title: SerpinB3, a new prognostic tool in breast cancer patients treated with neoadjuvant chemotherapy.
abstract: It is unclear which patients with breast cancer benefit from anthracycline-based neoadjuvant chemotherapy and whether taxanes increase survival. Hsp70 and serpinB3 inhibit a lysosomal cell death pathway induced in anthracycline and taxane treated cells, which may be critical for breast cancer cell survival. Thus we evaluated serpinB3 and Hsp70 as putative prognostic biomarkers in breast cancer patients treated with neoadjuvant chemotherapy. SerpinB3 and Hsp70 were measured by immunohistochemistry in residual breast tumours of patients without a complete pathological response [pCR] (n = 250), from a retrospective cohort of 296 patients treated with anthracycline-based chemotherapy with or without sequential docetaxel prior to surgical resection. SerpinB3 (P = 0.02) and Hsp70 (P = 0.008) positivity in residual tumour were associated with a poor pathological response and serpinB3 was an independent prognostic biomarker (HR 2.1 (95% CI 1.2-3.8), P = 0.02). Docetaxel significantly improved overall survival of breast cancer patients treated with neoadjuvant chemotherapy. Furthermore, serpinB3 positivity predicted poor survival in patients treated with anthracycline-based chemotherapy alone (P = 0.02), but those with serpinB3 negative tumours had as equally good survival as those also treated with docetaxel (P = 0.7). Survival was independent of serpinB3 expression in patients who received sequential docetaxel. The Nottingham prognostic index (NPI), calculated at surgical resection, predicted overall survival in these neoadjuvantly treated patients (P < 0.001) and serpinB3 status segregated patients with a moderate NPI into distinct prognostic subgroups. The use of clinical (NPI) and molecular (serpinB3) biomarkers measured at surgical resection to provide accurate prognostication in patients who do not achieve a pCR following neoadjuvant chemotherapy could facilitate optimal post-operative clinical management of these patients and is of significant clinical value. Furthermore, serpinB3 status in residual tumour is a biomarker of neoadjuvant docetaxel benefit in patients not achieving a pCR and use of serpinB3 molecular subtyping for adjuvant docetaxel treatment planning warrants further investigation.
authors.affiliation: Cancer Medicine, Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. e.collie-duguid@abdn.ac.uk
authors.forename: Elaina S R
authors.initials: ES
authors.lastname: Collie-Duguid
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sweeney
authors.forename: Keith N
authors.initials: KN
authors.lastname: Stewart
authors.forename: Iain D
authors.initials: ID
authors.lastname: Miller
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Smyth
authors.forename: Steven D
authors.initials: SD
authors.lastname: Heys
mesh_terms: D018943:Anthracyclines / Q000008:administration & dosage; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D044584:Carcinoma, Ductal / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D018275:Carcinoma, Lobular / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D000077143:Docetaxel; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D020360:Neoadjuvant Therapy; D018365:Neoplasm, Residual; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D015843:Serpins / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D018840:HSP70 Heat-Shock Proteins; D015843:Serpins; D043823:Taxoids; C051072:squamous cell carcinoma-related antigen; D000077143:Docetaxel