Association of molecular subtypes with Ki-67 changes in untreated breast cancer patients undergoing pre-surgical trials

Ann Oncol. 2014 Mar;25(3):618-623. doi: 10.1093/annonc/mdt528. Epub 2013 Dec 18.

Abstract

Background: Ki-67 is increasingly being used as a response biomarker in window of opportunity, pre-surgical trials for breast cancer patients. Since Ki-67 is often higher at surgery than at baseline core biopsy in subjects allocated to placebo, we investigated which factors affected this change.

Patients and methods: We retrieved data from 274 patients who received no active treatment in three consecutive pre-surgical trials from a single institution. We assessed the association between changes in Ki-67 from diagnostic biopsy to surgical specimen and the following factors: age, body mass index, tumor prognostic and predictive factors, including immunohistochemical molecular subtype, number and size of biopsy specimens, time from biopsy to surgery, circulating insulin-like growth factor-I, sex hormone-binding globulin and hsCRP.

Results: A total of 269 patients with paired measures of Ki-67 at biopsy and surgery were analyzed. Overall, the mean (±SD) change was 2.2 ± 9.2% after a median interval of 41 days (inter-quartile range 33-48). Molecular subtype was the only factor associated with a significant change of Ki-67 (P = 0.004), with a mean absolute increase of 5.3% [95% confidence interval (CI): 2.3-8.3, P = 0.0005] in estrogen receptor-negative HER2-positive tumors (n = 36) and 5.4% (95% CI: 2.9-7.9, P < 0.0001) in triple-negative tumors (n = 78). No significant change in luminal-A (n = 46), luminal-B (n = 85) and luminal-B HER2-positive (n = 24) tumors was observed.

Conclusions: A significant increase in Ki-67 from baseline biopsy to end point surgery in untreated subjects was ascertained in HER2-positive and triple-negative tumors. This biological association suggests a real increase in cancer proliferation, possibly as a result of a biopsy-driven wound healing effect, and should be considered in the design and interpretation of pre-surgical studies.

Registered clinical trial numbers: ISRCTN86894592; ISRCTN16493703.

Keywords: Ki 67 antigen; molecular subtype breast cancer; neoadjuvant treatment breast cancer; triple-negative breast cancer; window of opportunity.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics
  • Biopsy
  • Body Mass Index
  • Cell Proliferation
  • Female
  • Humans
  • Insulin-Like Growth Factor I
  • Ki-67 Antigen / genetics*
  • Molecular Typing*
  • Neoadjuvant Therapy
  • Placebos / therapeutic use
  • Prognosis
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Sex Hormone-Binding Globulin
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / mortality
  • Triple Negative Breast Neoplasms / surgery*

Substances

  • Biomarkers, Tumor
  • Ki-67 Antigen
  • Placebos
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Sex Hormone-Binding Globulin
  • Insulin-Like Growth Factor I
  • Receptor, ErbB-2

Associated data

  • ISRCTN/ISRCTN16493703
  • ISRCTN/ISRCTN86894592