Clinical validation of genetic variants associated with in vitro chemotherapy-related lymphoblastoid cell toxicity

Hematotoxicity is one of the major side effects of chemotherapy. The aim of this study was to examine the association between single nucleotide polymorphisms (SNPs) and hematotoxicity in breast cancer patients in a subset of patients of the SUCCESS prospective phase III chemotherapy study. All patients (n = 1678) received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel or docetaxel/gemcitabine, depending on randomization. Germline DNA was genotyped for 246 SNPs selected from a previous genome-wide association study (GWAS) in a panel of lymphoblastoid cell lines, with gemcitabine toxicity as the phenotype. All SNPs were tested for their value in predicting grade 3 or 4 neutropenic or leukopenic events (NLEs). Their prognostic value in relation to overall survival and disease-free survival was also tested. None of the SNPs was found to be predictive for NLEs during treatment with docetaxel/gemcitabine. Two SNPs in and close to the PIGB gene significantly improved the prediction of NLEs after FEC, in addition to the factors of age and body surface area. The top SNP (rs12050587) had an odds ratio of 1.38 per minor allele (95% confidence interval, 1.17 to 1.62). No associations were identified for predicting disease-free or overall survival. Genetic variance in the PIGB gene may play a role in determining interindividual differences in relation to hematotoxicity after FEC chemotherapy.

[1]  G. Lyman,et al.  Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review. , 2014, Critical reviews in oncology/hematology.

[2]  M. Rezai,et al.  Adjuvant gemcitabine for high-risk breast cancer (BC) patients: Final survival results of the randomized phase III SUCCESS-A study. , 2014 .

[3]  Tanja Fehm,et al.  Circulating Tumor Cells Predict Survival in Early Average-to-High Risk Breast Cancer Patients , 2014, Journal of the National Cancer Institute.

[4]  P. Neven,et al.  Multivariable regression analysis of febrile neutropenia occurrence in early breast cancer patients receiving chemotherapy assessing patient-related, chemotherapy-related and genetic risk factors , 2014, BMC Cancer.

[5]  Krishna R. Kalari,et al.  Discovery of genetic biomarkers contributing to variation in drug response of cytidine analogues using human lymphoblastoid cell lines , 2014, BMC Genomics.

[6]  J. Armitage,et al.  Colony-stimulating factors for febrile neutropenia during cancer therapy. , 2013, The New England journal of medicine.

[7]  J. Woo,et al.  Role of pharmacogenetics on adjuvant chemotherapy-induced neutropenia in Chinese breast cancer patients , 2013, Journal of Cancer Research and Clinical Oncology.

[8]  Y. Tamaki,et al.  MDM2 SNP309 and TP53 R72P associated with severe and febrile neutropenia in breast cancer patients treated with 5-FU/epirubicin/cyclophosphamide , 2012, Breast Cancer Research and Treatment.

[9]  S. Whyte,et al.  Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis , 2011, BMC Cancer.

[10]  Yusuke Nakamura,et al.  Genome-wide association study of epirubicin-induced leukopenia in Japanese patients , 2011, Pharmacogenetics and genomics.

[11]  R. Paridaens,et al.  Risk factors for chemotherapy-induced neutropenia occurrence in breast cancer patients: data from the INC-EU Prospective Observational European Neutropenia Study , 2011, Supportive Care in Cancer.

[12]  Ewout W Steyerberg,et al.  Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers , 2011, Statistics in medicine.

[13]  G. Lyman,et al.  Risk of mortality in patients with cancer who experience febrile neutropenia , 2010, Cancer.

[14]  S. Sleijfer,et al.  Effects of mannose-binding lectin polymorphisms on irinotecan-induced febrile neutropenia. , 2010, The oncologist.

[15]  D. Sargent,et al.  Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741. , 2010, Journal of Clinical Oncology.

[16]  M. Beckmann,et al.  Prevalence of CA 27.29 in primary breast cancer patients before the start of systemic treatment. , 2010, Anticancer research.

[17]  K. Tomic,et al.  Risk of mortality in patients with cancer experiencing febrile neutropenia. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  M. Paesmans,et al.  A general chemotherapy myelotoxicity score to predict febrile neutropenia in hematological malignancies. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[19]  Krishna R. Kalari,et al.  Gemcitabine and cytosine arabinoside cytotoxicity: association with lymphoblastoid cell expression. , 2008, Cancer research.

