Abstract P2-05-01: Clinico-pathological relationships with Ki67 in POETIC (CRUK/07/015) – Critical lessons for assessing Ki67 for prognosis and as a pharmacodynamic marker
Authors: Bliss JM , Morden J , Evans A , Holcombe C , Horgan K , Mallon E , Raghavan V , Skene A , Dodson A , Hills M , Detre S , Zabaglo L , Graf M , Banerji J , Gillman A , Robertson J , Dowsett M , Smith I ,   On Behalf of the POETIC Trialists
Published: February 2017

Abstract
Background Higher levels of the proliferation marker Ki67 at breast cancer (BC) diagnosis are increasingly recognised to indicate poorer prognosis. Change in ΔKi67 in response to endocrine treatment reflects response. The precise relationship between Ki67 and other clinico-path factors and how associations are affected by short exposure to aromatase inhibitor (AI) has been unclear.
Methods POETIC was a UK-wide, phase III, randomised trial which tested perioperative use of AI (anastrozole (A), letrozole (L)) in postmenopausal women with early BC (Dowsett JNCI Monogr 2011). Ki67 was measured in a single central lab at diagnosis (B=baseline) and 2 weeks later at surgery (S) allowing in vivo assessment of AI sensitivity. POETIC recruited 4483 women from 130 UK centres. Paired biopsies were available for 96%. Relationship between Ki67 and clinico-path factors is described by summary statistics (median) and independent associations explored in multivariable linear regression models (MVM). Analyses of Ki67 at S and ΔKi67 (reduction) were adjusted for B Ki67 and surgical sample type.
Results Absolute Ki67 (B) was associated with each classic prognostic factor. Factors affecting ΔKi67 in control pts were Ki67 (B), grade (B) and surgical sample type (core cut 4.1%; excision 17.7% p&lt;0.001). After 2 weeks of AI, variation in extent of ΔKi67 was dominated by PgR, HER2 and grade (B). Centres using L more often supplied excision samples (p&lt;0.001). In spite of this both surgical sample type and choice of AI (both p&lt;0.001) independently influenced ΔKi67 (core cut: A 65.1% L 73.8% excision A 75.2% L 81.3%). Pattern of change in grade between B and S differed for AI and control.
Baseline Ki67 %Ki67 change (%) with 2 weeks AIVariableNMedianln(Ki67) P value (MVM)NMedianln (Ki67(S)/Ki67 (B)) P Value (MVM)All patients391315.2 252877.6 PgR (local) 0.01 &lt;0.001Positive221914.6 141180.0 Negative47720.4 32661.1 Not known121715.1 79177.0 HER2 (local) &lt;0.001 &lt;0.001Negative345914.3 224079.2 Positive40226.8 26552.9 Unknown5213.9 2385.5 Tumour grade (B) &lt;0.001 &lt;0.001G15489.1 34378.6 G2227514.5 149479.6 G370330.1 44762.1 Unknown38714.0 24475.4 Tumour size (S) 0.002 0.49&lt;2cm150312.9 98379.1 2-5cm222117.5 142576.4 &gt;5cm17416.9 11474.1 Histological type (B) &lt;0.001 0.58Ductal313816.3 203077.5 Lobular54911.9 35379.0 Other/Not known22613.1 14574.0 Nodes involved 0.03 0.530235714.1 153577.6 1-3110815.8 70878.2 4+43320.3 27876.1 Vascular invasion &lt;0.001 0.03Yes112119.9 71175.9 No260313.6 169578.2 Unknown18914.6 12275.8
Summary POETIC provides the largest multi-centre series of women in whom centrally assessed Ki67 has been correlated with classic clinico-path factors and impact of short term AI exposure explored. Choice of AI and surgical sample type are both dictated by participating site and their inter-relationship requires further review. Whether the greater suppression of Ki67 following L, a drug associated with better E2 suppression and aromatisation than A has clinical consequences is beyond the scope of this work. Relationships found (e.g. sample type, grade) are critical for interpretation of studies using Ki67 for prognosis and ΔKi67 as a pharmacodynamic response marker.
Citation Format: Bliss JM, Morden J, Evans A, Holcombe C, Horgan K, Mallon E, Raghavan V, Skene A, Dodson A, Hills M, Detre S, Zabaglo L, Graf M, Banerji J, Gillman A, Robertson J, Dowsett M, Smith I, On Behalf of the POETIC Trialists. Clinico-pathological relationships with Ki67 in POETIC (CRUK/07/015) – Critical lessons for assessing Ki67 for prognosis and as a pharmacodynamic marker [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-01.