Quantitative assessment Ki-67 score for prediction of response to neoadjuvant chemotherapy in breast cancer

Abstract

Measurement of Ki-67, a marker of cell proliferation, has been associated with response to therapy, but methods of measurement are controversial. Here we use a quantitative objective measurement for Ki-67 to determine the best method for assessment of Ki-67 for prediction of response to neoadjuvant chemotherapy. Analysis was conducted on a cohort of 105 consecutive invasive breast cancer patients that received neoadjuvant therapy between 2002 and 2010, and on whom pre-surgical biopsies were obtainable. Ki-67 expression was measured using quantitative immunofluorescence automated quantitative analysis (AQUA) technology. Images for each specimen were collected for 5 to 115 fields of view (FOVs) and summary scores were obtained, corresponding to the average and maximum of all the FOVs. AQUA scoring (using both intensity and area) was comparable to automated calculation of percentage of positive nuclei for prediction of response to chemotherapy (OR: 2.832 vs 2.712). Both the average and maximum AQUA score showed Ki-67 expression was directly correlated to pathological complete response (pCR; average P ¼ 0.0002; maximum P ¼ 0.0011). Although examining the maximum FOV was more predictive of response to therapy (OR: 3.546 vs 2.832), averaging all fields provided more sensitivity and specificity (AUC 0.769 vs 0.732). Ki-67 average (P ¼ 0.0025) and maximum (P ¼ 0.0239) AQUA score were also significant predictors of pCR in a multivariable analysis, including tumor size, nuclear grade, nodal status, ER status, and HER2 status. Measurement of Ki-67 expression by objective quantitative methods shows increased Ki-67 levels are an independent predictor of response to neoadjuvant chemotherapy.

Integrated tumor identification and automated scoring minimizes pathologist involvement and provides new insights to key biomarkers in breast cancer

“…These results are perhaps surprising, given that it is well established that a high Ki67 labeling index is associated with worse prognosis. 16 Nevertheless, it is also known that Ki67 score can be predictive of neoadjuvant chemotherapy response, 29 and mean Ki67 labeling indices have been found to be higher in patients with a pathological complete response after neoadjuvant chemotherapy; this has led to the hypothesis that there may be a high cutoff above which prognosis is better than in patients with lower Ki67 values. 30 As all patients within the cohort in this study received anthracycline-based chemotherapy, 8 our findings that high Ki67 values within the ER-negative subgroup are significantly associated with better overall survival lends tentative support to this hypothesis, and warrants further investigation.…”

Patients with Slowly Proliferative Early Breast Cancer Have Low Five-Year Recurrence Rates in a Phase III Adjuvant Trial of Capecitabine

“…Given the hypothesis of a lesser benefit of adjuvant chemotherapy in indolent breast cancer, investigators have searched for molecular markers that may predict response to treatment, with a number of studies indicating a role for Ki-67 (9)(10)(11)(12). In a retrospective analysis of the Breast Cancer International Research Group 001 trial, significantly improved 3-year DFS was observed with docetaxel (T) plus doxorubicin (A) plus cyclophosphamide (C) versus fluorouracil (F) plus AC in patients with luminal B tumors [estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive and HER2-positive or Ki-67 !…”

Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer

“…There is evidence that tumours with higher expression levels of Ki67 respond better to adjuvant chemotherapy than those tumour having low levels of Ki67 [11,12]. Ki67 expression is an independent predictive of neoadjuvant chemotherapy in BC patients [13,14]. as well as the neoadjuvant endocrine therapy in postmenopausal patients.…”