title: Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer.
abstract: OBJECTIVE
  Predictive biomarkers offer the potential to improve the benefit:risk ratio of a therapeutic agent. Ixabepilone achieves comparable pathologic complete response (pCR) rates to other active drugs in the neoadjuvant setting. This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent.
  
  
  METHODS
  Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin/cyclophosphamide, followed by 1:1 randomization to ixabepilone (n = 148) or paclitaxel (n = 147). Rates of pCR were compared between treatment arms based on predefined biomarker sets: TUBB3, TACC3, and CAPG gene expression, a 20- and 26-gene expression model, MDR1 protein expression, and other potential markers of sensitivity. βIII-tubulin protein expression is reported separately but is referred to here for completeness. All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis before chemotherapy. Gene expression profiling data were used for molecular subtyping.
  
  
  RESULTS
  There was no significant difference in the rate of pCR in both treatment arms in βIII-tubulin-positive patients. Higher pCR rates were observed among βIII-tubulin-positive patients than in βIII-tubulin-negative patients. Furthermore, no correlation was evident between TUBB3, TACC3, and CAPG gene expression, MDR1 protein expression, multi-gene expression models, and the efficacy of ixabepilone or paclitaxel, even within the estrogen receptor-negative subset.
  
  
  CONCLUSIONS
  These results indicate that βIII-tubulin protein and mRNA expression, MDR1 protein expression, TACC3 and CAPG gene expression, and multigene expression models (20- and 26-gene) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early-stage breast cancer.
authors: Bristol-Myers Squibb, Princeton, New Jersey 08543, USA. christine.horak@bms.com
authors: Christine E
authors: CE
authors: Horak
authors: Lajos
authors: L
authors: Pusztai
authors: Guan
authors: G
authors: Xing
authors: Ovidiu C
authors: OC
authors: Trifan
authors: Cristina
authors: C
authors: Saura
authors: Ling-Ming
authors: LM
authors: Tseng
authors: Stephen
authors: S
authors: Chan
authors: Rosanne
authors: R
authors: Welcher
authors: David
authors: D
authors: Liu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D034261:Epothilones / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D014404:Tubulin / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014408:Biomarkers, Tumor; D034261:Epothilones; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C120551:TACC3 protein, human; C498585:TUBB3 protein, human; D014404:Tubulin; C066575:CAPG protein, human; D004317:Doxorubicin; D003520:Cyclophosphamide; C430592:ixabepilone; D017239:Paclitaxel