title: Association of molecular subtypes with Ki-67 changes in untreated breast cancer patients undergoing pre-surgical trials.
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.
  
  
  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.
  
  
  BACKGROUND
  ISRCTN86894592; ISRCTN16493703.
authors.affiliation: Divisions of Epidemiology and Biostatistics.
authors.forename: S
authors.initials: S
authors.lastname: Gandini
authors.affiliation: Cancer Prevention and Genetics.
authors.forename: A
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.affiliation: Pathology; School of Medicine, University of Milan, Milan.
authors.forename: G
authors.initials: G
authors.lastname: Pruneri
authors.affiliation: Cancer Prevention and Genetics.
authors.forename: D
authors.initials: D
authors.lastname: Serrano
authors.affiliation: Cancer Prevention and Genetics.
authors.forename: M
authors.initials: M
authors.lastname: Cazzaniga
authors.affiliation: Cancer Prevention and Genetics.
authors.forename: M
authors.initials: M
authors.lastname: Lazzeroni
authors.affiliation: Breast Surgery, European Institute of Oncology, Milan; School of Medicine, University of Milan, Milan.
authors.forename: P
authors.initials: P
authors.lastname: Veronesi
authors.affiliation: Cancer Prevention and Genetics.
authors.forename: H
authors.initials: H
authors.lastname: Johansson
authors.affiliation: Cancer Prevention and Genetics.
authors.forename: B
authors.initials: B
authors.lastname: Bonanni
authors.affiliation: Pathology; School of Medicine, University of Milan, Milan.
authors.forename: G
authors.initials: G
authors.lastname: Viale
authors.affiliation: Cancer Prevention and Genetics; Division of Medical Oncology, Department of Medicine, Galliera Hospital, Genoa, Italy. Electronic address: andrea.decensi@galliera.it.
authors.forename: A
authors.initials: A
authors.lastname: DeCensi
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001706:Biopsy; D015992:Body Mass Index; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I; D019394:Ki-67 Antigen / Q000235:genetics*; D058889:Molecular Typing; D020360:Neoadjuvant Therapy; D010919:Placebos / Q000627:therapeutic use; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012738:Sex Hormone-Binding Globulin; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000601:surgery*
chemical_list: D014408:Biomarkers, Tumor; D007334:Insulin-Like Growth Factor I; D019394:Ki-67 Antigen; D010919:Placebos; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012738:Sex Hormone-Binding Globulin
keywords: Ki 67 antigen; molecular subtype breast cancer; neoadjuvant treatment breast cancer; triple-negative breast cancer; window of opportunity