The introduction of PARP inhibitors as active agents to inhibit DNA repair was a revolution in cancer therapeutics. However, this approach only has shown results for a short duration in the majority of cases, due to secondary mutations and promoter gene methylation. Studies of patients with triple-negative breast cancer in particular, treated with PARP inhibitors show benefit from the agents for only a short time, until the tumor shows resistance and further the therapy fails. [1,2,3,4]
We discuss a case report of a patient with Stage IV refractory and resistant BRCA1 mutated triple-negative breast cancer, who responded to a combinational therapy, consisting of a PARP inhibitor and an epigenetic modifier. The purpose of this case report is to show that combination treatment of epigenetic therapies and PARP inhibitors is synergistic and results in improved clinical outcomes. The patient in this case had already exhausted a PARP inhibitor, which was evident by the presence of excessive BRCA positive altered circulating tumor DNA (ctDNA). The initial finding was 93% mutation allele fraction (MAF) of BRCA gene on liquid biopsy by Guardant360 laboratory. The liquid biopsy for ctDNA was repeated after two weeks of combination therapy, and showed complete disappearance (resolution of positive BRCA gene in ctDNA), reflecting a synergism by proposed modulation of resistance, as mechanism of action. The response reflects the epigenetic therapy as back-bone of treatment, as no other changes were made that could account for the response. To our knowledge, this is the first study of combinational therapies in a human. Our finding in this case could potentially change the standard of care in treating BRCA positive tumors, by providing a superior treatment to current standards.
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2. Dziadkowiec, K. N., Gąsiorowska, E., Nowak-Markwitz, E., & Jankowska, A. (2016). PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting. Przeglaąd Menopauzalny = Menopause Review, 15(4), 215-219. http://doi.org/10.5114/pm.2016.65667
3. Livraghi, L., & Garber, J. E. (2015). PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Medicine, 13(1). doi:10.1186/s12916-015-0425-1
4. Oshaughnessy, J., Schwartzberg, L., Danso, M. A., Miller, K. D., Rugo, H. S., et al. (2014). Phase III Study of Iniparib Plus Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin in Patients With Metastatic Triple-Negative Breast Cancer. Journal of Clinical Oncology, 32(34), 3840-3847. doi:10.1200/jco.2014.55.2984
Citation Format: M.A. Nezami, Jessica Garner. Biological modulation of PARP inhibition in triple negative breast cancer: A case report of combinational approach implementing histone deacetylase inhibition with PARP inhibition in advanced breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A25.