Evaluation of Ki-67 proliferation and apoptotic index before, during and after neoadjuvant chemotherapy for primary breast cancer

Breast Cancer Res. 2006;8(3):R31. doi: 10.1186/bcr1508. Epub 2006 Jun 21.


Introduction: 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).

Conclusion: 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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis*
  • Biomarkers, Tumor / analysis*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology*
  • Cell Proliferation*
  • Cyclophosphamide / administration & dosage
  • Epirubicin / administration & dosage
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Ki-67 Antigen / analysis*
  • Middle Aged
  • Neoadjuvant Therapy
  • Prognosis
  • Treatment Outcome


  • Biomarkers, Tumor
  • Ki-67 Antigen
  • Epirubicin
  • Cyclophosphamide
  • Fluorouracil

Supplementary concepts

  • FEC protocol