Validation of a Radiosensitivity Molecular Signature in Breast Cancer

Eschrich, Steven; Fulp, William J.; Pawitan, Yudi; Foekens, John A.; Smid, Marcel; Martens, John W.M.; Echevarria, M.; Kamath, Vidya; Lee, Ji‐Hyun; Harris, Eleanor; Bergh, Jonas; Torres-Roca, Javier F.

doi:10.1158/1078-0432.ccr-12-0891

Cited by 185 publications

(170 citation statements)

References 42 publications

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“…Previous attempts to identify radiation-specific signatures to predict likelihood of benefit to adjuvant radiotherapy have either failed independent validation or have not been disease-specific resulting in inconsistent performance in independent cohorts (8)(9)(10)(11)(12). A recent study demonstrated the feasibility of this approach in the postmastectomy setting using patient-derived gene expression data from the DBCG82bc trials (13).…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of a Novel Radiosensitivity Signature in Human Breast Cancer

Speers

Zhao

Liu

et al. 2015

Clinical Cancer Research

141

106

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Purpose: An unmet clinical need in breast cancer management is the accurate identification of patients who will benefit from adjuvant radiotherapy. We hypothesized that integration of postradiation clonogenic survival data with gene expression data across breast cancer cell (BCC) lines would generate a radiation sensitivity signature (RSS) and identify patients with tumors refractive to conventional therapy.Experimental Design: Using clonogenic survival assays, we identified the surviving fraction (SF-2Gy) after radiation across a range of BCC lines. Intrinsic radiosensitivity was correlated to gene expression using Spearman correlation. Functional analysis was performed in vitro, and enriched biologic concepts were identified. The RSS was generated using a Random Forest model and was refined, cross-validated, and independently validated in additional breast cancer datasets.Results: Clonogenic survival identifies a range of radiosensitivity in human BCC lines (SF-2Gy 77%-17%) with no significant correlation to the intrinsic breast cancer subtypes. One hundred forty-seven genes were correlated with radiosensitivity. Functional analysis of RSS genes identifies previously unreported radioresistance-associated genes. RSS was trained, cross-validated, and further refined to 51 genes that were enriched for concepts involving cell-cycle arrest and DNA damage response. RSS was validated in an independent dataset and was the most significant factor in predicting local recurrence on multivariate analysis, outperfoming all clinically used clinicopathologic features.Conclusions: We derive a human breast cancer-specific RSS with biologic relevance and validate this signature for prediction of locoregional recurrence. By identifying patients with tumors refractory to standard radiation this signature has the potential to allow for personalization of radiotherapy.

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Section: Introductionmentioning

confidence: 99%

Development and Validation of a Novel Radiosensitivity Signature in Human Breast Cancer

Speers

Zhao

Liu

et al. 2015

Clinical Cancer Research

141

106

View full text Add to dashboard Cite

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“…Multiple gene signatures associated with radiosensitivity have been described (11,12), but clinical models able to detect single gene variants associated with radiation response have not been validated. In the case of NSCLC, determination of local control rates for thoracic tumors are confounded by variations in multiple treatment factors including dose, tumor size, planning techniques, respiratory motion, the uncertainty of computed tomography-based target definition, and the interactive effects of systemically delivered therapy.…”

Section: Introductionmentioning

confidence: 99%

A Clinical Model for Identifying Radiosensitive Tumor Genotypes in Non–Small Cell Lung Cancer

Johung

Yao

et al. 2013

Clinical Cancer Research

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Purpose: Non-small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes.Experimental Design: Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments.Results: In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred infield (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFRmutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P ¼ 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment.Conclusions: This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.

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“…We have previously developed a multigene expression model of tumor radiosensitivity [14]. This model has been validated in multiple independent clinical cohorts including breast, rectal, esophageal, and head and neck cancers [14,15]. This model predicts a radiosensitivity index (RSI) that is directly proportional to tumor radioresistance, (RSI, high index = radioresistance).…”

Section: Introductionmentioning

confidence: 99%

Differences Between Colon Cancer Primaries and Metastases Utilizing a Molecular Assay for Tumor Radiosensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection

Ahmed

Berglund

Shridhar

et al. 2014

International Journal of Radiation Oncology*Biology*Physics

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Purpose/Objectives-We have previously developed a multigene expression model of tumor radiosensitivity (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck). The purpose of this study was to assess differences in RSI scores between primary colon cancer and metastases.Methods and Materials-Patients were identified from our institutional IRB approved prospective observational protocol. A total of 704 metastatic and 1,362 primary lesions were obtained from a de-identified meta-data pool. RSI was calculated using the previously published ranked based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiotherapy (SBRT) was used for validation.Results-The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors compared with 54% of primaries were in the RSI-radioresistant (RSI-RR) peak, suggesting that, metastatic tumors may be slightly more radioresistant than primaries (p=0.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases Corresponding Author: Javier F. Torres-Roca MD, H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, 12902 Magnolia Dr., Tampa, FL 33612 USA, Telephone: 00-1-813-745-3568, Fax: 00-1-813-745-7231, javier.torresroca@moffitt.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflicts of HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript in descending order of radioresistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31), p<0.0001. These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control (LC) rate over patients with liver metastases (2 yr LC 100% vs. 73.0%, p=0.026).Conclusions-Assessment of radiosensitivity between primary and metastatic tissues of colon cancer histology, reveals significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort.

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Validation of a Radiosensitivity Molecular Signature in Breast Cancer

Cited by 185 publications

References 42 publications

Development and Validation of a Novel Radiosensitivity Signature in Human Breast Cancer

Development and Validation of a Novel Radiosensitivity Signature in Human Breast Cancer

A Clinical Model for Identifying Radiosensitive Tumor Genotypes in Non–Small Cell Lung Cancer

Differences Between Colon Cancer Primaries and Metastases Utilizing a Molecular Assay for Tumor Radiosensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection

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