Exploratory biomarker analysis from a phase II clinical trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine for HER2-negative metastatic breast cancer patients (KCSG BR13-11)

the Breast Cancer Committee of the Korean Cancer Study Group

Research output: Contribution to journalArticle

Abstract

Purpose: We conducted an exploratory biomarker study from a phase II clinical trial of eribulin plus gemcitabine (EG) versus paclitaxel plus gemcitabine (PG) in HER2-negative metastatic breast cancer (BC) patients. Methods: We performed targeted deep sequencing with a customized cancer gene panel and RNA expression assay. Tumor mutation burden (TMB) and mutation signatures were determined based on genetic alteration in targeted regions. Gene set variation analysis was performed with PanCancer Immune Profiling and PanCancer Pathway Panels. Statistical analyses were conducted to identify the associations between genetic alterations and clinical outcomes. Results: Of 119 patients, 40 had available biomarker data. Among the 40 patients, 4 supported their post-treatment tissues. In targeted deep sequencing, FAT3 (48%) was the most frequently mutated gene, followed by PKHD1, TP53, GATA3, PARP4, and PIK3CA. In terms of gene expression, low expression of epithelial-mesenchymal transition (EMT) pathway genes was associated with prolonged progression-free survival (PFS) in the EG group, while high expression of the EMT pathway was associated with good prognosis in the PG group. Median TMB was 6.5 (range 2.44–46.34) and there was no relationship between TMB and patient prognosis. Analysis of mutation signatures showed that signatures 3, 20, and 26 were frequently observed in our cohort. Further survival analysis according to mutation signature showed that mutation signature 3, as a homologous recombinant deficiency-related signature, was highly associated with disease progression (hazard ratio (log2 scale) 8.21, 95% confidence interval 2.93–13.48, p = 0.002). Kaplan–Meier plot also showed that BCs with signature 3 had short PFS compared to those without these signatures (median PFS (months) for signature 3 (low vs. high): 17.2 vs. 8.1, p = 0.0026). Conclusions: Mutation signature 3, found in about 30% of MBCs regardless of hormone receptor status, was associated with short PFS for patients with cytotoxic chemotherapy. Trial registry: ClinicalTrials.gov number: NCT02263495.

Original languageEnglish
Pages (from-to)367-377
Number of pages11
JournalBreast Cancer Research and Treatment
Volume178
Issue number2
DOIs
StatePublished - 1 Nov 2019

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eribulin
gemcitabine
Phase II Clinical Trials
Paclitaxel
Biomarkers
Breast Neoplasms
Mutation
Disease-Free Survival
Tumor Burden
High-Throughput Nucleotide Sequencing
Epithelial-Mesenchymal Transition
Genes
Neoplasm Genes
Survival Analysis

Keywords

  • Eribulin
  • Metastatic breast cancer
  • Next-generation sequencing
  • Paclitaxel

Cite this

@article{c9774cfbf5d64b7395f399661c261e88,
title = "Exploratory biomarker analysis from a phase II clinical trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine for HER2-negative metastatic breast cancer patients (KCSG BR13-11)",
abstract = "Purpose: We conducted an exploratory biomarker study from a phase II clinical trial of eribulin plus gemcitabine (EG) versus paclitaxel plus gemcitabine (PG) in HER2-negative metastatic breast cancer (BC) patients. Methods: We performed targeted deep sequencing with a customized cancer gene panel and RNA expression assay. Tumor mutation burden (TMB) and mutation signatures were determined based on genetic alteration in targeted regions. Gene set variation analysis was performed with PanCancer Immune Profiling and PanCancer Pathway Panels. Statistical analyses were conducted to identify the associations between genetic alterations and clinical outcomes. Results: Of 119 patients, 40 had available biomarker data. Among the 40 patients, 4 supported their post-treatment tissues. In targeted deep sequencing, FAT3 (48{\%}) was the most frequently mutated gene, followed by PKHD1, TP53, GATA3, PARP4, and PIK3CA. In terms of gene expression, low expression of epithelial-mesenchymal transition (EMT) pathway genes was associated with prolonged progression-free survival (PFS) in the EG group, while high expression of the EMT pathway was associated with good prognosis in the PG group. Median TMB was 6.5 (range 2.44–46.34) and there was no relationship between TMB and patient prognosis. Analysis of mutation signatures showed that signatures 3, 20, and 26 were frequently observed in our cohort. Further survival analysis according to mutation signature showed that mutation signature 3, as a homologous recombinant deficiency-related signature, was highly associated with disease progression (hazard ratio (log2 scale) 8.21, 95{\%} confidence interval 2.93–13.48, p = 0.002). Kaplan–Meier plot also showed that BCs with signature 3 had short PFS compared to those without these signatures (median PFS (months) for signature 3 (low vs. high): 17.2 vs. 8.1, p = 0.0026). Conclusions: Mutation signature 3, found in about 30{\%} of MBCs regardless of hormone receptor status, was associated with short PFS for patients with cytotoxic chemotherapy. Trial registry: ClinicalTrials.gov number: NCT02263495.",
keywords = "Eribulin, Metastatic breast cancer, Next-generation sequencing, Paclitaxel",
author = "{the Breast Cancer Committee of the Korean Cancer Study Group} and Kim, {Ji Yeon} and Eunjin Lee and Kyunghee Park and Im, {Seock Ah} and Joohyuk Sohn and Lee, {Keun Seok} and Chae, {Yee Soo} and Kim, {Jee Hyun} and Kim, {Tae Yong} and Jung, {Kyung Hae} and Park, {Yeon Hee}",
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Exploratory biomarker analysis from a phase II clinical trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine for HER2-negative metastatic breast cancer patients (KCSG BR13-11). / the Breast Cancer Committee of the Korean Cancer Study Group.

