibitor therapy. The final analysis of the 4EVER sub study on bone marker levels in correlation with the efficacy data will provide more detailed insights into possible benefits of the combination of EVE plus EXE. Citation Format: Peyman Hadji, Hans Tesch, Oliver Stoetzer, Thomas Decker, Christian M Kurbacher, Romy Neumeister, Frederik Marmé, Andreas Schneeweiss, Christoph Mundhenke, Andrea Distelrath, Peter A Fasching, Micheal P Lux, Diana Lüftner, Wolfgang Janni, Mathias Muth, Julia Kreuzeder, Claudia Weiss, Eva-Maria Grischke. 4EVER: The impact of mTOR inhibition on bone health in postmenopausal women with hormone receptor positive (HR+) advanced breast cancer treated with everolimus (EVE) in combination with exemestane (EXE) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-04.