title: Circulating immunogenic cell death biomarkers HMGB1 and RAGE in breast cancer patients during neoadjuvant chemotherapy.
abstract: Neoadjuvant chemotherapy in breast cancer patients aims at preoperative reduction of tumor volume for better resection results and prognosis. As not all patients respond to neoadjuvant therapy, predictive biomarkers are needed for more efficient individual management. In prospectively collected sera of 51 consecutive locally confined breast cancer (LBC) patients receiving preoperative, neoadjuvant chemotherapy, value level kinetics of soluble high mobility group box 1 (HMGB1), soluble receptor for advanced glycation end products (sRAGE) as well as the established breast cancer biomarkers CA 15-3 and carcinoembryonic antigen (CEA) were investigated and correlated with therapy response objectified by pathological staging at surgery. In addition, biomarkers were measured in sera of 30 healthy controls (HC), 13 patients with benign breast diseases, and 28 metastatic breast cancer (MBC) patients. Pretherapeutic levels of soluble HMGB1 were decreased in MBC, while sRAGE was already decreased in LBC. In contrast, CA 15-3 and CEA were strongly elevated in MBC, but not in LBC. Combination of sRAGE and CA 15-3 enabled best discrimination of LBC from HC (AUC 78.2 %; sens 58 % at 95 % spec), while CA15-3 and CEA discriminated best between MBC and all controls (AUC 90.9 %; sens 70 % at 95 % spec). In LBC patients undergoing neoadjuvant chemotherapy, nine patients achieved complete remission (CR), 29 achieved partial remission (PR), while 13 had no change of disease (NC). NC patients tended to have higher HMGB1 and lower sRAGE levels before therapy onset (p = 0.056 and p = 0.054), while CA 15-3 and CEA did not predict therapeutic outcome. Furthermore, kinetics of HMGB1 during therapy correlated with efficacy of the treatment (p = 0.053). Markers of immunogenic cell death are valuable for the diagnosis of MBC and early estimation of response to neoadjuvant therapy in LBC patients.
authors.affiliation: Haematology and Oncology Outpatient Cancer Care Center, Franz-Schrank-Str. 2, 80638, Munich, Germany.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Stoetzer
authors.forename: Debora M I
authors.initials: DM
authors.lastname: Fersching
authors.forename: Christoph
authors.initials: C
authors.lastname: Salat
authors.forename: Oliver
authors.initials: O
authors.lastname: Steinkohl
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Gabka
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hamann
authors.forename: Michael
authors.initials: M
authors.lastname: Braun
authors.forename: Axel-Mario
authors.initials: AM
authors.lastname: Feller
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.forename: Barbara
authors.initials: B
authors.lastname: Siegele
authors.forename: Dorothea
authors.initials: D
authors.lastname: Nagel
authors.forename: Stefan
authors.initials: S
authors.lastname: Holdenrieder
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000097:blood; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000627:therapeutic use; D000077143:Docetaxel; D015251:Epirubicin / Q000627:therapeutic use; D005260:Female; D024243:HMGB1 Protein / Q000097:blood*; D006801:Humans; D018396:Mucin-1 / Q000097:blood; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000627:therapeutic use; D011379:Prognosis; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood*; D043823:Taxoids / Q000627:therapeutic use; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D024243:HMGB1 Protein; D018396:Mucin-1; D000067759:Receptor for Advanced Glycation End Products; D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D000068878:Trastuzumab; D017239:Paclitaxel