Spatial intratumoural heterogeneity in the expression of GIT1 is associated with poor prognostic outcome in oestrogen receptor positive breast cancer patients with synchronous lymph node metastases [version 2; referees: 2 approved]
Ibai Goicoechea,
Ricardo Rezola,
María Arestin,
María M. Caffarel,
Ana Rosa Cortazar,
Lorea Manterola,
Marta Fernandez-Mercado,
María Armesto,
Carla Sole,
Erika Larrea,
Angela M. Araujo,
Nerea Ancizar,
Arrate Plazaola,
Ander Urruticoechea,
Arkaitz Carracedo,
Irune Ruiz,
Isabel Alvarez Lopez,
Charles H. Lawrie
Affiliations
Ibai Goicoechea
Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, 20014, Spain
Ricardo Rezola
Department of Pathology and Anatomy, Onkologikoa- Instituto Oncológico, San Sebastián, 20014, Spain
María Arestin
Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, 20014, Spain
María M. Caffarel
IKERBASQUE, Basque Foundation for Science, Bilbao, 48013, Spain
Ana Rosa Cortazar
CIC bioGUNE, Derio, 48160, Spain
Lorea Manterola
Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, 20014, Spain
Marta Fernandez-Mercado
Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, 20014, Spain
María Armesto
Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, 20014, Spain
Carla Sole
Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, 20014, Spain
Erika Larrea
Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, 20014, Spain
Angela M. Araujo
Molecular Oncology Group, Biodonostia Research Institute, San Sebastián, 20014, Spain
Nerea Ancizar
Oncology Department, University Hospital Donostia, San Sebastián, 20014, Spain
Arrate Plazaola
Onkologikoa- Instituto Oncológico, San Sebastián, 20014, Spain
Ander Urruticoechea
Onkologikoa- Instituto Oncológico, San Sebastián, 20014, Spain
Arkaitz Carracedo
Department of Biochemistry and Molecular Biology, University of the Basque Country, Leioa , 48940, Spain
Irune Ruiz
Department of Pathology and Anatomy, University Hospital Donostia, San Sebastián, 20014, Spain
Isabel Alvarez Lopez
Oncology Department, University Hospital Donostia, San Sebastián, 20014, Spain
Charles H. Lawrie
Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK
Background: The outcome for oestrogen receptor positive (ER+) breast cancer patients has improved greatly in recent years largely due to targeted therapy. However, the presence of involved multiple synchronous lymph nodes remains associated with a poor outcome. Consequently, these patients would benefit from the identification of new prognostic biomarkers and therapeutic targets. The expression of G-protein-coupled receptor kinase-interacting protein 1 (GIT1) has recently been shown to be an indicator of advanced stage breast cancer. Therefore, we investigated its expression and prognostic value of GIT1 in a cohort of 140 ER+ breast cancer with synchronous lymph node involvement. Methods: Immunohistochemistry was employed to assess GIT1 expression in a tissue microarray (TMA) containing duplicate non-adjacent cores with matched primary tumour and lymph node tissue (n=140). GIT1 expression in tumour cells was scored and statistical correlation analyses were carried out. Results: The results revealed a sub-group of patients that displayed discordant expression of GIT1 between the primary tumour and the lymph nodes (i.e. spatial intratumoural heterogeneity). We observed that loss of GIT1 expression in the tumour cells of the metastasis was associated with a shorter time to recurrence, poorer overall survival, and a shorter median survival time. Moreover, multivariate analysis demonstrated that GIT1 expression was an independent prognostic indicator. Conclusions: GIT1 expression enabled the identification of a sub-class of ER+ patients with lymph node metastasis that have a particularly poor prognostic outcome. We propose that this biomarker could be used to further stratify ER+ breast cancer patients with synchronous lymph node involvement and therefore facilitate adjuvant therapy decision making.
