title: Cytoplasmic poly(adenosine diphosphate-ribose) polymerase expression is predictive and prognostic in patients with breast cancer treated with neoadjuvant chemotherapy.
abstract: OBJECTIVE
  Poly(adenosine diphosphate-ribose) polymerase (PARP) plays a key role in DNA repair and cellular stress response. Inhibitors of PARP show promising clinical activity in metastatic, triple-negative or BRCA-mutated breast cancer.
  
  
  METHODS
  We investigated cytoplasmic PARP (cPARP) and nuclear PARP (nPARP) expression by immunohistochemistry in 638 pretreatment biopsies from patients on the GeparTrio study and evaluated its predictive and prognostic value after neoadjuvant anthracycline/taxane-based chemotherapy.
  
  
  RESULTS
  cPARP expression was high in 23.7%, intermediate in 50.9%, and negative in 25.4% of tumors. High cPARP expression was significantly correlated with nonlobular histology (P < .001), undifferentiated grade (P < .001), positive nodal status (P = .049), and negative hormone receptor (HR) status (P < .001) but not with human epidermal growth factor receptor 2 (HER2) status. Expression was high in 35.5% of triple-negative tumors, 24.6% of HER2-positive tumors, and 18.0% of HR-positive/HER2-negative tumors (P < .001). Pathologic complete response (pCR) rates were 26.5%, 19.1%, and 8.0% in patients with high, intermediate, or negative expression, respectively (P < .001). This predictive effect was most prominent in HR-positive tumors (P = .035) or HER2-negative tumors (P < .001). High cPARP expression was a negative, but not independent, prognostic factor for disease-free survival (DFS; P = .0025) and overall survival (OS; P = .0022). cPARP expression was highly prognostic in patients without a pCR (DFS, P < .001; OS, P < .001) and in patients with HR-positive tumors (DFS, P < .001; OS, P < .001). No such correlations were found for nPARP expression.
  
  
  CONCLUSIONS
  High cPARP expression correlates with aggressive tumor pattern and predicts high sensitivity to neoadjuvant taxane/anthracycline-based chemotherapy but also unfavorable long-term prognosis. As a potential target for PARP inhibitors, cPARP-positive breast cancer might become a new, clinically relevant entity.
authors.affiliation: German Breast Group, Neu-Isenburg, Germany. Gunter.vonMinckwitz@germanbreastgroup.de
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
authors.forename: Berit Maria
authors.initials: BM
authors.lastname: Müller
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.forename: Claus
authors.initials: C
authors.lastname: Hanusch
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.forename: Jörn
authors.initials: J
authors.lastname: Hilfrich
authors.forename: Erich
authors.initials: E
authors.lastname: Weiss
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.forename: Jens Uwe
authors.initials: JU
authors.lastname: Blohmer
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
authors.forename: Dirk-Michael
authors.initials: DM
authors.lastname: Zahm
authors.forename: Fariba
authors.initials: F
authors.lastname: Khandan
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoffmann
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerber
authors.forename: Holger
authors.initials: H
authors.lastname: Eidtmann
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.forename: Keyur
authors.initials: K
authors.lastname: Mehta
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003520:Cyclophosphamide / Q000008:administration & dosage; D003593:Cytoplasm / Q000201:enzymology; D018572:Disease-Free Survival; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D066246:ErbB Receptors / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D015337:Multicenter Studies as Topic; D020360:Neoadjuvant Therapy; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D003520:Cyclophosphamide; D011065:Poly(ADP-ribose) Polymerases; D066246:ErbB Receptors