Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast‐conserving surgery: a long‐term follow‐up of the SweBCG91‐RT randomised trial
Experimental studies suggest that hepatocyte growth factor (HGF) and its transmembrane tyrosine kinase receptor, Met, in part also relying on Akt kinase activity, mediate radioresistance. We investigated the importance of these biomarkers for the risk of ipsilateral breast tumour recurrence (IBTR) a...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-11-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12803 |
| _version_ | 1819198942962778112 |
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| author | Martin Sjöström Cynthia Veenstra Erik Holmberg Per Karlsson Fredrika Killander Per Malmström Emma Niméus Mårten Fernö Olle Stål |
| author_facet | Martin Sjöström Cynthia Veenstra Erik Holmberg Per Karlsson Fredrika Killander Per Malmström Emma Niméus Mårten Fernö Olle Stål |
| author_sort | Martin Sjöström |
| collection | DOAJ |
| description | Experimental studies suggest that hepatocyte growth factor (HGF) and its transmembrane tyrosine kinase receptor, Met, in part also relying on Akt kinase activity, mediate radioresistance. We investigated the importance of these biomarkers for the risk of ipsilateral breast tumour recurrence (IBTR) after adjuvant radiotherapy (RT) in primary breast cancer. HGF, phosphorylated Met (pMet) and phosphorylated Akt (pAkt) were evaluated immunohistochemically on tissue microarrays from 1004 patients in the SweBCG91‐RT trial, which randomly assigned patients to breast‐conserving therapy, with or without adjuvant RT. HGF was evaluated in the stroma (HGFstr); pMet in the membrane (pMetmem); HGF, pMet and pAkt in the cytoplasm (HGFcyt, pMetcyt, pAktcyt); and pAkt in the nucleus (pAktnuc). The prognostic and treatment predictive effects were evaluated to primary endpoint IBTR as first event during the first 5 years. Patients with tumours expressing low levels of HGFcyt and pMetcyt and high levels of pAktnuc derived a larger benefit from RT [hazard ratio (HR): 0.11 (0.037–0.30), 0.066 (0.016–0.28) and 0.094 (0.028–0.31), respectively] compared to patients with high expression of HGFcyt and pMetcyt, and low pAktnuc [HR: 0.36 (0.19–0.67), 0.35 (0.20–0.64) and 0.47 (0.32–0.71), respectively; interaction analyses: P = 0.052, 0.035 and 0.013, respectively]. These differences remained in multivariable analysis when adjusting for patient age, tumour size, histological grade, St Gallen subtype and systemic treatment (interaction analysis, P‐values: 0.085, 0.027, and 0.023, respectively). This study suggests that patients with immunohistochemically low HGFcyt, low pMetcyt and high pAktnuc may derive an increased benefit from RT after breast‐conserving surgery concerning the risk of developing IBTR. |
| first_indexed | 2024-12-23T03:08:28Z |
| format | Article |
| id | doaj.art-efd64e9c664e42559b7651d5419d26bc |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-23T03:08:28Z |
| publishDate | 2020-11-01 |
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| series | Molecular Oncology |
| spelling | doaj.art-efd64e9c664e42559b7651d5419d26bc2022-12-21T18:02:17ZengWileyMolecular Oncology1574-78911878-02612020-11-0114112713272610.1002/1878-0261.12803Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast‐conserving surgery: a long‐term follow‐up of the SweBCG91‐RT randomised trialMartin Sjöström0Cynthia Veenstra1Erik Holmberg2Per Karlsson3Fredrika Killander4Per Malmström5Emma Niméus6Mårten Fernö7Olle Stål8Division of Oncology and Pathology Department of Clinical Sciences Lund Faculty of Medicine Lund University Lund SwedenDepartment of Biomedical and Clinical Sciences Linköping University Linköping SwedenDepartment of Oncology Institute of Clinical Sciences Sahlgrenska Academy Sahlgrenska University Hospital University of Gothenburg Gothenburg SwedenDepartment of Oncology Institute of Clinical Sciences Sahlgrenska Academy Sahlgrenska University Hospital University