Association between FGFR1 copy numbers, MAP3K1 mutations, and survival in axillary node-positive, hormone receptor-positive, and HER2-negative early breast cancer in the PACS04 and METABRIC studies

Breast Cancer Res Treat. 2020 Jan;179(2):387-401. doi: 10.1007/s10549-019-05462-y. Epub 2019 Oct 16.

Abstract

Purpose: Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) early breast cancer (BC) is the most prevalent BC subtype with substantial biological heterogeneity. Although clinicopathological (CP) characteristics have a clear prognostic value, additional biomarkers could refine survival prediction and guide treatment decision.

Methods: Copy number aberrations and somatic driver mutations were obtained with OncoScan CGH array and sequencing of 36 genes on HR+/HER2- node-positive early BC patients treated with chemotherapy from the PACS04 trial. We built a two-gene genomic score (GS) associated with distant disease-free survival (DDFS), whose prognostic value was assessed on the external METABRIC data (n = 1413) using overall survival (OS) and breast cancer-specific survival (BCSS).

Results: In the PACS04 trial (n = 327), the median follow-up for DDFS (65 events) was 9.6 years. FGFR1 amplifications ([Formula: see text] = 2.44, 95% CI [1.25; 4.76], p = 0.009) and MAP3K1 mutations ([Formula: see text] = 0.10, [0.01; 0.78], p = 0.03) were associated with DDFS beyond CP characteristics. A prognostic GS combining FGFR1 amplifications and MAP3K1 mutations added more information to CP model ([Formula: see text] = 12.97, [Formula: see text] < 0.001 and [Formula: see text] = 11.52, [Formula: see text] < 0.001). In the METABRIC study (n = 1413), FGFR1 amplifications ([Formula: see text] = 2.00 [1.40; 2.87], p < 0.001) and MAP3K1 mutations ([Formula: see text] = 0.58 [0.41; 0.83], p = 0.003) were significantly associated with BCSS beyond CP characteristics. The prognostic GS added significant prognostic information to CP model ([Formula: see text] = 15.39, [Formula: see text] < 0.001 and [Formula: see text] = 5.62, [Formula: see text] = 0.02).

Conclusion: In axillary node-positive, HR+, and HER2- early BC, amplifications of FGFR1 gene were strongly associated with increased risk for distant disease, while mutations of MAP3K1 gene were significantly associated with decreased risk.

Keywords: Biomarkers; Breast cancer (BC); Copy number aberrations (CNA); Cox regression; Mutations.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Axilla / pathology
  • Biomarkers, Tumor*
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality*
  • Clinical Trials, Phase III as Topic
  • DNA Copy Number Variations*
  • Female
  • Humans
  • Lymph Nodes / pathology
  • Lymphatic Metastasis
  • MAP Kinase Kinase Kinase 1 / genetics*
  • MAP Kinase Kinase Kinase 1 / metabolism
  • Mutation*
  • Neoplasm Staging
  • Prognosis
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism
  • Treatment Outcome

Substances

  • Biomarkers, Tumor
  • Receptors, Estrogen
  • Receptors, Progesterone
  • FGFR1 protein, human
  • Receptor, ErbB-2
  • Receptor, Fibroblast Growth Factor, Type 1
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human