Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015)

Abstract

Purpose: Ki67 assessed at diagnosis (Ki67_baseline) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki67_2week) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki67_2week) with recurrence-free survival. The aim was to define the association between Ki67_baseline and after aromatase inhibitor (AI) exposure ∆Ki67_2week and Ki67_2week with key prognostic and biologic factors utilising data from the POETIC study.

Patients and methods: In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks' presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression.

Results: Established associations of Ki67_baseline with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67_baseline. In control group Ki67_2week was 18% lower than Ki67_baseline (p < 0.001) when Ki67_2week was measured in excision biopsies but not when measured in core-cuts. Median suppression by AIs (∆Ki67_2week) was 79.3% (IQR: -89.9 to -54.6) and 53.7% (IQR: -78.9 to -21.1) for HER2-negative and HER2-positive cases, respectively. Significantly less suppression occurred in PgR- vs PgR + and HER2 + vs HER2- tumours which remained apparent after adjustment for 2-week sample type.

Conclusions: The magnitude of this study allowed characterisation of relationships between Ki67_baseline, ∆Ki67_2week and Ki67_2week with high degrees of confidence providing a reference source for other studies. Lower values of Ki67 occur when measured on excision biopsies and could lead to apparent but artefactual decreases in Ki67: this should be considered when either ∆Ki67_2week or Ki67_2week is used in routine clinical practice to aid treatment decisions or in clinical trials assessing new drug therapies.

Keywords: Aromatase inhibitor; Ki67; Primary breast cancer.