Abstract P2-09-19: Genomic biomarker for resistance to palbociclib in the NeoPalAna trial
Authors: Hoog JW , Treece T , Blumencranz L , Audeh W , Sanati S , Ellis MJ , Ma CX 
Published: February 2018

Abstract
Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors are being evaluated in the adjuvant setting for patients with resected early stage hormone receptor positive (HR+) and HER2 negative (HER2-) breast cancer (BC). However, biomarkers that predict benefit from this class of agents are unknown. We have recently reported results from the phase II neoadjuvant NeoPalAna trial which demonstrated that palbociclib (Pal) enhanced the anti-proliferative activity when added upon anastrozole (Ana) monotherapy in estrogen receptor (ER) positive and HER2 negative breast cancers. Interestingly, a small group of patients was resistant to Pal, exhibiting persistent tumor cell proliferation (Ki67 &gt;2.7%) on the combination of Ana and Pal. In this study, we evaluated the utility of a research algorithm for the 70-gene signature (70-GS) in identifying Pal resistant versus sensitive patients. Methods: Serial biopsies were collected from patients at four treatment timepoints: baseline (BL), cycle 1 day 1 (C1D1) following 28 days of Ana monotherapy, cycle 1 day 15 (C1D15) at 2 weeks post the addition of Pal, and at surgery (Surg). RNA was extracted from frozen tumor biopsies at each timepoint and run on Agilent full genome microarrays (GSE93204) at Washington University. As an exploratory analysis, genes from the GPL8253 array that match the 70-GS were used to calculate a research approximation of the 70-GS index (r-GS). The distribution of the r-GS across Ki67 response groups was evaluated. Results: Ki67 had previously been measured at each timepoint, and used to classify patients as being either Ana-sensitive (C1D1 Ki67 ≤2.7%), Pal-sensitive (C1D1 Ki67 &gt;2.7%, C1D15 Ki67 ≤2.7%), or Pal-resistant (C1D15 Ki67 &gt;2.7%). The r-GS was differentially regulated between sensitive (AI or Pal) and Pal-resistant groups at BL (p=0.012), C1D1 (p=0.039), and C1D15 (p=0.022). The r-GS values varied widely across patients at BL, and generally became more positive (more low risk) with treatment. There was no correlation between Ki67 levels and r-GS. Furthermore, gene expression analysis was performed to elucidate the difference between Pal-sensitive vs. Pal-resistant patients, and Ana-sensitive vs. Pal-sensitive patients. Conclusions: While on-treatment Ki67 indicated drug responsiveness, baseline r-GS significantly stratified patients into sensitive (Ana or Pal) versus Pal-resistant groups in the neoadjuvant setting. This preliminary finding suggests that the 70-GS may have clinical utility in identifying patients resistant to Pal for future studies. Additionally, results of the gene expression analysis may help to further develop genomic biomarkers for Pal and Ana sensitivity and resistance.
Citation Format: Hoog JW, Treece T, Blumencranz L, Audeh W, Sanati S, Ellis MJ, Ma CX. Genomic biomarker for resistance to palbociclib in the NeoPalAna trial [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 P2-09-19.