of Gothenburg Gothenburg SwedenDivision of Oncology and Pathology Department of Clinical Sciences Lund Faculty of Medicine Lund University Lund SwedenDivision of Oncology and Pathology Department of Clinical Sciences Lund Faculty of Medicine Lund University Lund SwedenDivision of Oncology and Pathology Department of Clinical Sciences Lund Faculty of Medicine Lund University Lund SwedenDivision of Oncology and Pathology Department of Clinical Sciences Lund Faculty of Medicine Lund University Lund SwedenDepartment of Biomedical and Clinical Sciences Linköping University Linköping SwedenExperimental studies suggest that hepatocyte growth factor (HGF) and its transmembrane tyrosine kinase receptor, Met, in part also relying on Akt kinase activity, mediate radioresistance. We investigated the importance of these biomarkers for the risk of ipsilateral breast tumour recurrence (IBTR) after adjuvant radiotherapy (RT) in primary breast cancer. HGF, phosphorylated Met (pMet) and phosphorylated Akt (pAkt) were evaluated immunohistochemically on tissue microarrays from 1004 patients in the SweBCG91‐RT trial, which randomly assigned patients to breast‐conserving therapy, with or without adjuvant RT. HGF was evaluated in the stroma (HGFstr); pMet in the membrane (pMetmem); HGF, pMet and pAkt in the cytoplasm (HGFcyt, pMetcyt, pAktcyt); and pAkt in the nucleus (pAktnuc). The prognostic and treatment predictive effects were evaluated to primary endpoint IBTR as first event during the first 5 years. Patients with tumours expressing low levels of HGFcyt and pMetcyt and high levels of pAktnuc derived a larger benefit from RT [hazard ratio (HR): 0.11 (0.037–0.30), 0.066 (0.016–0.28) and 0.094 (0.028–0.31), respectively] compared to patients with high expression of HGFcyt and pMetcyt, and low pAktnuc [HR: 0.36 (0.19–0.67), 0.35 (0.20–0.64) and 0.47 (0.32–0.71), respectively; interaction analyses: P = 0.052, 0.035 and 0.013, respectively]. These differences remained in multivariable analysis when adjusting for patient age, tumour size, histological grade, St Gallen subtype and systemic treatment (interaction analysis, P‐values: 0.085, 0.027, and 0.023, respectively). This study suggests that patients with immunohistochemically low HGFcyt, low pMetcyt and high pAktnuc may derive an increased benefit from RT after breast‐conserving surgery concerning the risk of developing IBTR.https://doi.org/10.1002/1878-0261.12803Aktbreast cancerHGFMetradiotherapytreatment prediction |
| spellingShingle | Martin Sjöström Cynthia Veenstra Erik Holmberg Per Karlsson Fredrika Killander Per Malmström Emma Niméus Mårten Fernö Olle Stål Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast‐conserving surgery: a long‐term follow‐up of the SweBCG91‐RT randomised trial Molecular Oncology Akt breast cancer HGF Met radiotherapy treatment prediction |
| title | Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast‐conserving surgery: a long‐term follow‐up of the SweBCG91‐RT randomised trial |
| title_full | Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast‐conserving surgery: a long‐term follow‐up of the SweBCG91‐RT randomised trial |
| title_fullStr | Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast‐conserving surgery: a long‐term follow‐up of the SweBCG91‐RT randomised trial |
| title_full_unstemmed | Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast‐conserving surgery: a long‐term follow‐up of the SweBCG91‐RT randomised trial |
| title_short | Expression of HGF, pMet, and pAkt is related to benefit of radiotherapy after breast‐conserving surgery: a long‐term follow‐up of the SweBCG91‐RT randomised trial |
| title_sort | expression of hgf pmet and pakt is related to benefit of radiotherapy after breast conserving surgery a long term follow up of the swebcg91 rt randomised trial |
| topic | Akt breast cancer HGF Met radiotherapy treatment prediction |
| url | https://doi.org/10.1002/1878-0261.12803 |
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