Abstract
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 5years. 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.
Highlights
Most women with a breast cancer diagnosis are treated with breast-conserving surgery followed by adjuvant whole-breast radiotherapy (RT)
The aim was to assess whether the expression of hepatocyte growth factor (HGF), phosphorylated Met and activated Akt predicts radiosensitivity in a large randomised trial of patients treated with breast-conserving surgery with or without RT and largely systemically untreated
In a previous study, we found that gene copy gain of MET was associated with adverse prognosis, especially for patients treated with adjuvant chemotherapy [17]
Summary
Most women with a breast cancer diagnosis are treated with breast-conserving surgery followed by adjuvant whole-breast radiotherapy (RT). The protein kinase Akt, activated downstream of Met and other growth factor receptors, is another protein that has been linked to radioresistance in experimental studies [6,7] Both Met and Akt can be targeted, and inhibitors are in clinical use or being tested in clinical trials of advanced cancer. The aim was to assess whether the expression of HGF, phosphorylated Met (pMet) and activated Akt (pAkt) predicts radiosensitivity in a large randomised trial of patients treated with breast-conserving surgery with or without RT and largely systemically untreated. We chose to evaluate the nuclear and cytoplasmic expression of pAkt and the cytoplasmic and membraneous expression of Met separately This unique cohort, with approximately half of the patients treated without postoperative therapy and with minimal use of systemic adjuvant therapy, allows for analysis of the prognostic and predictive value concerning radiotherapy separately and without confounding from other treatments
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