title: Evaluation of Ki-67 proliferation and apoptotic index before, during and after neoadjuvant chemotherapy for primary breast cancer.
abstract: BACKGROUND
  Biological markers that reliably predict clinical or pathological response to primary systemic therapy early during a course of chemotherapy may have considerable clinical potential. This study evaluated changes in Ki-67 labeling index and apoptotic index (AI) before, during, and after neoadjuvant anthracycline chemotherapy.
  
  
  METHODS
  Twenty-seven patients receiving neoadjuvant FEC (5-fluorouracil, epirubicin, and cyclophosphamide) chemotherapy for operable breast cancer underwent repeat core biopsy after 21 days of treatment. Tissue from pre-treatment biopsy, day 21 and surgery was analysed for Ki-67 index and AI.
  
  
  RESULTS
  The objective clinical response rate was 56%. Eight patients (31%) achieved a pathological response by histological criteria; two patients had a near-complete pathological response. A reduction in Ki-67 index was observed in 68% of patients at day 21 and 72% at surgery; Ki-67 index increased between day 21 and surgery in 54%. AI decreased in 50% of tumours by day 21, increased in 45% and was unchanged in one patient; 56% demonstrated rebound increases in AI by the time of surgery. Neither pre-treatment nor post-chemotherapy median Ki-67 index nor median AI at all three time points or relative changes at day 21 and surgery differed significantly between clinical or pathological responders and non-responders. Clinical responders had lower median Ki-67 indices at day 21 (11.4% versus 27.0%, p = 0.02) and significantly greater percentage reductions in Ki-67 at day 21 than did non-responders (-50.6% versus -5.3%, p = 0.04). The median day-21 Ki-67 was higher in pathological responders (30.3% versus 14.1%, p = 0.046). A trend toward increased AI at day 21 in pathological responders was observed (5.30 versus 1.68, p = 0.12). Increased day-21 AI was a statistically significant predictor of pathological response (p = 0.049). A strong trend for predicting pathological response was seen with higher Ki-67 indices at day 21 and AI at surgery (p = 0.06 and 0.06, respectively).
  
  
  CONCLUSIONS
  The clinical utility of early changes in biological marker expression during chemotherapy remains unclear. Until further prospectively validated evidence confirming the reliability of predictive markers is available, clinical decision-making should not be based upon individual biological tumour marker profiles.
authors.affiliation: Kent Oncology Centre, Maidstone Hospital, Hermitage Lane, Maidstone, Kent ME16 9QQ, UK. burcombe@nildram.co.uk
authors.forename: Russell
authors.initials: R
authors.lastname: Burcombe
authors.forename: George D
authors.initials: GD
authors.lastname: Wilson
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Ifty
authors.initials: I
authors.lastname: Khan
authors.forename: Paul I
authors.initials: PI
authors.lastname: Richman
authors.forename: Frances
authors.initials: F
authors.lastname: Daley
authors.forename: Simone
authors.initials: S
authors.lastname: Detre
authors.forename: Andreas
authors.initials: A
authors.lastname: Makris
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil