Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer.

PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m(2) every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.

[1]  Wang Yang.  DNA Repair by ERCC1 in Non-Small-Cell Lung Cancer and Cisplatin-Based Adjuvant Chemotherapy , 2010 .

[2]  P. Nederlof,et al.  High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. , 2009, Cancer research.

[3]  J. Kładny,et al.  Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients , 2009, Breast Cancer Research and Treatment.

[4]  Charles M Perou,et al.  The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas , 2008, Breast Cancer Research.

[5]  Carlos Caldas,et al.  A robust classifier of high predictive value to identify good prognosis patients in ER-negative breast cancer , 2008, Breast Cancer Research.

[6]  Thomas D. Schmittgen,et al.  Analyzing real-time PCR data by the comparative CT method , 2008, Nature Protocols.

[7]  Jing Wang,et al.  Evaluation of biological pathways involved in chemotherapy response in breast cancer , 2008, Breast Cancer Research.

[8]  K. Hess,et al.  Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  A. Rademaker,et al.  alphaB-crystallin is a novel predictor of resistance to neoadjuvant chemotherapy in breast cancer. , 2008, Breast cancer research and treatment.

[10]  A. Rademaker,et al.  αB-crystallin is a novel predictor of resistance to neoadjuvant chemotherapy in breast cancer , 2008, Breast Cancer Research and Treatment.

[11]  R. Gelber,et al.  Pathologic complete remission rate after cisplatin-based primary chemotherapy in breast cancer: correlation with p63 expression , 2008, Cancer Chemotherapy and Pharmacology.

[12]  P. Johnston,et al.  BRCA1 mRNA Expression Levels Predict for Overall Survival in Ovarian Cancer after Chemotherapy , 2007, Clinical Cancer Research.

[13]  Karla Kerlikowske,et al.  Abrogated response to cellular stress identifies DCIS associated with subsequent tumor events and defines basal-like breast tumors. , 2007, Cancer cell.

[14]  Larry Norton,et al.  HER2 and response to paclitaxel in node-positive breast cancer. , 2007, The New England journal of medicine.

[15]  Harry Bartelink,et al.  Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas , 2007, Breast Cancer Research.

[16]  Jos Jonkers,et al.  Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer , 2007, Proceedings of the National Academy of Sciences.

[17]  C. Sotiriou,et al.  p-53 gene mutations as a predictive marker in a population of advanced breast cancer patients randomly treated with doxorubicin or docetaxel in the context of a phase III clinical trial. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[18]  D. Sgroi,et al.  The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. , 2007, The Journal of clinical investigation.

[19]  C. Perou,et al.  The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes , 2007, Clinical Cancer Research.

[20]  A. Ashworth,et al.  BRCA1 dysfunction in sporadic basal-like breast cancer , 2007, Oncogene.

[21]  M. Espié,et al.  Exquisite Sensitivity of TP53 Mutant and Basal Breast Cancers to a Dose-Dense Epirubicin−Cyclophosphamide Regimen , 2007, PLoS medicine.

[22]  Chee-Onn Leong,et al.  Tumor-specific p73 up-regulation mediates p63 dependence in squamous cell carcinoma. , 2006, Cancer research.

[23]  J. Ross,et al.  Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  D. Berry,et al.  Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. , 2006, JAMA.

[25]  Z. Szallasi,et al.  A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers , 2006, Nature Genetics.

[26]  Shridar Ganesan,et al.  X chromosomal abnormalities in basal-like human breast cancer. , 2006, Cancer cell.

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

[28]  L. Ellisen,et al.  p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. , 2006, Cancer cell.

[29]  Roman Rouzier,et al.  Breast Cancer Molecular Subtypes Respond Differently to Preoperative Chemotherapy , 2005, Clinical Cancer Research.

[30]  Julian Peto,et al.  Prediction of BRCA1 Status in Patients with Breast Cancer Using Estrogen Receptor and Basal Phenotype , 2005, Clinical Cancer Research.

[31]  I. Irminger-Finger,et al.  Mutational spectrum of p53 mutations in primary breast and ovarian tumors. , 2004, Critical reviews in oncology/hematology.

[32]  A. Ashworth,et al.  Hallmarks of 'BRCAness' in sporadic cancers , 2004, Nature Reviews Cancer.

[33]  A. Gown,et al.  Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma , 2004, Clinical Cancer Research.

[34]  William D. Foulkes,et al.  Re: Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer , 2004 .

[35]  Ash A. Alizadeh,et al.  Gene Expression Signature of Fibroblast Serum Response Predicts Human Cancer Progression: Similarities between Tumors and Wounds , 2004, PLoS biology.

[36]  Sridhar Ramaswamy,et al.  Loss of Heterozygosity and Its Correlation with Expression Profiles in Subclasses of Invasive Breast Cancers , 2004, Cancer Research.

[37]  L. Bégin,et al.  Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. , 2004, Journal of the National Cancer Institute.

[38]  A. Hutcheon,et al.  A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. , 2003, Breast.

[39]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  D. Silver.  HIN-1 and the Nosology of Breast Cancer , 2003, Cancer biology & therapy.

[41]  C. Boland,et al.  BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells , 2003, British Journal of Cancer.

[42]  C. Ball,et al.  Identification of genes periodically expressed in the human cell cycle and their expression in tumors. , 2002, Molecular biology of the cell.

[43]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[45]  D. Livingston,et al.  Genetic analysis of BRCA1 function in a defined tumor cell line. , 1999, Molecular cell.

[46]  D. Birnbaum,et al.  Mutations at BRCA1: the medullary breast carcinoma revisited. , 1998, Cancer research.

[47]  J. Klijn,et al.  Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1 , 1998, The Lancet.

[48]  M N Pollak,et al.  Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women , 1997, Cancer.

[49]  T. Aas,et al.  Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients , 1996, Nature Medicine.

[50]  G M Lenoir,et al.  Hereditary breast cancer: Pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage , 1996, Cancer.

[51]  D. Housman,et al.  p53-dependent apoptosis modulates the cytotoxicity of anticancer agents , 1993, Cell.