Abstract P4-03-09: Chromosomal instability predicts taxane sensitivity in breast cancer
Authors: K Esbona, N Jin, KL Correia-Staudt, AM Lager, T Heidke, J Laffin, BA Weaver, ME Burkard
Journal: Cancer Research (2018)

Abstract Taxanes remain among the most effective agents for the treatment of breast cancer. However, ˜50% of patients who receive this therapy do not have a clinical response. Previously, we identified the mechanistic effects of taxane therapy by sampling primary human breast tumors 20 hours after infusion (Sci Trans Med 26:229ra43, 2014). We determined that paclitaxel caused cells to transit mitosis on multipolar spindles, resulting in increased chromosome gains and losses. Preclinical models suggest that tumors have enhanced sensitivity if they have baseline chromosome gains/losses, known as chromosome instability (CIN). The aim of this study was to compare CIN against other predictive biomarkers in a retrospective cohort of advanced breast cancer patients who receive single-agent taxane therapy. Methods: We identified 36 subjects with metastatic breast cancer and measurable disease who received taxane therapy and had available archived tissue. Responses were determined by RECIST 1.1 criteria. We evaluated chromosome number on a cell-by-cell basis using 6 centromeric FISH probes. Additionally we measured rates of proliferation by phospho-histone H3 (p-HH3) and Ki67, previously reported biomarkers, β-tubulin III, P-gp1 and MAD1 by quantitative immunofluorescence. CIN was estimated as the fraction of cells with non-modal chromosome numbers across chromosomes 3, 4, 7, 9, 10, and 17. Results: Of the 36 subjects, 19 had ER/PR+HER2- disease (53%), 9 had HER2-positive disease (25%), and 8 TNBC (22%). Single-agent chemotherapy was used for all including paclitaxel in 16, nab-paclitaxel in 17, and docetaxel in 3 (HER2+ patients received concurrent trastuzumab). RECIST responses ranged from disease progression (8%, n=3), stable disease (50%, n=18), and partial response (42%, n=15). No complete responses were observed. Time on therapy ranged from 1.4 months to 28 months. No statistically significant correlations were found between tumor type or prior chemotherapy and response to taxanes. Archived metastatic samples were available for 21 subjects. Analysis showed large variations in Ki67, pHH3, β-tubulin III, P-gp1, MAD1, and CIN amongst samples. The strongest correlation was found between tumor response and high levels of CIN, with a Spearman's correlation coefficient of 0.38 (p=0.04). Surprisingly, there was an inverse correlation between Ki67 and taxane response, although this did not reach statistical significance. Biomarkers correlated with response to taxaneN=21Ki67 (%)pHH3 (H)βtub3 (H)P-gp1 (H)MAD1 (H)CIN (%)min0.850.000.673.002.8324.2max45.14.8915129923165.8Spearman rho-0.3650.242-0.1650.232-0.08960.382p (1-tailed)0.05190.1400.2370.1550.3500.0425H = H-score; CIN is estimated as % of cells with non-modal chromosomes Conclusions: Chromosomal instability is a promising biomarker for predicting sensitivity to taxane therapies. Additional studies will be necessary to validate CIN as a biomarker and to determine whether 6-chromosome FISH can be supplanted by low-pass single-cell DNA sequencing. Citation Format: Esbona K, Jin N, Correia-Staudt KL, Lager AM, Heidke T, Laffin J, Weaver BA, Burkard ME. Chromosomal instability predicts taxane sensitivity in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-03-09.