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: 10592440
• 负责人: BEN H PARK
• 金额: $ 14.5万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592440
• 关键词: Address; Axillary Lymph Node Dissection; Biological Markers; Blood; Blood Tests; Blood specimen; Breast Cancer Patient; Breast Cancer gene; Breast Cancer therapy; Cancer Patient; Circulation; 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; Localized Disease; 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; Recommendation; Recurrence; Regimen; Research; Residual Cancers; Residual Neoplasm; 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; burden of illness; cancer cell; chemotherapy; digital; digital technology; empowerment; 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.

项目概要/摘要 使用针对患者的特定方案来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特征和临床情况推荐多种治疗方法 患者的阶段。然而，这些数据是大组患者的平均数据，然后应用于 每个人。因此，肿瘤学家最终会使用多种疗法来治疗大多数患者，因为他们知道 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，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来识别真正患有乳腺癌的患者 初步治疗后的微小残留疾病与已经治愈的疾病的比较。拟议项目 解决了这个难题。研究团队将采用数字 PCR (dPCR) 等新技术 下一代测序 (NGS)，可靠地检测和量化脱落的血浆肿瘤 DNA (ptDNA) 分子 从癌细胞进入循环系统。他们已经展示了检测微观残留物的能力 使用这些技术治疗早期乳腺癌患者的疾病。该团队提出了一个雄心勃勃的计划 项目旨在解决早期（治疗目的）乳腺癌中未满足的需求，最终确定谁真正 与那些已经治愈的患者相比，需要额外的治疗。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 ptDNA 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) 鉴定早期乳腺体细胞突变 使用 NGS 检测癌症。该团队将测试使用血浆DNA来识别肿瘤特异性的可行性 II/III 期乳腺癌患者在任何治疗前发生突变。这一目标的成功将阻止 需要获取用于 NGS 的诊断组织样本，而这些样本通常已用完或无法获取。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 by dPCR 将验证突变标记，以便对每位患者的血液样本进行连续检测。目标 3) ptDNA 对残留病灶和病理完全缓解 (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 的缺失是否可以预测 pCR。这 这项研究的成功将为未来的试验奠定基础，以确定患者术后是否无法检测到 ptDNA。 NAT 可以安全地放弃手术，类似于使用前哨淋巴结活检来避免手术的范式转变 腋窝解剖。此外，NAT 和手术后 ptDNA 的存在可以识别一部分患者 未来复发的风险很大，可以作为未来临床试验的平台。最终 测量 ptDNA 将使个体化治疗方案成为可能，并改变当前过度治疗的做法 早期疾病。

项目成果

Undetectable Tumor Cell-Free DNA in a Patient With Metastatic Breast Cancer With Complete Response and Long-Term Remission.

转移性乳腺癌患者的肿瘤游离 DNA 无法检测到，且具有完全缓解和长期缓解。

• DOI: 10.6004/jnccn.2019.7381
• 发表时间: 2020
• 期刊: Journal of the National Comprehensive Cancer Network : JNCCN
• 作者: Hunter,Natasha;Croessmann,Sarah;Cravero,Karen;Shinn,Daniel;Hurley,PaulaJ;Park,BenHo
• 通讯作者: Park,BenHo

Pathogenic Germline Variants in Patients With Metastatic Breast Cancer.

• DOI: 10.1001/jamaoncol.2019.3116
• 发表时间: 2019-08
• 期刊: JAMA oncology
• 影响因子: 28.4
• 作者: Kelsey Stuttgen;Sarah Croessmann;J. Fetting;V. Stearns;R. Nunes;R. Connolly;B. Park