Biological Modulation of Parp Inhibition in Triple Negative Breast Cancer, a Combinational Approach Implementing Multitargeted Epigenetic Therapy (Mtet) with Parp Inhibition, in Advanced Breast Cancer: A Case Study

Abstract

The introduction of PARP inhibitors as active agents to inhibit the DNA repair was a revolution in the cancer therapeutics, however , such approach only has shown promising results for a short time in majority of cases due to secondary mutations and promoter gene methylation, and most of patients with triple negative breast cancer when treated with such agents only benefit for a short time, until the tumor shows resistance and further the therapy fails [1] . Considering this category of drugs and their mechanism of action in DNA repair [ 2 ] [ 3 ] , several recent studies have focused on combination of PARP inhibitors with chemotherapy, immune therapy and interestingly relevant to this article, epigenetic therapies [ 4 ] . That said, to our knowledge the human data in this regard is missing. Here we discuss a case report of a patient with stage four refractory and resistant BRCA1 mutated triple negative breast cancer who responded in matter of two weeks to a combinational therapy, consisting of PARP inhibitor and epigenetic therapies. As the patient already had exhausted the PARP inhibitor by excessive presence of BRCA positive altered circulatory DNA, the response merely reflects the epigenetic therapy as back bone of treatment. The liquid biopsy repeated after two weeks of combination therapy showed complete disappearance (resolution of positive BRCA gene/c DNA), reflecting a synergism by proposed modulation of resistance as mechanism of action. (The initial c DNA showed 93 percent mutation allele fraction of BRCA gene . ) To our knowledge , this is the first study on combinational therapy in human. The finding in this case could potentially change the standard of care in treating BRCA positive tumors, by providing a superior treatment to current standards.