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.Electronic supplementary materialThe online version of this article (10.1186/s13014-018-1129-4) contains supplementary material, which is available to authorized users.

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Background: Locally advanced breast cancer (LABC) includes a heterogeneous group of breast neoplasms classified from stage IIB, IIIA to IIIB. LABC with ipsilateral supraclavicular adenopathy without evidence of distant disease is included in the stage IV (but regional stage IV). Purpose of this study was to assess the role of radiotherapy (RT) in combined treatment with systemic therapy (chemotherapy and hormonotherapy) in LABC with ipsilateral supraclavicular adenopathy. Methods: In 5-year period 45 patients with LABC and ipsilateral supraclavicular metastases were treated with radiotherapy and chemo- or hormonotherapy depending on the physical condition, age and steroid receptors (ER, PGR) content. Twenty patients received TD 30 Gy in 10 fractions on breast and regional lymph nodes and 25 patients received TD 51 Gy in 15 fractions on the breast and TD 45 Gy in 15 fractions on regional lymph nodes. Twenty-three patients received chemotherapy (CMF or FAC), 10 received hormonotherapy, and 12 received both chemo- and hormonotherapy. Results: After finishing complete treatment the overall response rate was 93.3%. Complete response was 20% and partial response was 73.3%. Locoregional relapse occurred in 5 patients and distant metastases occurred in 10 patients. Conclusion: Treatment of LABC with ipsilateral supraclavicular lymph node involvement should be aggressive, what means combined radiotherapy and systemic chemo-hormonotherapy. Such treatment provides for these patients maximum chance of long-term disease - free and overall survival