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

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 in-field (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 EGFR-mutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P = 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. Clin Cancer Res; 19(19); 5523–32. ©2013 AACR.

[1]  Jing Zhao,et al.  Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. , 2013, Clinical lung cancer.

[2]  Yan-Ze Jin,et al.  Discordance between anaplastic lymphoma kinase status in primary non‐small‐cell lung cancers and their corresponding metastases , 2013, Histopathology.

[3]  Young Hak Kim,et al.  Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer , 2012, Cancer Chemotherapy and Pharmacology.

[4]  Yudi Pawitan,et al.  Validation of a Radiosensitivity Molecular Signature in Breast Cancer , 2012, Clinical Cancer Research.

[5]  M. Insana,et al.  Stromal responses to fractionated radiotherapy , 2012, International journal of radiation biology.

[6]  M. Jamal-Hanjani,et al.  Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Epidermal Growth Factor Receptor–Mutant Non–Small Cell Lung Cancer Metastatic to the Brain , 2011, Clinical Cancer Research.

[7]  William Pao,et al.  "Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. , 2011, Neuro-oncology.

[8]  Cheng-Bo Han,et al.  EGFR Mutations, Gene Amplification, and Protein Expression and KRAS Mutations in Primary and Metastatic Tumors of Nonsmall Cell Lung Cancers and Their Clinical Implications: A Meta-Analysis , 2011, Cancer investigation.

[9]  Benjamin Movsas,et al.  Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. , 2011, Journal of the National Cancer Institute.

[10]  R. Mak,et al.  Outcomes after combined modality therapy for EGFR-mutant and wild-type locally advanced NSCLC. , 2011, The oncologist.

[11]  A. Shaw,et al.  Targeting Anaplastic Lymphoma Kinase in Lung Cancer , 2011, Clinical Cancer Research.

[12]  L. Sequist,et al.  EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. , 2010, Neuro-oncology.

[13]  L. Sequist,et al.  EGFR mutation status and survival after diagnosis of brain metastasis in non-small cell lung cancer. , 2010 .

[14]  Andrea Bezjak,et al.  Stereotactic body radiation therapy for inoperable early stage lung cancer. , 2010, JAMA.

[15]  W. Pao,et al.  High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer , 2010, Journal of Neuro-Oncology.

[16]  E. Cohen-Jonathan-Moyal,et al.  Basic fibroblast growth factor-2/beta3 integrin expression profile: signature of local progression after chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. , 2009, International journal of radiation oncology, biology, physics.

[17]  M. Loda,et al.  Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never-smokers. , 2009, Cancer research.

[18]  J. Maris,et al.  Inhibition of ALK Signaling for Cancer Therapy , 2009, Clinical Cancer Research.

[19]  Sang-We Kim,et al.  Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. , 2009, Lung cancer.

[20]  Patricia Greninger,et al.  A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. , 2009, Cancer cell.

[21]  Hemant Ishwaran,et al.  An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer , 2008, Proceedings of the National Academy of Sciences.

[22]  R. Rosell,et al.  Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. , 2008, International journal of radiation oncology, biology, physics.

[23]  Michael Becker,et al.  Establishment of Patient-Derived Non–Small Cell Lung Cancer Xenografts as Models for the Identification of Predictive Biomarkers , 2008, Clinical Cancer Research.

[24]  D. Haber,et al.  Increased Prevalence of EGFR-Mutant Lung Cancer in Women and in East Asian Populations: Analysis of Estrogen-Related Polymorphisms , 2008, Clinical Cancer Research.

[25]  Yih-Leong Chang,et al.  Radiotherapy in Lung Adenocarcinoma with Brain Metastases: Effects of Activating Epidermal Growth Factor Receptor Mutations on Clinical Response , 2008, Clinical Cancer Research.

[26]  Christer Lindquist,et al.  THE LEKSELL GAMMA KNIFE PERFEXION AND COMPARISONS WITH ITS PREDECESSORS , 2007, Neurosurgery.