In: Breast Cancer Research and Treatment, Vol. 178, No. 2, 01.11.2019, p. 367-377.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Exploratory biomarker analysis from a phase II clinical trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine for HER2-negative metastatic breast cancer patients (KCSG BR13-11)

AU - the Breast Cancer Committee of the Korean Cancer Study Group

AU - Kim, Ji Yeon

AU - Lee, Eunjin

AU - Park, Kyunghee

AU - Im, Seock Ah

AU - Sohn, Joohyuk

AU - Lee, Keun Seok

AU - Chae, Yee Soo

AU - Kim, Jee Hyun

AU - Kim, Tae Yong

AU - Jung, Kyung Hae

AU - Park, Yeon Hee

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Purpose: We conducted an exploratory biomarker study from a phase II clinical trial of eribulin plus gemcitabine (EG) versus paclitaxel plus gemcitabine (PG) in HER2-negative metastatic breast cancer (BC) patients. Methods: We performed targeted deep sequencing with a customized cancer gene panel and RNA expression assay. Tumor mutation burden (TMB) and mutation signatures were determined based on genetic alteration in targeted regions. Gene set variation analysis was performed with PanCancer Immune Profiling and PanCancer Pathway Panels. Statistical analyses were conducted to identify the associations between genetic alterations and clinical outcomes. Results: Of 119 patients, 40 had available biomarker data. Among the 40 patients, 4 supported their post-treatment tissues. In targeted deep sequencing, FAT3 (48%) was the most frequently mutated gene, followed by PKHD1, TP53, GATA3, PARP4, and PIK3CA. In terms of gene expression, low expression of epithelial-mesenchymal transition (EMT) pathway genes was associated with prolonged progression-free survival (PFS) in the EG group, while high expression of the EMT pathway was associated with good prognosis in the PG group. Median TMB was 6.5 (range 2.44–46.34) and there was no relationship between TMB and patient prognosis. Analysis of mutation signatures showed that signatures 3, 20, and 26 were frequently observed in our cohort. Further survival analysis according to mutation signature showed that mutation signature 3, as a homologous recombinant deficiency-related signature, was highly associated with disease progression (hazard ratio (log2 scale) 8.21, 95% confidence interval 2.93–13.48, p = 0.002). Kaplan–Meier plot also showed that BCs with signature 3 had short PFS compared to those without these signatures (median PFS (months) for signature 3 (low vs. high): 17.2 vs. 8.1, p = 0.0026). Conclusions: Mutation signature 3, found in about 30% of MBCs regardless of hormone receptor status, was associated with short PFS for patients with cytotoxic chemotherapy. Trial registry: ClinicalTrials.gov number: NCT02263495.

AB - Purpose: We conducted an exploratory biomarker study from a phase II clinical trial of eribulin plus gemcitabine (EG) versus paclitaxel plus gemcitabine (PG) in HER2-negative metastatic breast cancer (BC) patients. Methods: We performed targeted deep sequencing with a customized cancer gene panel and RNA expression assay. Tumor mutation burden (TMB) and mutation signatures were determined based on genetic alteration in targeted regions. Gene set variation analysis was performed with PanCancer Immune Profiling and PanCancer Pathway Panels. Statistical analyses were conducted to identify the associations between genetic alterations and clinical outcomes. Results: Of 119 patients, 40 had available biomarker data. Among the 40 patients, 4 supported their post-treatment tissues. In targeted deep sequencing, FAT3 (48%) was the most frequently mutated gene, followed by PKHD1, TP53, GATA3, PARP4, and PIK3CA. In terms of gene expression, low expression of epithelial-mesenchymal transition (EMT) pathway genes was associated with prolonged progression-free survival (PFS) in the EG group, while high expression of the EMT pathway was associated with good prognosis in the PG group. Median TMB was 6.5 (range 2.44–46.34) and there was no relationship between TMB and patient prognosis. Analysis of mutation signatures showed that signatures 3, 20, and 26 were frequently observed in our cohort. Further survival analysis according to mutation signature showed that mutation signature 3, as a homologous recombinant deficiency-related signature, was highly associated with disease progression (hazard ratio (log2 scale) 8.21, 95% confidence interval 2.93–13.48, p = 0.002). Kaplan–Meier plot also showed that BCs with signature 3 had short PFS compared to those without these signatures (median PFS (months) for signature 3 (low vs. high): 17.2 vs. 8.1, p = 0.0026). Conclusions: Mutation signature 3, found in about 30% of MBCs regardless of hormone receptor status, was associated with short PFS for patients with cytotoxic chemotherapy. Trial registry: ClinicalTrials.gov number: NCT02263495.

KW - Eribulin

KW - Metastatic breast cancer

KW - Next-generation sequencing

KW - Paclitaxel

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U2 - 10.1007/s10549-019-05400-y

DO - 10.1007/s10549-019-05400-y

M3 - Article

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VL - 178

SP - 367

EP - 377

JO - Breast cancer research and treatment

JF - Breast cancer research and treatment

SN - 0167-6806

IS - 2

ER -