Matt Thompson

Introduction. Breast cancer is responsible for 11.6% of cancer deaths globally and is the most diagnosed cancer in women.¹ Approximately 50% of hereditary breast cancer cases carry mutations in the BRCA1/BRCA2 genes, which encode proteins responsible for DNA repair.^1,2 Poly-ADP ribose polymerase (PARP) participates in this process by aiding in homologous recombination repair of DNA strand breaks.³ PARP exhibits synthetic lethality with BRCA1/2; a cell will not be viable if both PARP and BRCA1/2 are damaged.⁴ PARP inhibitors (PARPi) have been used as chemotherapeutic agents in breast cancer and are effective in ~60% of BRCA1/2 deficient breast cancer patients.¹ After prolonged use, PARPi resistance is often developed, and homologous recombination again repairs DNA damage, leading to relapse and proliferation of cancer.¹ Recently, multiple mechanisms have been targeted as potential therapy for PARPi resistance. One of these mechanisms is modulation of the immune system. Methods. Mammary carcinomas were introduced in immunocompetent or immunodeficient mice, which were then treated with either vehicle or the PARPi Olaparib. Immunocompetent mice were then treated with an anti-CD8 antibody and survival time in all groups was assessed.⁵ BRCA1-deficient mice with breast tumors were subjected to either vehicle, anti-CSF-1R (M2 macrophage-specific immunosuppressant), Olaparib, or a combination of the latter two. Overall survival was measured.⁶ Mice with induced tumors were treated with either M279 (anti-M2), TKP (pro-M2), or saline, and tumor size was measured.⁷ The PARPi veliparib was administered to patients with the chemotherapeutic agent doxorubicin and the immunosuppressant cyclophosphamide, and tolerability levels were assessed.⁸ Results. Olaparib + anti-CD8 in immunocompetent mice decreased survival from 241 days in the Olaparib-only group to 139 days.⁵ Olaparib + anti-CSF-1R led to an average survival of 82.5 days compared to 63 days in Olaparib alone and 11 days in the vehicle group.⁶ Mice subjected to M279 had decreased tumor size compared to saline, and those subjected to TKP had increased tumor size, suggesting differences in tumor viability based on macrophage phenotype.⁷ Veliparib in combination with cyclophosphamide and doxorubicin was well-tolerated at potentially therapeutic doses.⁸ Conclusions. A competent immune system is necessary for PARPi effectivity. Because anti-inflammatory M2 macrophages support tumor growth and pro-inflammatory M1 macrophages suppress tumors, M2-specific immunosuppressant therapy (anti-CSF-1R) shows promise in reversing PARPi resistance in BRCA1/2 mutant breast cancer via an increase in the M1:M2 ratio. A phase 1 clinical trial has shown the safety of this therapy and supports the progression to phase 2 trials.

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