Breast Cancer Research and Treatment

, Volume 121, Issue 2, pp 431–437 | Cite as

Ki67: a time-varying biomarker of risk of breast cancer in atypical hyperplasia

  • Marta Santisteban
  • Carol Reynolds
  • Emily G. Barr Fritcher
  • Marlene H. Frost
  • Robert A. Vierkant
  • Stephanie S. Anderson
  • Amy C. Degnim
  • Daniel W. Visscher
  • V. Shane Pankratz
  • Lynn C. HartmannEmail author


Uncontrolled proliferation is a defining feature of the malignant phenotype. Ki67 is a marker for proliferating cells and is overexpressed in many breast cancers. Atypical hyperplasia is a premalignant lesion of the breast (relative risk ~ 4.0). Here, we asked if Ki67 expression could stratify risk in women with atypia. Ki67 expression was assessed immunohistochemically by digital image analysis in archival sections from 192 women with atypia diagnosed at the Mayo Clinic 1/1/67–12/31/91. Risk factor and follow-up data were obtained via study questionnaire and medical records. Observed breast cancer events were compared to population expected rates (Iowa SEER) using standardized incidence ratios (SIRs). We examined two endpoints: risk of breast cancer within 10 years and after 10 years of atypia biopsy. Thirty-two (16.7%) of the 192 women developed breast cancer over a median of 14.6 years. Thirty percent (58) of the atypias had ≥2% cells staining for Ki67. In these women, the risk of breast cancer within 10 years after atypia was increased (SIR 4.42 [2.21–8.84]) but not in those with <2% staining. Specifically, the cumulative incidence for breast cancer at 10 years was 14% in the high Ki67 vs. 3% in the low Ki67 group. Conversely, after 10 years, risk in the low Ki67 group rose significantly (SIR 5.69 [3.63–8.92]) vs. no further increased risk in the high Ki67 group (SIR 0.78 [0.11–5.55]). Ki67 appears to be a time-varying biomarker of risk of breast cancer in women with atypical hyperplasia.


Atypical hyperplasia Breast cancer risk Ki-67 Immunohistochemistry 



This work was supported by NCI RO1 grant CA132879, Mayo Clinic Breast Cancer SPORE CA116201, and the Martha and Bruce Atwater Foundation. We thank Linda Murphy for immunostaining; Teresa Allers, Jo Johnson, Mary Campion, Melanie Kasner, and Romayne Thompson for data collection; Joel Worra for database development; Ann Harris and the Survey Research Center for patient follow-up; and Vicki Shea for assistance with manuscript preparation.


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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Marta Santisteban
    • 1
  • Carol Reynolds
    • 2
  • Emily G. Barr Fritcher
    • 2
  • Marlene H. Frost
    • 3
  • Robert A. Vierkant
    • 4
  • Stephanie S. Anderson
    • 4
  • Amy C. Degnim
    • 5
  • Daniel W. Visscher
    • 6
  • V. Shane Pankratz
    • 4
  • Lynn C. Hartmann
    • 3
    Email author
  1. 1.Department of OncologyClinica Universitaia de NavarraNavarraSpain
  2. 2.Department of Laboratory Medicine and Pathology, Mayo Clinic Cancer Center, Mayo Graduate School of Medical EducationMayo Clinic College of MedicineRochesterUSA
  3. 3.Division of Medical Oncology, Department of Oncology, Mayo Clinic Cancer Center, Mayo Graduate School of Medical EducationMayo Clinic College of MedicineRochesterUSA
  4. 4.Department of Health Sciences Research—Biostatistics, Mayo Clinic Cancer Center, Mayo Graduate School of Medical EducationMayo Clinic College of MedicineRochesterUSA
  5. 5.Department of General Surgery, Mayo Clinic Cancer Center, Mayo Graduate School of Medical EducationMayo Clinic College of MedicineRochesterUSA
  6. 6.Department of PathologyUniversity of MichiganAnn ArborUSA

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