Assessment of γH2AX levels in circulating tumor cells in patients treated with veliparib in combination with doxorubicin and cyclophosphamide in metastatic breast cancer.

Abstract

2582 Background: Veliparib (V) is a potent PARP inhibitor that delays repair of DNA damage induced by chemotherapeutic agents. In metastatic breast cancer pts, we evaluated V with doxorubicin (A) and cyclophosphamide (C) given both on day 1 with V at 100 mg po BID for 7 days post-chemotherapy every 21 days, to increase DNA damage. We report use of γH2AX, (phosphorylated histone protein), a marker of DNA double-strand breaks, in circulating tumor cells (CTCs) to assess DNA damage. We evaluated number of CTCs and percentage of γH2AX-positive CTCs pre- and post-treatment. Methods: Eligibility included prior A ≤ 300 mg/m2 and EF ≥ 50%. Further A was omitted after a cumulative dose of 420 mg/m2. Primary objective was to assess DNA damage response to treatment by measuring γH2AX-positive CTCs during cycle 1 on days 1 (pre-treatment), 2, 7, and 14. Cell Search System was used to enumerate CTCs. γH2AX was quantitated using a validated assay. Results: Eleven pts enrolled. Median age was 53 (34 – 73); median ECOG PS 1 (0 – 2); there were 1 ER-negative/HER2+, 4 triple-negative (BRCA2+, n =1), and 6 ER+/PR+/HER2-negative (BRCA2+, n =2) tumors. Most common drug-related toxicities were grade (gr) 4 neutropenia, gr 2 anemia and thrombocytopenia, and gr 1 nausea and vomiting. In BRCA2+ pts, there were 2 PRs and 1 SD. In BRCA wt or unknown status, 5 pts had SD ≥ 3 mo and there were 3 PDs. CTCs (≥ 8) were detected in 10/11 pts on days 1 and 2. Day 7 samples were not obtainable in 2 pts. On day 7, 1/8 pts had 0 CTCs and rest had ≥ 3 CTCs. A decrease in CTCs (p < 0.0001) occurred from day 1 (median: 22, range, 8-1216) to day 7 (median: 5, range 3-37). At baseline, 7 pts had ≥ 10% γH2AX-positive CTCs. Fraction of CTCs positive for γH2AX increased to ≥ 50% by day 7 in 6/7 pts and persisted to day 14 in 5 pts. Conclusions: The toxicity profile of V 100 mg BID days 1-7 with AC (60/600 mg/m2) on day 1 on a 21-day cycle was expected. Objective antitumor activity was seen in BRCA mutation carriers. CTCs decreased and percentage of γH2AX-positive CTCs increased after combination treatment with a PARP inhibitor and chemotherapy. This observation is notable and we plan to extend dosing of V to 14 days. This work is supported by NCI U01-CA132194. Clinical trial information: NCT00740805.