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Constitutive gene expression profile segregates toxicity in locally advanced breast cancer patients treated with high-dose hyperfractionated radical radiotherapy.

ABSTRACT: Breast cancer patients show a wide variation in normal tissue reactions after radiotherapy. The individual sensitivity to x-rays limits the efficiency of the therapy. Prediction of individual sensitivity to radiotherapy could help to select the radiation protocol and to improve treatment results. The aim of this study was to assess the relationship between gene expression profiles of ex vivo un-irradiated and irradiated lymphocytes and the development of toxicity due to high-dose hyperfractionated radiotherapy in patients with locally advanced breast cancer. Raw data from microarray experiments were uploaded to the Gene Expression Omnibus Database http://www.ncbi.nlm.nih.gov/geo/ (GEO accession GSE15341). We obtained a small group of 81 genes significantly regulated by radiotherapy, lumped in 50 relevant pathways. Using ANOVA and t-test statistical tools we found 20 and 26 constitutive genes (0 Gy) that segregate patients with and without acute and late toxicity, respectively. Non-supervised hierarchical clustering was used for the visualization of results. Six and 9 pathways were significantly regulated respectively. Concerning to irradiated lymphocytes (2 Gy), we founded 29 genes that separate patients with acute toxicity and without it. Those genes were gathered in 4 significant pathways. We could not identify a set of genes that segregates patients with and without late toxicity. In conclusion, we have found an association between the constitutive gene expression profile of peripheral blood lymphocytes and the development of acute and late toxicity in consecutive, unselected patients. These observations suggest the possibility of predicting normal tissue response to irradiation in high-dose non-conventional radiation therapy regimens. Prospective studies with higher number of patients are needed to validate these preliminary results.

SUBMITTER: Henriquez Hernandez LA

PROVIDER: S-EPMC2698866 | biostudies-other | 2009

REPOSITORIES: biostudies-other

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Constitutive gene expression profile segregates toxicity in locally advanced breast cancer patients treated with high-dose hyperfractionated radical radiotherapy.

Henríquez Hernández Luis Alberto LA Lara Pedro Carlos PC Pinar Beatriz B Bordón Elisa E Rodríguez Gallego Carlos C Bilbao Cristina C Fernández Pérez Leandro L Flores Morales Amílcar A

Radiation oncology (London, England) 20090604

Breast cancer patients show a wide variation in normal tissue reactions after radiotherapy. The individual sensitivity to x-rays limits the efficiency of the therapy. Prediction of individual sensitivity to radiotherapy could help to select the radiation protocol and to improve treatment results. The aim of this study was to assess the relationship between gene expression profiles of ex vivo un-irradiated and irradiated lymphocytes and the development of toxicity due to high-dose hyperfractionat ...[more]

PMID: 19497124

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Project description:BackgroundBrain metastases (BM) happen frequently in lung cancer patients and lead to a poor prognosis as well as a lower quality of life. The aim of this study was to identify risk factors for BM in locally advanced non-small cell lung cancer (LA-NSCLC) patients receiving radical radiotherapy, which will be useful for selecting appropriate patient population for further intervention and future trial design.MethodsThis was a retrospective cohort study. Patients with inoperable stage IIB-IIIC NSCLC were treated consecutively with definitive thoracic radiotherapy from January 2018 to December 2021, and were retrospectively reviewed and enrolled. Patients with various clinical variables were analyzed to clarify their impact on BM with competing risk models by Fine and Gray.ResultsA total of 134 patients were enrolled in this study. The median follow-up for all patients was 37 months [95% confidence interval (CI): 30.5-43.5 months]. BM occurred in 25 patients at the time of analysis. The 1-year and 3-year cumulative BM incidence were 10.5% and 19.9%, respectively. Patients with BM had worse overall survival than those without BM [stratified hazard ratio (HR) for death: 2.83; 95% CI:1.31-6.11; P<0.001]. Based on univariate analyses, non-squamous cell carcinoma (non-SCC), biological effective dose (BED) and planning target volume (PTV) were used as input variables in multivariable analysis (P<0.01). According to multivariate analysis, non-SCC (P<0.001; HR: 6.08; 95% CI: 2.26-16.37), BED <72 Gy (P=0.017; HR: 2.81; 95% CI: 1.20-6.57), and PTV >157.73 cm3 (P=0.043; HR: 2.56; 95% CI: 1.03-6.35) were independent risk factors for BM. In subgroup analysis of adenocarcinoma with known epidermal growth factor receptor (EGFR) mutation status, PTV >157.73 cm3 and positive EGFR mutation were independent predictors for BM.ConclusionsIn this retrospective study, we found that BED <72 Gy and PTV >157.73 cm3 were significantly associated with BM development and we validated that non-SCC and positive EGFR mutation were risk factors for BM. More research is required to screen the high-risk patient population.

Project description:BACKGROUND:Radiation 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. METHODS:The 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%). RESULTS:We 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. CONCLUSIONS:This 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.

Dataset Information

Constitutive gene expression profile segregates toxicity in locally advanced breast cancer patients treated with high-dose hyperfractionated radical radiotherapy.

Publications

Constitutive gene expression profile segregates toxicity in locally advanced breast cancer patients treated with high-dose hyperfractionated radical radiotherapy.

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