Abstract P3-11-07: Exploratory biomarker analysis from a phase II, multicenter, randomized trial of eribulin plus gemcitabine(EG) versus paclitaxel plus gemcitabine(PG) as first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)- negative metastatic breast cancer(MBC): Korean cancer study group trial (KCSG BR13-11)
Authors: Kim J-Y , Lee EJ , Park KH , Im S-A , Kim S-B , Sohn SH , Lee KS , Chae YS , Lee KH , Kim JH , Im Y-H , Kim T-Y , Lee K-H , Ahn J-H , Kim GM , Park IH , Lee SJ , Han HS , Kim SH , Jung KH , Park YH 
Published: May 2019

Introduction : A phase II, multicenter, randomized clinical trial of the comparison between eribulin plus gemcitabine (EG) and paclitaxel plus gemcitabine (PG) as first-line chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) found EG was less neurotoxic, but had similar efficacy of PG. In this study, we performed exploratory biomarker analysis of the impact of genetic alterations on the efficacy according to EG and PG chemotherapy.

Methods : This biomarker study was conducted using tumor samples from 40patients. When tissue collection was possible after disease progression, we performed paired sample analysis. Tumor DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissues. To perform targeted deep sequencing, we used CancerScanTM, a 375 cancer gene panel. And we performed an nCounter expression assay for gene expression analysis using 730 PanCancer panel and 730 Immune panel.

Results: In total, we obtained 44 tissue samples from 40 patients. Twenty two patients were assigned in EG arm and 18 patients were in PG arm. Thirty-eight were at baseline and six after disease progression. Gene expression assay were performed in 44 tissue samples but only 31 samples were possible to be targeted deep sequencing.

We performed differently expressed gene(DEG) analysis for detecting the association between level of gene expression and disease progression. In this analysis, high expression of CCNE1, TGFB4 and BAMBI and low expression of DDB2, CD14 and SHC3 were associated with disease progression among 730 PanCancer panel genes (p&lt;0.05, respectively). In terms of immune panel genes, most of immune related genes were highly expressed in a group without disease progression compared with that with disease progression. Only 2 genes, C8G and CD24 were highly expressed in a group with disease progression. Paired sample analysis showed that expression levels of THBS4 and CD27 decreased after disease progression while those of CCNE2 and FGFR4 increased.

In targeted deep sequencing, FAT3 (42.3%) was most frequently mutated gene followed by PKHD1, PIK3CA and TP53. Among mutated genes, EWSR1 mutation and upstream mutation of ETV1 were associated with disease progression, respectively (p&lt;0.05, respectively). In mutation signature analysis, signature 1 (S, age related), S3(homologous recombination deficiency, HRD), S6 (mismatch repair, MMR), S20(MMR) and S21(microsatellite instability, MSI) were enriched in this population. Mutation signature 3 related to short disease free survival (p=0.0026).

Conclusion: In gene expression analysis, high expression of TGF-B signaling pathway related genes was associated with disease progression while high expression of immune related genes were related to prolonged disease free survival. In mutation analysis, EWSR1 and ETV1 mutations indicated short disease free interval and HRD mutation signature was also related to poor prognosis.

Citation Format: Kim J-Y, Lee EJ, Park KH, Im S-A, Kim S-B, Sohn SH, Lee KS, Chae YS, Lee KH, Kim JH, Im Y-H, Kim T-Y, Lee K-H, Ahn J-H, Kim GM, Park IH, Lee SJ, Han HS, Kim SH, Jung KH, Park YH. Exploratory biomarker analysis from a phase II, multicenter, randomized trial of eribulin plus gemcitabine(EG) versus paclitaxel plus gemcitabine(PG) as first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)- negative metastatic breast cancer(MBC): Korean cancer study group trial (KCSG BR13-11) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-07.