B63
BubR1 as a predictive marker of anthracycline sensitivity in the BR9601 trial
Alison Munro1, David Cameron2, Christopher Twelves3, Jeremy Thomas4, John Bartlett1
1University of Edinburgh, UK, 2University of Leeds, UK, 3Cancer Research UK, Leeds, UK, 4Western General Hospital, Edinburgh, UK
Background
We have recently presented data suggesting chromosome 17 polysomy predicts
anthracycline benefit. Spindle checkpoint failure could be a mechanism for this
observation. BubR1 is a spindle assembly checkpoint protein which prevents
progression to anaphase. BubR1-deficient cells have lower basal p53 levels and
a reduction in G2/M cell cycle arrest, following anthracycline treatment,
compared to wild type cells. BubR1 competitively binds, phosphorylates and
stabilises p53 during mitosis, at a site overlapping that of MDM2. Therefore,
BubR1 is implicated in both spindle assembly and DNA damage checkpoints. We
investigated BubR1 as a predictive marker of anthracycline sensitivity in
breast cancer.
Method
We evaluated BubR1 protein expression in 321 tumours from patients in the
BR9601 trial, which compared E-CMF with CMF as adjuvant therapy for breast
cancer. Relapse-free survival (RFS) was estimated using Kaplan-Meier curves.
Results
BubR1 overexpression (≥5% moderate/strong cytoplasmic staining) was
detected in 49.2% of tumours and was associated with chromosome 17 polysomy
(p=0.0003), ER negativity (p<0.0001), high grade (p<0.0001), and high
proliferation (p<0.0001). BubR1 overexpression was associated with reduced
RFS (HR: 1.58, 95%C.I. 1.06-2.37, p=0.024). However, there was a trend (HR for
interaction: 1.70 95%C.I. 0.74-3.87. NS) towards greater benefit from the
addition of anthracyclines to CMF in tumours with high BubR1 expression (HR:
0.455, 95%C.I. 0.263-0.788), versus those with low BubR1 expression (HR: 0.755,
95%C.I. 0.406-1.406), similar to that recently seen with polysomy 17. Combining
BubR1 with polysomy 17 showed a trend towards reduced RFS in tumours with both
markers present (p=0.04).
Conclusion
BubR1 overexpression is associated with an aggressive phenotype and decreased
RFS in BR9601 patients. Tumours with BubR1 overexpression showed an increased
sensitivity to anthracycline therapy compared to those with low BubR1 levels.
Further work in larger patient cohorts is required.
