Molecular Complete Response in Blood as a Predictor for a Pathologic Complete Response after Neoadjuvant Therapy fo Breast Cancer

血液中的分子完全缓解作为乳腺癌新辅助治疗后病理完全缓解的预测因子

• 批准号: 10380582
• 负责人: BEN H PARK
• 金额: $ 22.87万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-12 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380582
• 关键词: Address; Axillary Lymph Node Dissection; Biological Markers; Blood; Blood Circulation; Blood Tests; Blood specimen; Breast Cancer Patient; Breast Cancer gene; Breast Cancer therapy; Cancer Patient; Clinical; Clinical Oncology; Clinical Trials; DNA; Data; Detection; Detection of Minimal Residual Disease; Diagnostic; Disease; ERBB2 gene; Evaluable Disease; Family; Foundations; Future; In complete remission; Individual; Knowledge; Lead; Liquid substance; Local Therapy; Logistics; Malignant Neoplasms; Measures; Methods; Microscopic; Mind; Molecular; Monitor; Mutation; Mutation Detection; Neoadjuvant Therapy; Oncologist; Operative Surgical Procedures; Pathologic; Patients; Physicians; Plasma; Polymerase Chain Reaction; Postoperative Period; Predictive Value; Prior Therapy; Prognosis; Public Health; Publishing; Radiation therapy; Recurrence; Regimen; Research; Residual Cancers; Residual Tumors; Residual state; Risk; Sampling; Sensitivity and Specificity; Sentinel Lymph Node Biopsy; Somatic Mutation; Source; Specificity; Systemic Therapy; Technology; Testing; Therapeutic; Time; Tissue Sample; Tissues; Toxic effect; Tumor Burden; Tumor Tissue; Woman; Work; base; burden of illness; cancer cell; chemotherapy; digital; exhaust; experience; feasibility testing; gene panel; high risk; individual patient; individualized medicine; malignant breast neoplasm; neoplastic cell; new technology; next generation sequencing; overtreatment; patient population; patient subsets; peace; precision medicine; prospective; success; treatment planning; treatment response; trial design; tumor; tumor DNA; virtual

Project Summary/Abstract The ability to treat breast cancer using patient specific regimens is not yet feasible. For example, oncologists use prior clinical trials data to recommend multiple therapies based upon features of the tumor and clinical stage of the patient. However, these data are averaged from large groups of patients that are then applied to each individual. Therefore, oncologists end up treating the majority of patients with multiple therapies knowing from past clinical trials that most patients do not need these additional therapies, resulting in overtreatment. For early stage breast cancer, this is because there is no reliable method to identify patients that truly have microscopic residual disease after primary therapy versus those that are already cured. The proposed project addresses this conundrum. The research team will employ the newer technologies of digital PCR (dPCR) and next generation sequencing (NGS), to reliably detect and quantify plasma tumor DNA (ptDNA) molecules shed into the circulation from cancer cells. They have already demonstrated the ability to detect microscopic residual disease using these technologies in early stage breast cancer patients. The team proposes an ambitious project to address unmet needs in early stage (curative intent) breast cancer, to ultimately determine who truly needs additional therapy vs. those patients that are already cured. They propose to evaluate Stage II/III breast cancer patients undergoing neoadjuvant therapy (NAT) and define whether absence of ptDNA after NAT can predict for complete elimination of tumor cells at the time of surgery, termed a pathologic complete response (pCR). Three specific aims are proposed. Aim 1) Identification of somatic mutations in early stage breast cancer using NGS. The team will test the feasibility of using plasma DNA to identifying tumor specific mutations in Stage II/III breast cancer patients prior to any therapy. The success of this aim will preclude the need for obtaining diagnostic tissue samples for NGS, which are often exhausted or unobtainable. Aim 2) Detection of somatic mutations in plasma using dPCR. The successful detection of mutations in preNAT blood by dPCR will validate mutation markers for serial testing of blood samples for each individual patient. Aim 3) Predictive value of ptDNA for residual disease and pathologic complete response (pCR). Using dPCR, the team will determine whether absence of ptDNA in blood after NAT but prior to surgery predicts for pCR. The success of this study will set the stage for future trials to determine if patients without detectable ptDNA after NAT can safely forego surgery, similar to the paradigm shift in using sentinel lymph node biopsies to avoid axillary dissection. Additionally, the presence of ptDNA after NAT and surgery may identify a subset of patients with significant risk for future recurrence, which could serve as a platform for future clinical trials. Ultimately measuring ptDNA will enable individual therapy options and change the current practice of overtreatment in early stage disease.

项目摘要/摘要 使用患者特定方案治疗乳腺癌的能力尚不可行。例如，肿瘤学家 使用先前的临床试验数据，建议基于肿瘤和临床特征的多种疗法 病人的阶段。但是，这些数据是由大量患者平均的，然后将其应用于 每个人。因此，肿瘤学家最终会治疗多种疗法的大多数患者 从过去的临床试验中，大多数患者不需要这些额外的疗法，从而导致过度治疗。 对于早期乳腺癌，这是因为没有可靠的方法可以识别出真正具有的患者 初级治疗后的微观残留疾病与已经治愈的残留疾病。拟议的项目 解决这个难题。研究团队将采用数字PCR（DPCR）和 下一代测序（NGS），可靠地检测和量化血浆肿瘤DNA（ptDNA）分子棚 进入癌细胞的循环。他们已经证明了检测微观残留的能力 在早期乳腺癌患者中使用这些技术的疾病。团队提出了雄心勃勃的 计划在早期（治愈意图）乳腺癌中解决未满足的需求，最终确定谁真正 与已经治愈的患者相比，需要额外的疗法。他们建议评估II/III期乳房 接受新辅助治疗（NAT）的癌症患者，并确定NAT后不存在PtDNA是否可以 预测手术时完全消除肿瘤细胞，称为病理完全反应 （PCR）。提出了三个具体目标。目标1）鉴定早期乳房中的体突变 使用NGS的癌症。该团队将测试使用血浆DNA识别特定肿瘤的可行性 在进行任何治疗之前，II/III期乳腺癌患者的突变。这个目标的成功将排除 需要获取NGS的诊断组织样品，这些NGS通常会筋疲力尽或无法获得。目标2） 使用DPCR检测血浆中体细胞突变。成功检测Prenat血液中的突变 通过DPCR，将验证每个患者血液样本的系列测试突变标记。目标3） PtDNA对残留疾病和病理完全反应（PCR）的预测值。使用DPCR， 团队将确定NAT后血液中缺乏PtDNA，但在手术前预测PCR。这 这项研究的成功将为以后的试验奠定阶段，以确定未经检测到的患者是否在 NAT可以安全放弃手术，类似于使用前哨淋巴结活检中的范式转移 腋窝解剖。此外，NAT和手术后的PTDNA存在可能鉴定出一部分患者 未来复发的危险很高，可以作为未来临床试验的平台。最终 测量ptDNA将使个人治疗方案能够改变当前的过度治疗实践 早期疾病。