[20]  K. Gelmon,et al.  Identifying Patients at High Risk for Neutropenic Complications During Chemotherapy for Metastatic Breast Cancer With Doxorubicin or Pegylated Liposomal Doxorubicin: The Development of a Prediction Model , 2008, American journal of clinical oncology.

[21]  Tianxi Cai,et al.  The Performance of Risk Prediction Models , 2008, Biometrical journal. Biometrische Zeitschrift.

[22]  R. Souchon,et al.  DEGRO Practical Guidelines for Radiotherapy of Breast Cancer II , 2008, Strahlentherapie und Onkologie.

[23]  R. Paridaens,et al.  Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study , 2008, British journal of haematology.

[24]  M. Pencina,et al.  Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond , 2008, Statistics in medicine.

[25]  R. Souchon,et al.  DEGRO Practical Guidelines for Radiotherapy of Breast Cancer I , 2007, Strahlentherapie und Onkologie.

[26]  G. Lyman,et al.  Dose intensity and hematologic toxicity in older cancer patients receiving systemic chemotherapy , 2005, Cancer.

[27]  P. Nathan,et al.  Meta-analysis: Effect of Prophylactic Hematopoietic Colony-Stimulating Factors on Mortality and Outcomes of Infection , 2007, Annals of Internal Medicine.

[28]  G. Lyman,et al.  Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  J. Ware.  The limitations of risk factors as prognostic tools. , 2006, The New England journal of medicine.

[30]  D. Levy,et al.  Multiple biomarkers for the prediction of first major cardiovascular events and death. , 2006, The New England journal of medicine.

[31]  S. Loibl,et al.  Feasibility, toxicity and quality of life of first-line chemotherapy with platinum/paclitaxel in elderly patients aged >or=70 years with advanced ovarian cancer--a study by the AGO OVAR Germany. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[32]  N. Kearney,et al.  EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. , 2006, European journal of cancer.

[33]  G. Lyman,et al.  Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients , 2006, Cancer.

[34]  G. Lyman,et al.  Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  M. Pepe,et al.  Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. , 2004, American journal of epidemiology.

[36]  G. Kerr,et al.  Moderate neutropenia with adjuvant CMF confers improved survival in early breast cancer , 2003, British Journal of Cancer.

[37]  É. Azoulay,et al.  Impact of neutropenia duration on short-term mortality in neutropenic critically ill cancer patients , 2002, Intensive Care Medicine.

[38]  A. Oliphant,et al.  BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. , 2002, BioTechniques.

[39]  M. Hussain,et al.  Clinical characteristics and therapeutic outcome of patients with febrile neutropenia who present in shock: need for better strategies. , 2001, The Journal of infection.

[40]  L. Elting,et al.  The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  A. Salar,et al.  Prognostic Factors Influencing Mortality in Cancer Patients with Neutropenia and Bacteremia , 1999, European Journal of Clinical Microbiology and Infectious Diseases.

[42]  F. Harrell,et al.  Prognostic/Clinical Prediction Models: Multivariable Prognostic Models: Issues in Developing Models, Evaluating Assumptions and Adequacy, and Measuring and Reducing Errors , 2005 .

[43]  P. Grambsch,et al.  Proportional hazards tests and diagnostics based on weighted residuals , 1994 .

[44]  R. Finberg,et al.  Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  M. Beckmann,et al.  Participation in the SUCCESS-A Trial Improves Intensity and Quality of Care for Patients with Primary Breast Cancer. , 2013, Geburtshilfe und Frauenheilkunde.

[46]  Bin Zhang,et al.  Prognostic value of chemotherapy-induced neutropenia in early-stage breast cancer , 2011, Breast Cancer Research and Treatment.

[47]  N. Kearney,et al.  2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. , 2011, European journal of cancer.

[48]  S. Freeman,et al.  Pretreatment haematological laboratory values predict for excessive myelosuppression in patients receiving adjuvant FEC chemotherapy for breast cancer. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[49]  G. Lyman,et al.  Dose intensity and hematologic toxicity in older breast cancer patients receiving systemic chemotherapy , 2009, Cancer.

[50]  G. Schwarzer,et al.  Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. , 2004, The Cochrane database of systematic reviews.

[51]  J. Shaffer.  Multiple Hypothesis Testing , 1995 .

[52]  S. Holm.  A Simple Sequentially Rejective Multiple Test Procedure , 1979 .