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)

Breast Cancer Res Treat. 2019 Nov;178(2):367-377. doi: 10.1007/s10549-019-05400-y. Epub 2019 Aug 12.

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.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor*
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / etiology*
  • Clinical Trials, Phase II as Topic
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Female
  • Furans / administration & dosage
  • Humans
  • Kaplan-Meier Estimate
  • Ketones / administration & dosage
  • Middle Aged
  • Multicenter Studies as Topic
  • Mutation
  • Neoplasm Staging
  • Paclitaxel / administration & dosage
  • Prognosis
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Risk Factors
  • Treatment Outcome
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Furans
  • Ketones
  • Deoxycytidine
  • gemcitabine
  • Receptor, ErbB-2
  • eribulin
  • Paclitaxel

Associated data

  • ClinicalTrials.gov/NCT02263495