Short-Term Changes in Ki-67 during Neoadjuvant Treatment of Primary Breast Cancer with Anastrozole or Tamoxifen Alone or Combined Correlate with Recurrence-Free Survival

• Published in: Clinical cancer research Vol. 11; no. 2; pp. 951s - 958s
• Main Authors: Dowsett, Mitch, Smith, Ian E, Ebbs, Steve R, Dixon, J Michael, Skene, Anthony, Griffith, Clive, Boeddinghaus, Irene, Salter, Janine, Detre, Simone, Hills, Margaret, Ashley, Susan, Francis, Stephen, Walsh, Geraldine
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 15-01-2005
• Subjects: adjuvant therapy; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; apoptosis; Apoptosis - drug effects; aromatase inhibitor; biomarker; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Proliferation - drug effects; Chemotherapy, Adjuvant; Disease-Free Survival; Double-Blind Method; Female; Follow-Up Studies; Humans; Ki-67 Antigen - metabolism; Neoadjuvant Therapy; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Nitriles - administration & dosage; preoperative; Survival Rate; Tamoxifen - administration & dosage; Treatment Outcome; Triazoles - administration & dosage
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.951s.11.2

Purpose: Neoadjuvant (preoperative) therapy for breast cancer may allow for the development of intermediate markers of treatment benefit,
thereby circumventing the need for efficacy trials of adjuvant therapy, which require much larger patient numbers and longer
follow-up. The aim of this study—as part of the Immediate Preoperative “Arimidex” (anastrozole), Tamoxifen, or Arimidex Combined
with Tamoxifen (IMPACT) trial ( n = 330)—was to test the hypotheses that changes in Ki-67 after 2 weeks and/or 12 weeks: (i) differed between treatments, (ii)
predicted clinical tumor response, and/or (iii) may predict long-term outcome differences between treatments in adjuvant therapy.
Experimental Design: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared these same agents in the adjuvant setting. Biomarkers
were measured in biopsy specimens taken before and after 2 and 12 weeks of treatment.
Results: Suppression of the proliferation marker Ki-67 after 2 and 12 weeks was significantly greater with anastrozole than with tamoxifen
( P = 0.004 and P < 0.001) but was similar between tamoxifen and the combination ( P = 0.600 and P = 0.912). This result closely parallels that seen for the relative recurrence-free survival with the treatments after a median
follow-up of 31 months in the ATAC trial in 9,366 patients. Against expectations, apoptosis was not increased in any of the
treatment arms.
Conclusions: The data indicate that short-term changes in proliferation in the neoadjuvant setting may be able to predict outcome during
adjuvant use of the same treatments. If this can be confirmed, these findings could lead to a profound change in approaches
to drug development in breast cancer. The data indicate that estrogen is not an important survival factor for human breast
cancer cells.