title: Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index.
abstract: BACKGROUND
  Recurrence risk in breast cancer varies throughout the follow-up time. We examined if these changes are related to the level of expression of the proliferation pathway and intrinsic subtypes.
  
  
  METHODS
  Expression of estrogen and progesterone receptor, Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) was performed on tissue-microarrays constructed from a large and uniformly managed series of early breast cancer patients (N = 1,249). Subtype definitions by four biomarkers were as follows: luminal A (ER + and/or PR+, HER2−, Ki-67 <14), luminal B (ER + and/or PR+, HER2−, Ki-67 ≥14), HER2-enriched (any ER, any PR, HER2+, any Ki-67), triple-negative (ER−, PR−, HER2−, any Ki-67). Subtype definitions by six biomarkers were as follows: luminal A (ER + and/or PR+, HER2−, Ki-67 <14, any CK 5/6, any EGFR), luminal B (ER + and/or PR+, HER2−, Ki-67 ≥14, any CK 5/6, any EGFR), HER2-enriched (ER−, PR−, HER2+, any Ki-67, any CK 5/6, any EGFR), Luminal-HER2 (ER + and/or PR+, HER2+, any Ki-67, any CK 5/6, any EGFR), Basal-like (ER−, PR−, HER2−, any Ki-67, CK5/6+ and/or EGFR+), triple-negative nonbasal (ER−, PR−, HER2−, any Ki-67, CK 5/6−, EGFR−). Each four- or six-marker defined intrinsic subtype was divided in two groups, with Ki-67 <14% or with Ki-67 ≥14%. Recurrence hazard rate function was determined for each intrinsic subtype as a whole and according to Ki-67 value.
  
  
  RESULTS
  Luminal A displayed a slow risk increase, reaching its maximum after three years and then remained steady. Luminal B presented most of its relapses during the first five years. HER2-enriched tumors show a peak of recurrence nearly twenty months post-surgery, with a greater risk in Ki-67 ≥14%. However a second peak occurred at 72 months but the risk magnitude was greater in Ki-67 <14%. Triple negative tumors with low proliferation rate display a smooth risk curve, but with Ki-67 ≥14% show sharp peak at nearly 18 months.
  
  
  CONCLUSIONS
  Each intrinsic subtype has a particular pattern of relapses over time which change depending on the level of activation of the proliferation pathway assessed by Ki-67. These findings could have clinical implications both on adjuvant treatment trial design and on the recommendations concerning the surveillance of patients.
authors.forename: Nuria
authors.initials: N
authors.lastname: Ribelles
authors.forename: Lidia
authors.initials: L
authors.lastname: Perez-Villa
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Jerez
authors.forename: Bella
authors.initials: B
authors.lastname: Pajares
authors.forename: Luis
authors.initials: L
authors.lastname: Vicioso
authors.forename: Begoña
authors.initials: B
authors.lastname: Jimenez
authors.forename: Vanessa
authors.initials: V
authors.lastname: de Luque
authors.forename: Leonardo
authors.initials: L
authors.lastname: Franco
authors.forename: Elena
authors.initials: E
authors.lastname: Gallego
authors.forename: Antonia
authors.initials: A
authors.lastname: Marquez
authors.forename: Martina
authors.initials: M
authors.lastname: Alvarez
authors.forename: Alfonso
authors.initials: A
authors.lastname: Sanchez-Muñoz
authors.forename: Luis
authors.initials: L
authors.lastname: Perez-Rivas
authors.forename: Emilio
authors.initials: E
authors.lastname: Alba
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D049109:Cell Proliferation; D016208:Databases, Factual; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D012307:Risk Factors; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor