Molecular Analysis of NeoAdjuvant Platinum in Triple Negative Breast Cancer

三阴性乳腺癌新辅助铂的分子分析

基本信息

批准号：
7945302
负责人：
RICHARD JAMES COTE
金额：
$ 49.61万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7945302
关键词：
Accounting Address Adjuvant Chemotherapy African Aftercare Age Area Axilla Bioinformatics Biological Markers Biology Breast Cancer Biology Cancer Etiology Cancer Patient Candidate Disease Gene Caucasians Caucasoid Race Cessation of life Characteristics Chemotherapy-Oncologic Procedure Chromosome abnormality Clinical Clinical Data Clinical Research Comprehensive Cancer Center Consensus Copy Number Polymorphism DNA DNA Repair Data Diagnostic Diagnostic Neoplasm Staging Disease Epidermal Growth Factor Receptor Estrogen Receptors Ethnic Origin Exhibits Formalin Freezing Gene Chips Gene Dosage Gene Expression Genes Genome Genomics Goals Hispanics Hospitals Human In complete remission Incidence Inflammatory Institution Knowledge Laboratories Loss of Heterozygosity Mammary Gland Parenchyma Mammary Neoplasms Methodology Molecular Analysis Molecular Profiling Neoadjuvant Therapy Normal tissue morphology Outcome Paraffin Embedding Pathologic Patients Pharmaceutical Preparations Platinum Premenopause Progesterone Receptors RNA Reporting Residual state Reverse Transcriptase Polymerase Chain Reaction Salts Sampling Second Primary Cancers Specimen Staging Subgroup TNM Techniques Technology Testing Tissue Banking Tissue Banks Tissue Sample Toxic effect Tumor Tissue Tumor stage Universities Validation Woman advanced disease base cancer diagnosis chemotherapy cohort demographics density design effective therapy follow-up genome-wide homologous recombination innovation malignant breast neoplasm novel outcome forecast pre-clinical public health relevance response triple-negative invasive breast carcinoma tumor

