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）：本申请涉及广泛的挑战领域 (04) 临床研究，以及具体的挑战主题 04-GM-101：个性化药物反应和毒性。挑战和潜在影响：乳腺癌的全球发病率为每年 1,151,298 例，是女性中最常诊断的癌症，也是女性癌症死亡的第二大原因（465,000 人/年）。三阴性乳腺癌 (TNBC) 是指雌激素受体 (ER)、孕激素受体 (PR) 和人表皮生长因子受体 2 (HER-2) 缺乏表达，占所有乳腺癌的 15-20%并且与不良的临床结果相关，部分原因是缺乏可用的靶向治疗。目前，对于此类患者的最佳化疗方案尚未达成共识。临床前数据表明，TNBC 可能对铂类化疗敏感，因为 BRCA 相关 DNA 修复缺陷，特别是同源重组缺陷。因此，我们假设在局部晚期三阴性乳腺癌患者中将发现基因表达变化，这些变化与对铂类化疗的病理和/或临床完全反应相关。本研究的目的是评估接受新辅助铂类化疗的 TNBC 患者中与病理 (pCR) 和临床完全缓解 (cCR) 相关的基因表达谱和/或拷贝数变异，以确定稳健的生物标志物响应预测。方法：为了应对这一挑战，我们回顾性分析了 1999 年 1 月至 2008 年 6 月期间在迈阿密大学西尔维斯特综合癌症中心/杰克逊纪念医院接受新辅助化疗的 674 名局部晚期乳腺癌 (LABC) 患者。其中，125 名 (18.5%) 患者经组织病理学证实为 TNBC。所有患者均接受新辅助铂盐治疗。病理完全缓解（pCR）严格定义为乳房和腋窝无残留浸润性疾病。 RFS 和 OS 估计值根据 Kaplan-Meier (K-M) 分析计算。患者人口统计数据表明，中位年龄为 50 岁（范围为 28-86 岁），其中 60% 为绝经前患者，54% 为西班牙裔，34% 为非洲裔，其余为白种人。就诊时的 TNM 分期分布：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 11%，中位数肿瘤大小 = 9.5 厘米。随访时间为0.2至8.9年。 125 名患者中有 42 名观察到 pCR（34%；95% CI 26-42%）。在实现 pCR 的患者亚组中，K-M 分析尚未达到中位 RFS，而非 pCR 患者的中位 RFS 为 2.6 年 (P=0.0002)。此外，达到 pCR 的患者的 OS 显着更高（未达到中位 OS 与 5.1 年，pCR 与非 pCR 分别；P=0.001）。迄今为止，这是报道的最大的单一机构队列，采用铂类化疗方案统一治疗局部晚期 TNBC。为了检验我们的假设，我们将完成以下具体目标：目标 I：识别局部晚期三阴性 BC 样本中病理完全应答者和无应答者之间基因表达的全基因组差异。目标 2：在未表现出 pCR 的患者的局部晚期三阴性 BC 样本中，确定临床完全缓解者和无缓解者之间基因表达的全基因组差异。目标 3：研究与基因表达差异相关的可能的染色体改变。表达阵列技术的使用历来依赖于新鲜冷冻肿瘤组织中完整RNA的可用性进行分析，因此不可能对许多大型回顾性队列进行研究并进行注释临床随访。然而，利用创新方法，我们最近成功测试了新型阵列探针，该探针专门设计用于检测迈阿密大学样本中 FFPE 乳腺肿瘤材料中部分降解的 RNA。使用具有极端 3' 序列的探针组缓解了先前的技术限制，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，这是在经过充分表征的铂类治疗的局部晚期三阴性乳腺癌队列中进行的第一项研究）。这种方法将允许识别特定的拷贝数变异和杂合性损失，以及它们与基因表达变化的关系。我们的最终目标是进一步了解疾病生物学，并开发预测性生物标志物，以便有效治疗预后不良的 TNBC 亚组。公共卫生相关性：乳腺癌的全球发病率为每年 1,151,298 例，是女性中最常诊断的癌症，也是女性癌症死亡的第二大原因（465,000 人/年）。三阴性乳腺癌 (TNBC) 是指雌激素受体 (ER)、孕激素受体 (PR) 和人表皮生长因子受体 2 (HER-2) 缺乏表达，占所有乳腺癌的 15-20%并且与不良的临床结果相关，部分原因是缺乏可用的靶向治疗。目前，对于治疗此类患者的最佳化疗方案尚未达成共识。临床前数据表明，TNBC 可能对铂类化疗敏感，因为 BRCA 相关 DNA 修复缺陷，特别是同源重组缺陷。因此，我们假设在局部晚期三阴性乳腺癌患者中将发现基因表达变化，这些变化与对铂类化疗的病理和/或临床完全反应相关。本研究的目的是评估接受新辅助铂类化疗的 TNBC 患者中与病理 (pCR) 和临床完全缓解 (cCR) 相关的基因表达谱和/或拷贝数变异，以确定稳健的生物标志物响应预测