Circulating plasma tumor DNA as a biomarker for early stage breast cancer

循环血浆肿瘤 DNA 作为早期乳腺癌的生物标志物

基本信息

批准号：
9392301
负责人：
BEN H PARK
金额：
$ 6.8万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-26 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9392301
关键词：
Address Biological Markers Biopsy Blood Blood Circulation Blood Tests Blood specimen Breast Breast Cancer Patient Breast Cancer therapy Breast Oncology Cancer Patient Clinical Clinical Oncology Clinical Trials DNA DNA Markers Data Detection Diagnostic Disease Ensure Evaluable Disease Evolution Family Foundations Future Goals Human In complete remission Individual Knowledge Lead Liquid substance Local Therapy Malignant Neoplasms Malignant neoplasm of anus Measures Methods Microscopic Mind Modeling Mutation Neoadjuvant Therapy Oncogenes Oncologist Operative Surgical Procedures Pathologic Patient risk Patients Physicians Plasma Polymerase Chain Reaction Postoperative Period Predictive Value Primary Neoplasm Prior Therapy Public Health Publishing Radiation therapy Recurrence Research Residual Cancers Residual Tumors Residual state Risk Sample Size Sampling Somatic Mutation Specificity Systemic Therapy Technology Testing Therapeutic Time Toxic effect Tumor Burden Uncertainty Woman Work actionable mutation base burden of illness cancer cell chemotherapy clinical decision-making digital experience gene panel high risk improved outcome individual patient individualized medicine lymph nodes malignant breast neoplasm new technology new therapeutic target next generation sequencing outcome forecast patient population patient subsets peace personalized medicine precision medicine prospective public health relevance response trial design tumor tumor DNA virtual

项目摘要

DESCRIPTION (provided by applicant): Personalized medicine for breast oncology is in evolution. Currently, oncologists use prior clinical trials data to recommend multiple therapies based upon features of the tumor and clinical stage of the patient. A limitation with this approach is that these data are averaged from large groups of patients that are then applied to each individual. This creates uncertainty as there is currently no reliable method to identify individua patients who truly have microscopic residual disease after primary therapy from those that are already cured. Thus, oncologists tend to treat the majority of patients with multiple therapies knowing from past clinical trials that most patients do not need these additional therapies, resulting in overtreatment. This project proposes an alternative model that will lead to a paradigm shift in how oncologists recommend and follow responses to therapy. The research team proposes that using the newer technologies of droplet digital PCR (ddPCR) and next generation sequencing (NGS), plasma tumor DNA (ptDNA) molecules shed into the circulation from cancer cells can be reliably detected and measured. They have already demonstrated the ability to detect microscopic residual disease using these technologies in early stage breast cancer patients. The team proposes a transforming project to address specific unmet needs in early stage (curative intent) breast cancer. It is well known that there are subsets of breast cancer patients who upon completion of preoperative chemotherapy (neoadjuvant therapy; NAT) have no evidence of cancer in the breast and lymph nodes. This is termed a pathologic complete response (pCR), and is associated with a favorable prognosis. This raises the question of whether these patients need surgery after NAT, however, patients must undergo surgery to know that they have achieved a pCR. The team will solve this conundrum by determining if the absence of detectable ptDNA after NAT will predict for a pCR and they will therefore define a "liquid pCR". Based on their data, the team hypothesizes that >95% of patients without detectable ptDNA after NAT will have a pCR. This will set the stage for future studies to determine if patients without detectable ptDNA after NAT can safely forego surgery and/or radiation therapy, similar to the paradigm shift in treating anal cancer decades ago. A second long-term goal of this work is to determine in future studies whether the presence of ptDNA after NAT identifies a subset of patients with significant risk for future recurrence, which could therefore serve as a platform for clinical trials with new targeted therapies for patients wih detectable ptDNA. Ultimately measuring ptDNA will enable individual therapy options and change the current practice of overtreatment in early stage disease.

描述（应用程序提供）：乳腺肿瘤学的个性化医学正在进化。目前，肿瘤学家使用先前的临床试验数据，建议基于肿瘤和患者临床阶段的特征进行多种疗法。这种方法的限制是这些数据是从随后应用于每个人的大量患者中取平均值。这会引起不确定性，因为目前尚无可靠的方法来鉴定单个患者的单个患者，这些患者在初级治疗后真正治愈的患者确实患有微观残留疾病。肿瘤学家倾向于治疗大多数患有多种疗法的患者，从过去的临床试验中知道大多数患者不需要这些额外的疗法，从而导致过度治疗。该项目提出了一个替代模型，该模型将导致肿瘤学家推荐和遵循对治疗的反应的范式转变。研究团队提出的建议，可以可靠地检测和测量使用液滴数字PCR（DDPCR）和下一代测序（NGS），血浆肿瘤DNA（PTDNA）分子从癌细胞中流入循环中的血浆肿瘤DNA（PTDNA）分子。他们已经证明了在早期乳腺癌患者中使用这些技术检测微观残留疾病的能力。团队提出一个转型项目，以满足早期（治愈意图）乳腺癌的特定未满足需求。众所周知，有一些乳腺癌患者的子集在完成术前化疗（Neoadjuvant Therapy; NAT）后没有乳腺癌和淋巴结癌的证据。这称为病理完全反应（PCR），与有利的预后有关。但是，这提出了一个问题，即这些患者是否需要在NAT之后需要手术，但是，患者必须接受手术才能知道他们已经达到了PCR。该团队将通过确定NAT后是否缺乏可检测的PtDNA来解决这个难题，因此他们将定义“液体PCR”。根据他们的数据，团队假设> 95％的患者在NAT后没有可检测到的PTDNA的患者将具有PCR。这将为将来的研究奠定阶段，以确定NAT后没有可检测到的PTDNA的患者是否可以安全放弃手术和/或放射治疗，类似于几十年前治疗肛门癌的范式转移。这项工作的第二个长期目标是在未来的研究中确定NAT后PTDNA的存在是否识别出有重大风险的未来复发风险的子集，因此可以作为对可检测到的PTDNA的新靶向疗法的临床试验的平台。最终测量ptDNA将使个人治疗选择并改变早期疾病中当前过度治疗的做法。