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) Clinical Research, and specific Challenge topic 04-GM-101: Personalized drug response and toxicity. The Challenge and Potential Impact: With a global incidence of 1,151,298 each year, breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death (465,000/year) in women. Triple-negative breast cancer (TNBC), defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), accounts for 15-20% of all breast cancers and is associated with poor clinical outcome, in part due to the lack of available targeted treatments. Currently, there is no consensus regarding optimal chemotherapy regimens for the treatment of such patients. Preclinical data suggests that TNBC may be sensitive to platinum-based chemotherapy because of deficiencies in BRCA-associated DNA repair, especially defective homologous recombination. We therefore hypothesize that gene expression changes will be identified in locally advanced triple negative breast cancer patients which are associated with pathological and/or clinical complete response to platinum-based chemotherapy. The aim of this study is to evaluate gene expression profiles and/or copy number variation associated with pathologic (pCR) and clinical complete response (cCR), in patients with TNBC treated with neoadjuvant platinum-based chemotherapy, in order to identify robust biomarkers for response prediction. The Approach: In order to address this challenge, we retrospectively reviewed 674 patients with locally advanced breast cancer (LABC) who received neoadjuvant chemotherapy between January 1999 and June 2008 at the University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital. Of these, 125 (18.5%) patients had histopathologic confirmation of TNBC. All patients received neoadjuvant platinum salts. Pathologic complete response (pCR) was strictly defined as no residual invasive disease in breast and axilla. RFS and OS estimates were calculated according to Kaplan-Meier (K-M) analysis. Patient demographics indicate a median age of 50 years (range 28-86 years), 60% premenopausal, 54% Hispanic, 34% African descent, and the remainder Caucasian. The TNM stage distribution at presentation: T1 0.9%, T2 5.2%, T3 53.4%, T4 40.5%, N0 25.0%, N1 36.2%, N2 35.4%, N3 3.4%, M0 100%, inflammatory breast cancer 11%, median tumor size = 9.5cm. Follow up duration ranged from 0.2 to 8.9 years. pCR was observed in 42 of 125 patients (34%; 95% CI 26-42%). Median RFS by K-M analysis has not yet been reached in the subgroup of patients achieving a pCR, while the median RFS for non-pCR was 2.6 years (P=0.0002). Moreover, patients achieving pCR had significantly higher OS (median OS not reached vs. 5.1 years, pCR vs. non-pCR, respectively; P=0.001). To date, this is the largest reported single institution cohort of locally advanced TNBC uniformly treated with platinum-based chemotherapy regimens. In order to test our hypothesis, we will complete the following specific aims: Aim I: Identify genome-wide differences in gene expression between pathological complete responders and non-responders in locally advanced triple negative BC samples. Aim 2: Identify genome-wide differences in gene expression between clinical complete responders and nonresponders among locally advanced triple negative BC samples from patients which do not exhibit pCR. Aim 3: Investigate possible chromosomal alterations associated with gene expression differences. The use of expression array technology historically has been dependent upon the availability of intact RNA from fresh frozen tumor tissue for analysis, thus study of the many large retrospective cohorts with annotated clinical follow-up has not been possible. However, using an innovative approach we have recently successfully tested novel array probes specifically designed to detect partially degraded RNA from FFPE breast tumor material from samples at the University of Miami. The use of a probeset with extreme 3' sequence mitigates this previous technical limitation, and thus is considered highly innovative. Importantly, integration of high density array CGH technology with the expression array data is novel (to our knowledge, the first study in a well characterized platinum-treated locally advanced triple negative breast cancer cohort). This approach will allow identification of specific copy number variations and loss of heterozygosity, and their relation to gene expression changes. Our eventual goal will be to develop further understanding of biology of disease, and develop predictive biomarkers, for effective treatment for the subgroup of TNBC, who otherwise have poor prognosis. PUBLIC HEALTH RELEVANCE: With a global incidence of 1,151,298 each year, breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death (465,000/year) in women. Triple-negative breast cancer (TNBC), defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), accounts for 15-20% of all breast cancers and is associated with poor clinical outcome, in part due to the lack of available targeted treatments. Currently, there is no consensus regarding optimal chemotherapy regimens for the treatment of such patients. Preclinical data suggests that TNBC may be sensitive to platinum-based chemotherapy because of deficiencies in BRCA-associated DNA repair, especially defective homologous recombination. We therefore hypothesize that gene expression changes will be identified in locally advanced triple negative breast cancer patients which are associated with pathological and/or clinical complete response to platinum-based chemotherapy. The aim of this study is to evaluate gene expression profiles and/or copy number variation associated with pathologic (pCR) and clinical complete response (cCR), in patients with TNBC treated with neoadjuvant platinum-based chemotherapy, in order to identify robust biomarkers for response prediction

描述（由申请人提供）：此申请涉及广泛的挑战领域（04）临床研究，具体挑战主题04-gm-101：个性化药物反应和毒性。挑战和潜在的影响：乳腺癌每年的全球发病率为1,151,298，是最常被诊断出的癌症，也是癌症死亡的第二大主要原因（465,000/年）。由缺乏雌激素受体（ER），孕酮受体（PR）和人表皮生长因子受体2（HER-2）表达的三阴性乳腺癌（TNBC）（TNBC），占所有乳腺癌的15-20％，并且占所有临床预后不良，部分原因是缺乏可用的目标治疗。当前，关于此类患者的最佳化学疗法方案尚无共识。临床前数据表明，由于BRCA相关的DNA修复（尤其是同源性重组）的缺乏，TNBC可能对基于铂的化学疗法敏感。因此，我们假设将在局部晚期三重阴性乳腺癌患者中鉴定基因表达变化，这些患者与病理学和/或临床完全反应对基于铂的化学疗法有关。这项研究的目的是评估与新辅助铂基化学疗法治疗的TNBC患者中，与病理学（PCR）和临床完全反应相关的基因表达谱和/或拷贝数变化，以识别出可靠的生物标志物以进行反应预测。方法：为了应对这一挑战，我们回顾性地审查了674例局部晚期乳腺癌患者（LABC），他们在1999年1月至2008年6月在迈阿密Sylvester大学综合癌症中心/杰克逊纪念医院接受了新辅助化疗。其中，有125名（18.5％）患者对TNBC有组织病理学证实。所有患者接受新辅助铂盐。病理完全反应（PCR）严格定义为乳房和腋窝中没有残留的侵入性疾病。根据Kaplan-Meier（K-M）分析计算RFS和OS估计值。患者人口统计学表明，中位年龄为50岁（28-86岁），60％的绝经前，54％的西班牙裔，34％的非洲血统和其余的高加索人。介绍时的TNM阶段分布：T1 0.9％，T2 5.2％，T3 53.4％，T4 40.5％，N0 25.0％，N1 36.2％，N2 35.4％，N3 3.4％，M0 100％，炎性乳腺癌，炎症性乳腺癌11％，中位肿瘤大小= 9.5cm。后续持续时间范围为0.2至8.9年。在125例患者中有42例（34％； 95％CI 26-42％）观察到PCR。在获得PCR的患者亚组中，通过K-M分析的RFS中位数尚未达到，而非PCR的中位RF为2.6岁（P = 0.0002）。此外，达到PCR的患者的OS明显更高（未达到5.1岁的OS和PCR和非PCR； P = 0.001）。迄今为止，这是报告的最大的单一机构队列，该机构统一用铂基化疗方案统一治疗。为了检验我们的假设，我们将完成以下特定目的：目标I：确定全基因组在局部先进的三重阴性BC样本中病理完整反应者和非反应者之间基因表达的差异。 AIM 2：从不表现出PCR的患者的局部晚期三重阴性BC样品中，临床完整反应者和无反应者之间的基因表达差异。目标3：研究与基因表达差异相关的可能的染色体改变。从历史上看，表达阵列技术的使用一直取决于新鲜冷冻肿瘤组织的完整RNA进行分析，因此对许多具有带注释的临床随访的大型回顾性队列的研究是不可能的。但是，使用创新方法，我们最近成功地测试了专门设计的新型阵列探针，该探针专门从迈阿密大学的样品中检测出FFPE乳腺肿瘤材料的部分降解的RNA。使用具有极端3'序列的探针的使用可缓解先前的技术限制，因此被认为是高度创新的。重要的是，高密度阵列CGH技术与表达阵列数据的整合是新颖的（据我们所知，这是一项经过良好表征的铂金处理的局部先进的三重阴性乳腺癌队列中的第一项研究）。这种方法将允许识别特定的拷贝数变化和杂合性丧失及其与基因表达变化的关系。我们的最终目标是发展对疾病生物学的进一步了解，并开发预测性生物标志物，以有效治疗TNBC的亚组，而TNBC的预后不良。公共卫生相关性：乳腺癌每年的全球发病率为1,151,298，是最常见的癌症，是女性癌症死亡（465,000/年）的第二大主要原因。由缺乏雌激素受体（ER），孕酮受体（PR）和人表皮生长因子受体2（HER-2）表达的三阴性乳腺癌（TNBC）（TNBC），占所有乳腺癌的15-20％，并且占所有临床预后不良，部分原因是缺乏可用的目标治疗。当前，关于此类患者的最佳化学疗法方案尚无共识。临床前数据表明，由于BRCA相关的DNA修复（尤其是同源性重组）的缺乏，TNBC可能对基于铂的化学疗法敏感。因此，我们假设将在局部晚期三重阴性乳腺癌患者中鉴定基因表达变化，这些患者与病理学和/或临床完全反应对基于铂的化学疗法有关。这项研究的目的是评估与新辅助铂基化学疗法治疗的TNBC患者中，与病理学（PCR）和临床完全反应相关的基因表达谱和/或拷贝数变化，以识别可靠的生物标志物以识别出可靠的生物标志物以进行反应预测。