Molecularly Tailored Adjuvant Chemotherapy for Resected Non-small Cell Lung Cancer: A Time for Excitement and Equipoise

In patients with previously-untreated, completely-resected pathologic stage II–III non-small cell lung cancer, 4 months of postoperative cisplatin-based chemotherapy reduces the risk of death by approximately 20%. To date, the only prospectively validated prognostic and predictive factor which can be used to guide clinical practice is pathologic stage. Higher stage patients have a worse prognosis, but derive more benefit from adjuvant chemotherapy. Numerous molecular markers are being developed with the potential to help decide which patients to treat with adjuvant chemotherapy, and which drugs to use. This paper will review the molecular markers which are having immediate impact on treatment decisions in routine practice, and which merit further study in the next generation of adjuvant chemotherapy trials.

[1]  M. Ladanyi,et al.  Epidermal Growth Factor Receptor Mutation Testing in Lung Cancer: Searching for the Ideal Method , 2007, Clinical Cancer Research.

[2]  E. Brambilla,et al.  PD2-3-4: Prognostic and predictive value of apoptosis related factors Fas, FasL and survivin in non small cell lung carcinoma patients enrolled in the IALT Trial , 2007 .

[3]  J. Pignon,et al.  D3-03: IALT-Bio: a challenging research to improve adjuvant chemotherapy of completely resected NSCLC , 2007 .

[4]  Alan Cantor,et al.  Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  J. Pignon,et al.  Multidrug Resistance Proteins Do Not Predict Benefit of Adjuvant Chemotherapy in Patients with Completely Resected Non–Small Cell Lung Cancer: International Adjuvant Lung Cancer Trial Biologic Program , 2007, Clinical Cancer Research.

[6]  J. Pignon,et al.  Cell cycle regulators and outcome of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer: the International Adjuvant Lung Cancer Trial Biologic Program. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  D. Gandara,et al.  Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Shu-Feng Zhou.  ERCC1 and non-small-cell lung cancer. , 2007, The New England journal of medicine.

[9]  R. Wood,et al.  ERCC1 and non-small-cell lung cancer [8] , 2007 .

[10]  P. Jänne,et al.  Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  N. Hayward,et al.  Gene Expression Signature Predicts Recurrence in Lung Adenocarcinoma , 2007, Clinical Cancer Research.

[12]  Roy S Herbst,et al.  KRAS Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer , 2007, Clinical Cancer Research.

[13]  L. Seymour,et al.  Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Zhong Zheng,et al.  DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. , 2007, The New England journal of medicine.

[15]  J. Mackey,et al.  Class III β-Tubulin Expression and Benefit from Adjuvant Cisplatin/Vinorelbine Chemotherapy in Operable Non–Small Cell Lung Cancer: Analysis of NCIC JBR.10 , 2007, Clinical Cancer Research.

[16]  J. Massagué.  Sorting out breast-cancer gene signatures. , 2007, The New England journal of medicine.

[17]  A. Dupuy,et al.  Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting. , 2007, Journal of the National Cancer Institute.

[18]  Jeremy J. W. Chen,et al.  A five-gene signature and clinical outcome in non-small-cell lung cancer. , 2007, The New England journal of medicine.

[19]  M Volante,et al.  ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  Zhifu Sun,et al.  A Gene Expression Signature Predicts Survival of Patients with Stage I Non-Small Cell Lung Cancer , 2006, PLoS medicine.

[21]  N. Hayward,et al.  Expression profiling defines a recurrence signature in lung squamous cell carcinoma. , 2006, Carcinogenesis.

[22]  G. Bepler,et al.  RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  F. Cappuzzo,et al.  Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  Elisabeth Brambilla,et al.  DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. , 2006, The New England journal of medicine.

[25]  Julio Astudillo,et al.  Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. , 2006, The Lancet. Oncology.

[26]  P. Febbo,et al.  Noise and bias in microarray analysis of tumor specimens. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  Daniel W Lin,et al.  Influence of surgical manipulation on prostate gene expression: implications for molecular correlates of treatment effects and disease prognosis. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  S. Mukherjee,et al.  A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. , 2006, The New England journal of medicine.

[29]  Yi Zhang,et al.  Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung. , 2006, Cancer research.

[30]  M. Meyerson,et al.  Exon 19 Deletion Mutations of Epidermal Growth Factor Receptor Are Associated with Prolonged Survival in Non–Small Cell Lung Cancer Patients Treated with Gefitinib or Erlotinib , 2006, Clinical Cancer Research.

