title: A prospective randomized pilot study to evaluate predictors of response in serial core biopsies to single agent neoadjuvant doxorubicin or paclitaxel for patients with locally advanced breast cancer.
abstract: BACKGROUND
  Response to neoadjuvant chemotherapy for locally advanced breast cancer can be correlated with long-term outcomes. Surrogate end-point biomarkers may be used to assess response to the treatment. Most reported studies assessed the effects of combination chemotherapy. We assessed the feasibility of obtaining serial core breast biopsies, and correlated rates of apoptosis, proliferation, and expression of related proteins at baseline, during, and after neoadjuvant single agent chemotherapy for locally advanced breast cancer with response.
  
  
  METHODS
  Women with a histologically confirmed unresected T(3) or T(4) infiltrating carcinoma of the breast were eligible. The first 20 patients received three cycles of doxorubicin 90 mg/m(2) followed by three cycles of paclitaxel 250 mg/m(2), or the reverse. Nine women received four cycles of each (doxorubicin 60 mg/m(2) and paclitaxel 175 mg/m(2)). Cycles were administered 14 days apart with filgastrim. End points included: (a). clinical and pathological response; (b). serial apoptotic [terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling] and proliferation (immunohistochemistry, IHC) rates; and (c). expression (IHC) of estrogen receptor, HER2, bcl2, and p53.
  
  
  RESULTS
  From April 1997 to June 2001, 29 women were randomized. Twelve patients (42%) had a clinical complete response (cCR), and 16 (55%) had a clinical partial response. Five women (17%) had a pathological complete response, 7 (24%) had microscopic residual disease, and 17 (58%) had macroscopic residual disease. Higher baseline apoptosis and proliferation were associated with an improved pathological response (P = 0.006 and 0.003, respectively). Among 14 evaluable patients, apoptosis increased in women who had a cCR to the first agent but not in women without a cCR. Estrogen receptor-positive patients had a worse pathological response (P = 0.004).
  
  
  CONCLUSIONS
  The selected regimen is efficacious. It is feasible to obtain serial core biopsies that are informative for studies of apoptosis and IHC. This clinical design can serve as a model for combining standard chemotherapy and novel agents.
authors.affiliation: Department of Medicine, Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC 20007, USA. vstearn1@jhmi.edu
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
authors.forename: Theodore
authors.initials: T
authors.lastname: Tsangaris
authors.forename: Jeanette G
authors.initials: JG
authors.lastname: Crawford
authors.forename: Antonella
authors.initials: A
authors.lastname: Novielli
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Claudine
authors.initials: C
authors.lastname: Isaacs
authors.forename: Marie
authors.initials: M
authors.lastname: Pennanen
authors.forename: Cecilia
authors.initials: C
authors.lastname: Tibery
authors.forename: Ahmad
authors.initials: A
authors.lastname: Farhad
authors.forename: Rebecca
authors.initials: R
authors.lastname: Slack
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division; D002986:Clinical Trials as Topic; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000627:therapeutic use*; D010865:Pilot Projects; D011897:Random Allocation; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D014408:Biomarkers, Tumor; D004317:Doxorubicin; D017239:Paclitaxel