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Hypoxia-related biological markers as predictors of epirubicin-based treatment responsiveness and resistance in locally advanced breast cancer.

ABSTRACT: To identify hypoxia-related biomarkers indicative of response and resistance to epirubicin treatment in patients with locally advanced breast cancer.One hundred seventy-six women with T2-4 N0-1 breast tumours were randomly assigned to receive epirubicin 120 mg/m2/1-21 (EPI ARM), epirubicin 120 mg/m2/1-21 + erythropoietin 10.000 IU sc three times weekly (EPI-EPO ARM) and epirubicin 40 mg/m2/w-q21 (EPI-W ARM). Sixteen tumour proteins involved in cell survival, hypoxia, angiogenesis and growth factor, were assessed by immunohistochemistry in pre-treatment samples. A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization.VEGF and GLUT-1 expression were significantly positively associated with complete response (CR) to treatment in all leave-one-out iterations. Bcl-2 expression was inversely correlated with pCR, whilst EPO expression was positively correlated with pathological complete response (pCR). Haemaglobin and HIF-1a nuclear expression were inversely correlated with pCR. HB and HIF-1a expression were associated with a higher risk of relapse and overall survival.Hypoxic biomarkers determines the epirubicin resistance in breast cancer. Assessment of such biomarkers, may be useful for predicting chemosensitivity and also anthracycline-based treatment outcome.

SUBMITTER: Milani M

PROVIDER: S-EPMC5668004 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Hypoxia-related biological markers as predictors of epirubicin-based treatment responsiveness and resistance in locally advanced breast cancer.

Milani Manuela M Venturini Sergio S Bonardi Simone S Allevi Giovanni G Strina Carla C Cappelletti Maria Rosa MR Corona Silvia Paola SP Aguggini Sergio S Bottini Alberto A Berruti Alfredo A Jubb Adrian A Campo Leticia L Harris Adrian L AL Gatter Kevin K Fox Stephen B SB Generali Daniele D Roviello Giandomenico G

Oncotarget 20170814 45

<h4>Purpose</h4>To identify hypoxia-related biomarkers indicative of response and resistance to epirubicin treatment in patients with locally advanced breast cancer.<h4>Patients and methods</h4>One hundred seventy-six women with T2-4 N0-1 breast tumours were randomly assigned to receive epirubicin 120 mg/m2/1-21 (EPI ARM), epirubicin 120 mg/m2/1-21 + erythropoietin 10.000 IU sc three times weekly (EPI-EPO ARM) and epirubicin 40 mg/m2/w-q21 (EPI-W ARM). Sixteen tumour proteins involved in cell su ...[more]

PMID: 29108271

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Project description:BackgroundOur goal was to identify gene signatures predictive of response to preoperative systemic chemotherapy (PST) with epirubicin/cyclophosphamide (EC) in patients with primary breast cancer.MethodsNeedle biopsies were obtained pre-treatment from 83 patients with breast cancer and mRNA was profiled on Affymetrix HG-U133A arrays. Response ranged from pathologically confirmed complete remission (pCR), to partial remission (PR), to stable or progressive disease, "No Change" (NC). A primary analysis was performed in breast tissue samples from 56 patients and 5 normal healthy individuals as a training cohort for predictive marker identification. Gene signatures identifying individuals most likely to respond completely to PST-EC were extracted by combining several statistical methods and filtering criteria. In order to optimize prediction of non responding tumors Student's t-test and Wilcoxon test were also applied. An independent cohort of 27 patients was used to challenge the predictive signatures. A k-Nearest neighbor algorithm as well as two independent linear partial least squares determinant analysis (PLS-DA) models based on the training cohort were selected for classification of the test samples. The average specificity of these predictions was greater than 74% for pCR, 100% for PR and greater than 62% for NC. All three classification models could identify all pCR cases.ResultsThe differential expression of 59 genes in the training and the test cohort demonstrated capability to predict response to PST-EC treatment. Based on the training cohort a classifier was constructed following a decision tree. First, a transcriptional profile capable to distinguish cancerous from normal tissue was identified. Then, a "favorable outcome signature" (31 genes) and a "poor outcome signature" (26 genes) were extracted from the cancer specific signatures. This stepwise implementation could predict pCR and distinguish between NC and PR in a subsequent set of patients. Both PLS-DA models were implemented to discriminate all three response classes in one step.ConclusionIn this study signatures were identified capable to predict clinical outcome in an independent set of primary breast cancer patients undergoing PST-EC.

Project description:This phase I/II neoadjuvant trial determined maximally-tolerated doses (MTD), dose-limiting toxicities (DLT), response-to-therapy, and explored the role of new response biomarkers. The combination regimens were delivered with acceptable toxicity, good clinical response, inducing changes in tumor RNA content and integrity. Pre-treatment gene expressions impacted clinical response, including several near 17q12, which with ERBB2, may better identify chemoresponsiveness. The NCIC Clinical Trials Group MA.22 phase I/II clinical trial (ClinicalTrials.gov identifier NCT00066443) sought to determine the optimal dosing regimens for docetaxel/epirubicin combination chemotherapy in women with locally advanced (over 95% of patients) or inflammatory breast cancer. The protocol was approved by Health Canada and local Ethics Review Boards, and patients provided written, informed consent. Various doses of epirubicin and docetaxel were administered to patients in either a standard q3 weekly (Schedule A) or dose dense q2 weekly (Schedule B) regimen. Doses for Schedule A were 75 mg/m2 IV of docetaxel and 75, 90, 105, or 120 mg/m2 IV of epirubicin (with 6 mg of pegfilgrastim per cycle on day 2 to prevent neutropenia). Doses for both docetaxel and epirubicin in Schedule B were 50, 60, and 70 mg/m2 IV (with identical pegfilgrastim support). For each schedule, phase I was dose finding for phase II. Patients were allocated to the various phases and dosing regimens of the trial without randomization. None of the patients received trastuzumab in the initial years of the study and HER2+ patients were not enrolled on study, once trastuzumab funding became available. Six tumor biopsy cores were obtained pre-, mid-, and post-treatment: 3 cores for pathologic assessment; 3 cores for microarray studies. Total RNA was isolated from these cores and RNA integrity was assessed using Agilent Bioanalyzer. One of the RNA samples with the best quality was used for microarray study. One colour microarray of Agilent whole human genome nucleotide arrays was conducted with one array per patient. The current data set represents pre-treatment set. MA.22 clinical trial accrued T3N0, any N2 or N3, and T4 breast cancer patients (according to the classification described at; http://emedicine.medscape.com/article/2007112-overview). However, since the current study does not focus on the tumor grade/stage, the information was not provided in the current records.

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Hypoxia-related biological markers as predictors of epirubicin-based treatment responsiveness and resistance in locally advanced breast cancer.

Publications

Hypoxia-related biological markers as predictors of epirubicin-based treatment responsiveness and resistance in locally advanced breast cancer.

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