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: 9925755
• 负责人: BEN H PARK
• 金额: $ 23.33万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925755
• 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; 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; gene panel; high risk; individual patient; individualized medicine; malignant breast neoplasm; neoplastic cell; new technology; next generation sequencing; outcome forecast; overtreatment; patient population; patient subsets; peace; precision medicine; prospective; response; success; treatment planning; 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.

项目总结/摘要 使用患者特异性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，根据肿瘤和临床特征推荐多种治疗方法 患者的阶段。然而，这些数据是从大量患者中平均得到的，然后应用于 每一个人因此，肿瘤学家最终用多种疗法治疗大多数患者， 从过去的临床试验来看，大多数患者不需要这些额外的治疗，导致过度治疗。 对于早期乳腺癌，这是因为没有可靠的方法来识别真正患有乳腺癌的患者。 与那些已经治愈的相比，初级治疗后的微观残留疾病。拟建项目 解决了这个难题研究团队将采用数字PCR（dPCR）的新技术， 下一代测序（NGS），以可靠地检测和定量血浆肿瘤DNA（ptDNA）分子脱落 从癌细胞进入血液循环他们已经展示了检测微小残留物的能力 在早期乳腺癌患者中使用这些技术。该团队提出了一个雄心勃勃的 解决早期（治疗目的）乳腺癌未满足需求的项目，以最终确定谁真正 需要额外的治疗，而不是那些已经治愈的患者。他们建议评估II/III期乳腺癌 接受新辅助治疗（NAT）的癌症患者，并确定NAT后ptDNA的缺失是否可以 预测手术时肿瘤细胞的完全消除，称为病理完全缓解 （pCR）。提出了三个具体目标。目的1）早期乳腺癌的体细胞突变鉴定 癌症使用NGS该团队将测试使用血浆DNA识别肿瘤特异性的可行性。 II/III期乳腺癌患者在任何治疗之前的突变。这一目标的成功将排除 需要获得用于NGS的诊断组织样品，这些样品通常耗尽或无法获得。目标2） 使用dPCR检测血浆中的体细胞突变。成功检测NAT前血液中的突变 通过dPCR将验证突变标志物，用于对每个患者的血液样本进行系列检测。目标3） ptDNA对残留疾病和病理完全缓解（pCR）的预测价值。使用dPCR， 研究小组将确定NAT后但手术前血液中ptDNA缺失是否预示pCR。的 这项研究的成功将为未来的试验奠定基础，以确定是否没有检测到ptDNA的患者， NAT可以安全地放弃手术，类似于使用前哨淋巴结活检以避免 腋窝淋巴结清扫此外，NAT和手术后ptDNA的存在可能会识别出一部分患者， 未来复发的风险很大，这可以作为未来临床试验的平台。最终 测量ptDNA将使个体治疗选择成为可能，并改变目前过度治疗的做法。 早期疾病。