Abstract P2-01-01: Early relapses in breast cancer can be prevented by a perioperative NSAID, which would be a solution to a 2000 year old problem
Authors: Retsky MW , Baum M , Vaidya JS , Rogers RA , Hrushesky WJ , Demicheli R , Forget P 
Published: May 2019

Abstract
A bimodal pattern of hazard of relapse among early stage breast cancer patients has been identified in multiple databases from US, Europe and Asia. We have been studying these data to determine if this can lead to new ideas on how to prevent relapse in breast cancer. Using computer simulation and access to a very high quality database from Milan for patients treated with mastectomy only, we proposed that relapses within 3 years of surgery are stimulated somehow by the surgical procedure. During the week post surgery, metastatic development is enhanced 100 fold according to the simulation. Most relapses in breast cancer are in this early category. Retrospective data from a Brussels anesthesiology group suggested a plausible mechanism. Use of ketorolac, a common NSAID analgesic used in surgery was associated with far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. Transient systemic inflammation accompanying surgery (identified by IL-6 in serum) could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. Similar bimodal patterns have been identified in other cancers suggesting a general effect. Based on the writings of Galen and Celsus, metastatic development after breast tumors were removed was known to them 2000 years ago.
This effect has been demonstrated recently in a mouse model by Krall et al Science Translational Medicine and reviewed in NEJM by Komaroff. In a series of experiments in 273 mice, aggressive mouse breast cancer cells were implanted in various locations. Initially, the tumor cells grew but then became dormant. This dormancy occurred only in mice with intact immunity, which suggests that the immune system can contain certain dormant metastases. Surgery of any type (including resection of a primary tumor) led to aggressive growth of metastases in 60% of animals, compared with 10% of control animals that did not undergo surgery. Surgical procedures caused systemic inflammatory responses. Activated monocytes from the marrow traveled to the sites of the dormant metastases and became tumor associated macrophages. These macrophages suppressed the immune system near the tumor, awakening the metastases from their dormancy. Treating the animals with NSAIDs before and immediately following surgery greatly attenuated growth of these metastases.
Since this effect has by now been shown in two Belgian retrospective studies as well as a mouse model we suggest this be tested in one or more clinical trials. We also note that the bleeding potential from using NSAIDs before surgery can apparently be reduced with the use of Tranexamic Acid – currently being tested in a clinical trial for mastectomy.
Citation Format: Retsky MW, Baum M, Vaidya JS, Rogers RA, Hrushesky WJ, Demicheli R, Forget P. Early relapses in breast cancer can be prevented by a perioperative NSAID, which would be a solution to a 2000 year old problem [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-01.