Research Papers:

Low Ki67/high ATM protein expression in malignant tumors predicts favorable prognosis in a retrospective study of early stage hormone receptor positive breast cancer

Xiaolan Feng _, Haocheng Li, Elizabeth N . Kornaga, Michelle Dean, Susan P. Lees-Miller, Karl Riabowol, Anthony M. Magliocco, Don Morris, Peter H. Watson, Emeka K . Enwere, Gwyn Bebb and Alexander Paterson

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Oncotarget. 2016; 7:85798-85812. https://doi.org/10.18632/oncotarget.12622

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Xiaolan Feng1,2,3, Haocheng Li3,4, Elizabeth N. Kornaga5,6, Michelle Dean5,6, Susan P. Lees-Miller7, Karl Riabowol7, Anthony M. Magliocco8, Don Morris3,6, Peter H. Watson9, Emeka K. Enwere5,6, Gwyn Bebb3,6 and Alexander Paterson3

1 Department of Oncology, BC Cancer Agency-Vancouver Island Center, Victoria, British Columbia, Canada

2 Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada

3 Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada

4 Department of Community Health Science, TRW Building, University of Calgary, Calgary, Alberta, Canada

5 Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada

6 Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada

7 Department of Biochemistry and Molecular Biology, Health Science Building, University of Calgary, Alberta, Canada

8 Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

9 Department of Pathology, BC Cancer Agency-Vancouver Island Center, Victoria, British Columbia, Canada

Correspondence to:

Xiaolan Feng, email:

Keywords: ATM, Ki67, early stage hormone receptor positive breast cancer, automated quantitative immunofluorescence analysis, disease specific overall survival

Received: August 26, 2016 Accepted: October 05, 2016 Published: October 12, 2016


Introduction: This study was designed to investigate the combined influence of ATM and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (< 4 cm) and fewer than four positive lymph nodes.

Methods: 532 formalin-fixed paraffin-embedded specimens of resected primary breast tumors were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using fluorescence and brightfield immunohistochemistry respectively, and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome.

Results: Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up (p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively (p = 0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status (p = 0.02).

Conclusions: These data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC.

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