[27]  E. Glatstein.  Non–Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation , 2008 .

[28]  Tongtong Zhang,et al.  Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. , 2007, Lung cancer.

[29]  Mitsuo Sato,et al.  Somatic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma. , 2007, Cancer research.

[30]  Peng Liu,et al.  Genetic polymorphisms and treatment response in advanced non-small cell lung cancer. , 2007, Lung cancer.

[31]  David J. Chen,et al.  Influence of tumor cell and stroma sensitivity on tumor response to radiation. , 2007, Cancer research.

[32]  V. Rusch,et al.  Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  J. Minna,et al.  Non-small-cell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. , 2006, Cancer research.

[34]  L. Wilson,et al.  Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Ming-Sound Tsao,et al.  K-ras mutations in non-small-cell lung carcinoma: a review. , 2006, Clinical lung cancer.

[36]  S. Lam,et al.  Establishment in Severe Combined Immunodeficiency Mice of Subrenal Capsule Xenografts and Transplantable Tumor Lines from a Variety of Primary Human Lung Cancers: Potential Models for Studying Tumor Progression–Related Changes , 2006, Clinical Cancer Research.

[37]  Hiroki Shirato,et al.  Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases: A Randomized Controlled Trial , 2007 .

[38]  G. Barnett,et al.  Local control of brain metastases by stereotactic radiosurgery in relation to dose to the tumor margin. , 2006, Journal of neurosurgery.

[39]  Y. Yatabe,et al.  EGFR mutations in patients with brain metastases from lung cancer: association with the efficacy of gefitinib. , 2006, Neuro-oncology.

[40]  J. Minna,et al.  Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. , 2006, Journal of the National Cancer Institute.

[41]  K. Lim,et al.  Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. , 2005, Cancer cell.

[42]  Hyae-Young Kim,et al.  Gefitinib as a First-Line Therapy of Advanced or Metastatic Adenocarcinoma of the Lung in Never-Smokers , 2005, Clinical Cancer Research.

[43]  C. Chiu,et al.  Gefitinib is active in patients with brain metastases from non-small cell lung cancer and response is related to skin toxicity. , 2005, Lung cancer.

[44]  K. Kiura,et al.  Effect of gefitinib ('Iressa', ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer. , 2004, Lung cancer.

[45]  F. Cappuzzo,et al.  Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[46]  Maria Werner-Wasik,et al.  Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial , 2004, The Lancet.

[47]  F. Cappuzzo,et al.  Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC). , 2003, Lung cancer.

[48]  S. Hassenbusch,et al.  The Role of Tumor Size in the Radiosurgical Management of Patients with Ambiguous Brain Metastases , 2003, Neurosurgery.

[49]  J H Hwang,et al.  Apoptosis and bcl-2 expression as predictors of survival in radiation-treated non-small-cell lung cancer. , 2001, International journal of radiation oncology, biology, physics.

[50]  J W Arends,et al.  Cell proliferation and apoptosis in stage III inoperable non-small cell lung carcinoma treated by radiotherapy. , 2000, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[51]  L Souhami,et al.  Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. , 2000, International journal of radiation oncology, biology, physics.

[52]  J. Minna,et al.  NCI series of cell lines: An historical perspective , 1996, Journal of cellular biochemistry. Supplement.

[53]  Lee-Jen Wei,et al.  Cox-Type Regression Analysis for Large Numbers of Small Groups of Correlated Failure Time Observations , 1992 .

[54]  Related Topics,et al.  Survival analysis : state of the art , 1992 .

[55]  L. J. Wei,et al.  The Robust Inference for the Cox Proportional Hazards Model , 1989 .

[56]  H. Hansen,et al.  Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. , 1988, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  T. Puck,et al.  ACTION OF X-RAYS ON MAMMALIAN CELLS , 1956, The Journal of experimental medicine.