ERBB2 mRNA Expression and Response to Ado-Trastuzumab Emtansine (T-DM1) in HER2-Positive Breast Cancer.
Gaia GriguoloFara Brasó-MaristanyBlanca González-FarréTomás PascualNúria ChicTamara SauríRonald KatesOleg GluzDébora MartínezLaia ParéVassilena TsvetkovaDavid PesantezMaria VidalBarbara AdamoMontserrat MuñozPatricia GalvánLaura BarberáMiriam CuatrecasasMathias ChristgenHans KreipeInés Monge-EscartínPatricia VillagrasaDolors SoyTommaso GiarratanoMaria Vittoria DieciPierFranco ConteNadia HarbeckValentina GuarneriAleix PratPublished in: Cancers (2020)
Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20-8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.
Keyphrases
- tyrosine kinase
- epidermal growth factor receptor
- metastatic breast cancer
- papillary thyroid
- advanced non small cell lung cancer
- positive breast cancer
- poor prognosis
- squamous cell
- end stage renal disease
- rectal cancer
- clinical trial
- glycemic control
- endothelial cells
- ejection fraction
- binding protein
- single cell
- squamous cell carcinoma
- small cell lung cancer
- free survival
- chronic kidney disease
- prognostic factors
- locally advanced
- genome wide
- type diabetes
- lymph node metastasis
- gene expression
- randomized controlled trial
- bone marrow
- dna methylation
- adipose tissue
- cell therapy
- open label
- current status
- low grade
- young adults
- smoking cessation