[31]  G. Scagliotti,et al.  Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  D. Sugarbaker,et al.  Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  L. Paz-Ares,et al.  A prospective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR). , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  Xianglin Shi,et al.  Constructing Molecular Classifiers for the Accurate Prognosis of Lung Adenocarcinoma , 2006, Clinical Cancer Research.

[35]  P. Ravdin,et al.  Prognosis of patients with resected non-small cell lung cancer: impact of clinical and pathologic variables. , 2006, Lung cancer.

[36]  M. Ladanyi,et al.  Clinical Course of Patients with Non–Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated with Gefitinib or Erlotinib , 2006, Clinical Cancer Research.

[37]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[38]  M. Fridman,et al.  Dose‐dense vinorelbine and docetaxel with Filgrastim support in patients with advanced nonsmall cell lung carcinoma , 2005, Cancer.

[39]  C. Nabhan,et al.  Erlotinib in lung cancer. , 2005, The New England journal of medicine.

[40]  M. Ladanyi,et al.  Erlotinib in lung cancer. , 2005, The New England journal of medicine.

[41]  T. Shibata,et al.  Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  Xin Li,et al.  TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  P. Jänne,et al.  Epidermal growth factor receptor mutations in patients with non-small cell lung cancer. , 2005, Cancer research.

[44]  M. Ostland,et al.  Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  M. Ladanyi,et al.  Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. , 2005, The Journal of molecular diagnostics : JMD.

[46]  Lesley Seymour,et al.  Erlotinib in lung cancer - molecular and clinical predictors of outcome. , 2005, The New England journal of medicine.

[47]  Renato Martins,et al.  Erlotinib in previously treated non-small-cell lung cancer. , 2005, The New England journal of medicine.

[48]  Robert Livingston,et al.  Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. , 2005, The New England journal of medicine.

[49]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[50]  Elisa Rossi,et al.  Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. , 2005, Journal of the National Cancer Institute.

[51]  William Pao,et al.  Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  H. Varmus,et al.  KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib , 2005, PLoS medicine.

[53]  M Paesmans,et al.  The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis , 2004, British Journal of Cancer.

[54]  Y. Maehara,et al.  Regulation of p27 by S-phase kinase-associated protein 2 is associated with aggressiveness in non-small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[56]  L. Dwyer-Nield,et al.  Mutation-Selective Tumor Remission with Ras-Targeted, Whole Yeast-Based Immunotherapy , 2004, Cancer Research.

[57]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[58]  L. Gelbert,et al.  An Increase in the Expression of Ribonucleotide Reductase Large Subunit 1 Is Associated with Gemcitabine Resistance in Non-Small Cell Lung Cancer Cell Lines , 2004, Cancer Research.

[59]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[60]  Alan Cantor,et al.  RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  H. Kato,et al.  A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. , 2004, The New England journal of medicine.

[62]  Bengt Bergman,et al.  Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. , 2004, The New England journal of medicine.

[63]  David Cella,et al.  Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. , 2003, JAMA.

[64]  Chan Zeng,et al.  Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  A. Ardizzoni,et al.  Prognostic significance of K-ras, p53, bcl-2, PCNA, CD34 in radically resected non-small cell lung cancers. , 2003, European journal of cancer.

[66]  S. Miyoshi,et al.  Prognostic significance of p27KIP1 expression in resected non–small cell lung cancers: Analysis in combination with expressions of p16INK4A, pRB, and p53 , 2002, Journal of surgical oncology.

[67]  David E. Misek,et al.  Gene-expression profiles predict survival of patients with lung adenocarcinoma , 2002, Nature Medicine.

[68]  D. Gandara,et al.  Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[69]  M. Tyers,et al.  Molecular profiling of non-small cell lung cancer and correlation with disease-free survival. , 2002, Cancer research.

[70]  Michael Thomas,et al.  Trimodality treatment in Stage III nonsmall cell lung carcinoma , 2002, Cancer.

[71]  D. Sidransky,et al.  Cigarette smoking is strongly associated with mutation of the K‐ras gene in patients with primary adenocarcinoma of the lung , 2001, Cancer.

[72]  M. Kris,et al.  Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  E. Mark,et al.  Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. , 1999, Journal of the National Cancer Institute.

[74]  C R Cantor,et al.  Chip-based genotyping by mass spectrometry. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[75]  J. Muscat,et al.  K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases. , 1999, Carcinogenesis.

[76]  F. Shepherd,et al.  Reduced expression of the cell cycle inhibitor p27Kip1 in non-small cell lung carcinoma: a prognostic factor independent of Ras. , 1999, Cancer research.

[77]  Esposito,et al.  Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. , 1997, Cancer research.

[78]  Alona Muzikansky,et al.  Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. , 2007, The oncologist.