Circulating HMGB1 Levels Increase in Locally-Advanced Breast Cancer Patients Treated on a Protocol of Neoadjuvant Paclitaxel and Radiation

Abstract

Overall survival (OS) has been correlated to the interaction between circulating HMGB1 (cHMGB1, released from dying tumor cells) and toll-like receptor 4 (TLR4, expressed by dendritic cells [DCs] and required for tumor antigen cross-presentation) in breast and esophageal cancer patients treated with radiation therapy (RT) and chemotherapy (CT). We previously demonstrated that locally advanced breast cancer (LABC) patients treated with neoadjuvant concurrent paclitaxel (PTX) and RT achieved high pathologic response rates (34% pCR and pPR) with an associated OS benefit. Importantly, hormone receptor (HR) -ve tumors (thought to be more immunogenic) achieved an even higher pathologic response (54%) versus HR +ve tumors (18%). We hypothesized that neoadjuvant concurrent PTX and RT can increase cHMGB1, thereby, contributing to host anti-tumor immune responses and OS in LABC patients. Thus, we measured the amount of cHMGB1 pre and post-neoadjuvant concurrent PTX and RT in LABC patients. Women ≥ 18 years of age with biopsy-proven LABC (stages IIB-IIIC) were eligible and treated with PTX (30 mg/m2 intravenously twice a week) for 10-12 weeks. Daily RT was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of PTX treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy per fraction. Statistical analysis was achieved with a paired T-test. Pre and post-treatment blood samples were identified from 21 LABC (12 HR +ve and 9 HR -ve) patients treated with neoadjuvant concurrent PTX and RT. There was a significant increase in cHMGB1 in all patients, from 1.82 ± 0.26 ng/mL to 2.75 ± 0.45 ng/mL (p = 0.037). Interestingly, when analyzed separately, HR -ve patients demonstrated a significant increase of cHMGB1 (from 2.24 ± 0.34 ng/mL to 3.86 ± 0.75 ng/mL, p = 0.043), whereas, HR +ve patients did not (from 1.51 ± 0.36 ng/mL to 1.91 ± 0.45 ng/mL, p = 0.43). These results demonstrate an increase of cHMGB1 in LABC patients, specifically those that are HR -ve, treated with neoadjuvant PTX and RT. However, further research is warranted to link cHMGB1 with improved outcomes in these patients.