Abstract P3-06-07: Ki67 as a Predictive Marker of Response to Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer (ESBC): A Systematic Review and Evidence Summary
Authors: Lyman GH , Culakova E , Poniewierski MS , Wogu AF , Barry W , Ginsburg GS , Marcom PK , Ready N , Abernethy A , Geradts J , Hwang S , Kuderer NM 
Published: August 2014

Abstract
Background: Immunohistochemical (IHC) assessment of the proportion of cells staining for the KI67 nuclear antigen is being increasing utilized in the management of patients with early-stage breast cancer (ESBC). A comprehensive systematic review and evidence synthesis of biomarkers potentially predictive of response to systemic therapy was initiated as a part of an NCI-funded comparative effectiveness research program.
Methods: Studies of chemotherapy response prediction based on baseline IHC assessment of Ki67 in patients with ESBC receiving neoadjuvant systemic therapy were identified. Response was specified as pathologic complete response (pCR) or clinical response (ClinR). Assay predictive performance for response was assessed on the basis of sensitivity, specificity, predictive value and predictive odds ratio (POR±95%CLs) utilizing mixed effects models. Study results were fitted in an ROC analysis based on the method of DerSimonian and Laird. Publication bias was evaluated on the basis of funnel plot asymmetry assessed by Egger's regression intercept and Begg and Mazumdar's rank correlation.
Results: Of 469 potentially eligible studies, dual blind full text review identified 42 eligible studies reporting 44 independent cohorts with 6,716 patients (21–979). While Ki67 cutpoints varied considerably, they were most commonly between 10%–30% (median 20%, range 1–50%). The analysis prsented here is limited to the 30 studies of ESBC patients (N = 3,343) receiving neoadjuvant therapy of which 14 reported fewer than 100 patients. The proportion of patients with elevated Ki67 across studies ranged from 0.20–0.92 (median = 0.54). Sensitivity and specificity for treatment response in patients with high vs. low baseline Ki67 was 0.65 [0.61, 0.68] and 0.52 [0.50, 0.54], respectively. Estimated response rates across studies in patients with high vs. low Ki67 were 31% [29%, 34%] and 19% [17%, 21%], respectively. The estimated POR for response across studies was 2.82 [2.14, 3.72; P &lt; .001].

POR was significantly greater in studies of anthracycline-based [3.0] than non-anthracycline regimens [0.92](Pinteraction = .043) and of cyclophosphamide-based [3.41] compared to non-cyclophosphamide regimens [2.00](P interaction=.039) but was not associated with treatment based on other drug classes. Although Ki67 predictive performance was not significantly associated with the cutpoint utilized or the proportion of patients with ER or PR+, Her2+, or high grade tumors across studies, analysis based on individual patient data is needed to assess performance in specific clinical subgroups. No significant publication bias was found.
Conclusions: A compelling need exists for larger studies with greater methodologic rigor and standardization to assess the clinical validity of Ki67 in ESBC as well its clinical utility in guiding neoadjuvant treatment decisions compared to the use of conventional predictive markers.
Funding: NCI: RC2CA14041-01
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-07.