Abstract
BackgroundRadiation therapy is an indispensable part of various treatment modalities for breast cancer. Specifically, for non-inflammatory locally advanced breast cancer (LABC) patients, preoperative radiotherapy (pRT) is currently indicated as a second line therapy in the event of lack of response to neoadjuvant chemotherapy. Still approximately one third of patients fails to respond favourably to pRT. The aim of this study was to explore molecular mechanisms underlying differential response to radiotherapy (RT) to identify predictive biomarkers and potential targets for increasing radiosensitivity.MethodsThe study was based on a cohort of 134 LABC patients, treated at the Institute of Oncology and Radiology of Serbia (IORS) with pRT, without previous or concomitant systemic therapy. Baseline transcriptional profiles were established using Agilent 60 K microarray platform in a subset of 23 formalin-fixed paraffin-embedded (FFPE) LABC tumour samples of which 11 radiotherapy naïve and 3 post-radiotherapy samples passed quality control and were used for downstream analysis. Biological networks and signalling pathways underlying differential response to RT were identified using Ingenuity Pathways Analysis software. Predictive value of candidate genes in the preoperative setting was further validated by qRT-PCR in an independent subset of 60 LABC samples of which 42 had sufficient quality for data analysis, and in postoperative setting using microarray data from 344 node-negative breast cancer patients (Erasmus cohort, GSE2034 and GSE5327) treated either with surgery only (20%) or surgery with RT (80%).ResultsWe identified 192 significantly differentially expressed genes (FDR < 0.10) between pRT-responsive and non-responsive tumours, related to regulation of cellular development, growth and proliferation, cell cycle control of chromosomal replication, glucose metabolism and NAD biosynthesis II route. APOA1, MAP3K4, and MMP14 genes were differentially expressed (FDR < 0.20) between pRT responders and non-responders in preoperative setting, while MAP3K4 was further validated as RT-specific predictive biomarker of distant metastasis free survival (HR = 2.54, [95%CI:1.42–4.55], p = 0.002) in the postoperative setting.ConclusionsThis study pinpoints MAP3K4 as a putative biomarker of response to RT in both preoperative and postoperative settings and a potential target for radiosensitising combination therapy, warranting further pre-clinical studies and prospective clinical validation.
Highlights
Radiation therapy is an indispensable part of various treatment modalities for breast cancer
Neoadjuvant systemic therapy (CHT) is usually administered to downstage the tumour for breast-conserving surgery, while preoperative radiotherapy is often indicated if there is no objective reduction of tumour volume after the administration of neoadjuvant (CHT)
Given the rarity of this treatment modality only a few studies looked into the effects of preoperative radiotherapy in combination with breast conserving surgery on locoregional recurrence and overall survival reporting similar results compared to protocols involving neoadjuvant chemotherapy without irradiation [6,7,8,9]
Summary
Radiation therapy is an indispensable part of various treatment modalities for breast cancer. For non-inflammatory locally advanced breast cancer (LABC) patients, preoperative radiotherapy (pRT) is currently indicated as a second line therapy in the event of lack of response to neoadjuvant chemotherapy. Non-inflammatory locally advanced breast carcinoma (LABC) is a late stage breast cancer presented as a bulky primary chest wall tumour and/or extensive adenopathy including patients with large (> 5 cm), usually inoperable tumours and node positive disease [1]. It is a common presentation worldwide but is of special concern in developing countries with limited breast cancer awareness and efficient population screening programs. The molecular basis of tumour sensitivity to radiotherapy is complex, and at present, there are no conclusive biomarkers in clinical use to predict if a patient will, benefit from radiotherapy
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