Intraductal cisplatin treatment in a BRCA -associated breast cancer mouse model attenuates tumor development but leads to systemic tumors in aged female mice

// Jolien S. de Groot 1 , Paul J. van Diest 1 , Miranda van Amersfoort 1 , Eva J. Vlug 1 , Xiaojuan Pan 1 , Natalie D. ter Hoeve 1 , Hilde Rosing 2 , Jos H. Beijnen 2,3 , Sameh A. Youssef 4 , Alain de Bruin 4,5 , Jos Jonkers 6 , Elsken van der Wall 7 and Patrick W.B. Derksen 1 1 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands 2 Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands 3 Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands 4 Department of Pathobiology, Dutch Molecular Pathology Center, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands 5 Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 6 Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands 7 Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands Correspondence to: Patrick W.B. Derksen, email: // Keywords : breast cancer, BRCA, intraductal, cisplatin, olaparib Received : February 03, 2017 Accepted : April 06, 2017 Published : June 15, 2017 Abstract BRCA deficiency predisposes to the development of invasive breast cancer. In BRCA mutation carriers this risk can increase up to 80%. Currently, bilateral prophylactic mastectomy and prophylactic bilateral salpingo-oophorectomy are the only preventive, albeit radical invasive strategies to prevent breast cancer in BRCA mutation carriers. An alternative non-invasive way to prevent BRCA1 -associated breast cancer may be local prophylactic treatment via the nipple. Using a non-invasive intraductal (ID) preclinical intervention strategy, we explored the use of combined cisplatin and poly (ADP)-ribose polymerase 1 (PARP1) inhibition to prevent the development of hereditary breast cancer. We show that ID cisplatin and PARP-inhibition can successfully ablate mammary epithelial cells, and this approach attenuated tumor onset in a mouse model of Brca1-associated breast cancer from 153 to 239 days. Long-term carcinogenicity studies in 150 syngeneic wild-type mice demonstrated that tumor incidence was increased in the ID treated mammary glands by 6.3% due to systemic exposure to cisplatin. Although this was only evident in aged mice (median age = 649 days), we conclude that ID cisplatin treatment only presents a safe and feasible local prevention option if systemic exposure to the chemotherapy used can be avoided.