Emilie Le Rhun1, Nicolas Bertrand2, Aurélie Dumont3, Emmanuelle Tresch4, Marie-Cécile Le Deley5, Audrey Mailliez6, Matthias Preusser7, Michael Weller8, Françoise Revillion9, Jacques Bonneterre10. 1. Univ. Lille, F-59000 Lille, France; Inserm, U-1192, F-59000 Lille, France; CHU Lille, General and Stereotaxic Neurosurgery service, F-59000 Lille, France; Oscar Lambret Center, Medical Oncology Department, F-59000 Lille, France. Electronic address: E-lerhun@o-lambret.fr. 2. Univ. Lille, F-59000 Lille, France; Oscar Lambret Center, Medical Oncology Department, F-59000 Lille, France. Electronic address: nicolas.bertrand.onco@gmail.com. 3. Oscar Lambret Center, Human Molecular Oncology Unit, Lille, France; Clinical Division of Oncology, Department of Medicine 1, CNS Unit Comprehensive Cancer Center Vienna (CCC-CNS), Vienna, Austria. Electronic address: a-dumont@o-lambret.fr. 4. Oscar Lambret Center, Biostatistic Unit, Lille, France; Medical University of Vienna, Vienna, Austria. Electronic address: e-tresch@o-lambret.fr. 5. Univ. Lille, F-59000 Lille, France; Oscar Lambret Center, Biostatistic Unit, Lille, France; Medical University of Vienna, Vienna, Austria. Electronic address: m-ledeley@o-lambret.fr. 6. Oscar Lambret Center, Medical Oncology Department, F-59000 Lille, France. Electronic address: a-mailliez@o-lambret.fr. 7. Oscar Lambret Center, Human Molecular Oncology Unit, Lille, France; Clinical Division of Oncology, Department of Medicine 1, CNS Unit Comprehensive Cancer Center Vienna (CCC-CNS), Vienna, Austria; Oscar Lambret Center, Biostatistic Unit, Lille, France; Medical University of Vienna, Vienna, Austria. Electronic address: matthias.preusser@meduniwien.ac.at. 8. Department of Neurology & Brain Tumor Center, University Hospital, Switzerland; University of Zurich, Switzerland. Electronic address: michael.weller@usz.ch. 9. Oscar Lambret Center, Human Molecular Oncology Unit, Lille, France; Clinical Division of Oncology, Department of Medicine 1, CNS Unit Comprehensive Cancer Center Vienna (CCC-CNS), Vienna, Austria. Electronic address: f-revillion@o-lambret.fr. 10. Univ. Lille, F-59000 Lille, France; Oscar Lambret Center, Medical Oncology Department, F-59000 Lille, France. Electronic address: j-bonneterre@o-lambret.fr.
Abstract
INTRODUCTION: The PI3K-AKT-mTOR pathway may be involved in the development of central nervous system (CNS) metastasis from breast cancer. Accordingly, herein we explored whether single nucleotide polymorphisms (SNPs) of this pathway are associated with altered risk of CNS metastasis formation in metastatic breast cancer patients. METHODS: The GENEOM study (NCT00959556) included blood sample collection from breast cancer patients treated in the neoadjuvant, adjuvant or metastatic setting. We identified patients with CNS metastases for comparison with patients without CNS metastasis, defined as either absence of neurological symptoms or normal brain magnetic resonance imaging (MRI) before death or during 5-year follow-up. Eighty-eight SNPs of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway genes were selected for analysis: AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). RESULTS: Of 342 patients with metastases, 207 fulfilled the inclusion criteria: One-hundred-and-seven patients remained free of CNS metastases at last follow-up or date of death whereas 100 patients developed CNS metastases. Among clinical parameters, hormonal and human epidermal growth factor receptor-2 (HER2) status as well as vascular tumour emboli was associated with risk of CNS metastasis. Only PI3KR1-rs706716 was associated with CNS metastasis in univariate analysis after Bonferroni correction (p < 0.00085). Multivariate analysis showed associations between AKT1-rs3803304, AKT2-rs3730050, PDK1-rs11686903 and PI3KR1-rs706716 and CNS metastasis . CONCLUSION: PI3KR1-rs706716 may be associated with CNS metastasis in metastatic breast cancer patients and could be included in a predictive composite score to detect early CNS metastasis irrespective of breast cancer subtype.
INTRODUCTION: The PI3K-AKT-mTOR pathway may be involved in the development of central nervous system (CNS) metastasis from breast cancer. Accordingly, herein we explored whether single nucleotide polymorphisms (SNPs) of this pathway are associated with altered risk of CNS metastasis formation in metastatic breast cancerpatients. METHODS: The GENEOM study (NCT00959556) included blood sample collection from breast cancerpatients treated in the neoadjuvant, adjuvant or metastatic setting. We identified patients with CNS metastases for comparison with patients without CNS metastasis, defined as either absence of neurological symptoms or normal brain magnetic resonance imaging (MRI) before death or during 5-year follow-up. Eighty-eight SNPs of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway genes were selected for analysis: AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). RESULTS: Of 342 patients with metastases, 207 fulfilled the inclusion criteria: One-hundred-and-seven patients remained free of CNS metastases at last follow-up or date of death whereas 100 patients developed CNS metastases. Among clinical parameters, hormonal and humanepidermal growth factor receptor-2 (HER2) status as well as vascular tumour emboli was associated with risk of CNS metastasis. Only PI3KR1-rs706716 was associated with CNS metastasis in univariate analysis after Bonferroni correction (p < 0.00085). Multivariate analysis showed associations between AKT1-rs3803304, AKT2-rs3730050, PDK1-rs11686903 and PI3KR1-rs706716 and CNS metastasis . CONCLUSION: PI3KR1-rs706716 may be associated with CNS metastasis in metastatic breast cancerpatients and could be included in a predictive composite score to detect early CNS metastasis irrespective of breast cancer subtype.
Authors: Thomas Crezee; Mirela Petrulea; Doina Piciu; Martin Jaeger; Jan W A Smit; Theo S Plantinga; Carmen E Georgescu; Romana Netea-Maier Journal: Endocr Connect Date: 2020-11 Impact factor: 3.335