Abstract P6-11-06: Efficacy of carboplatin alone or with ABT888 in an intracranial murine model of BRCA-mutated, basal-like, triple negative breast cancer (TNBC)
Authors: Karginova O , Adamo B , Deal A , Santos C , Darr D , Bash R , Sandison K , Zamboni B , Miller CR , Anders CK 
Published: August 2014

Background: TNBC frequently spreads to the central nervous system and is associated with poor outcome. Twenty percent of women with TNBC harbor a BRCA mutation(mut). BRCA dysfunction impairs repair of DNA double-strand breaks by homologous recombination(HR) and sensitizes tumor cells to DNA-damaging cytotoxic agents. Emerging evidence suggests that TNBC responds to platinums(Pt) and drugs potentiating efficiency of DNA damage, such as PARP inhibitors; combination therapy may enhance DNA damage and induce additional cytotoxicity. Recognizing that Pt and many PARP inhibitors penetrate the blood brain barrier(BBB), we evaluated the efficacy of carboplatin(Carbo) alone and with the PARP inhibitor, ABT888(ABT), in murine intracranial(IC) TNBC models characterized by BRCA status.

Methods: Athymic (nu/nu) mice(10wks) were inoculated intracerebrally with 2×105 SUM149(BRCA1mut, pTEN-; basal) cells expressing luciferase. On day14, tumor-bearing mice began treatment with Control(PBS IP weekly), Carbo(50mg/kg IP weekly) and ABT(25mg/kg OG daily) as single agents, or in combination. Survival and IC tumor growth via bioluminescence were compared by treatment. Net PAR levels(PARpg/ml/100ug total protein) were measured in IC tumor tissue(ELISA pharmacodynamic assay) 14days post ABT. Presence of Pt DNA adducts was measured in IC tumor tissue following Carbo+/-ABT by ICP-MS. Survival and IC tumor growth via bioluminescence of the MDA-MB468(BRCAnon-mut, pTEN-; basal) IC model treated with the same regimens were assessed.

Results: In the SUM149 TNBC IC model, Carbo+/-ABT resulted in improved survival compared to control (Table). Single agent ABT did not yield a survival benefit over control. Combination Carbo/ABT showed a modest advantage in survival compared to Carbo alone (p = 0.28). IC tumor mean net PAR levels ± SEM were significantly lower in ABT-treated animals compared to control (182.1 ± 91.3 vs 825.7 ± 174.7, p = 0.0043). Addition of ABT did not impair Carbo BBB penetration; Mean ± SEM Pt-DNA adducts were detected in IC tumor after administration of Carbo and Carbo/ABT (0.91±0.13 and 1.46±0.03 pgPt/ugDNA). In contrast to the SUM149 IC model, there was no survival improvement for the MDA-MB468 IC model treated with Carbo+/-ABT compared to control(p = 0.81).

 SUM149(BRCA1mut)MDA-MB468(BRCA1non-mut)TreatmentNMedian Survival (95%CI), dayspValueNMedian Survival (95%CI), daysControl1736(34-40)N/A535(29-57)ABT1039(30-46)p = 0.22544(33-57)Carbo1658(47-67)p&lt;.0001537(33-54)Carbo/ABT1764(59-75)p&lt;.0001537(33-50)

Conclusions: This study shows Pt analogues, specifically Carbo, represent a promising treatment strategy for TNBC brain metastases with BRCA dysfunction. Improved survival relies on the ability of Pt analogues to penetrate the BBB and higher cytotoxicity may be due to compromised HR in TNBC as compared to models with functional BRCA. Although inhibitory activity of ABT was detected in IC tumors, we did not observe a significant additive effect of ABT to Carbo when used in combination. Confirmatory studies in additional IC TNBC models, including claudin-low subtype, as well as mechanistic studies evaluating DNA damage via γH2AX foci and differential gene expression in response to treatment are ongoing.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-06.