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Treatment monitoring in early and locally advanced breast cancer using circulating tumor DNA analysis

使用循环肿瘤 DNA 分析监测早期和局部晚期乳腺癌的治疗

基本信息

批准号：
10304444
负责人：
Muhammed Murtaza
金额：
$ 20.69万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304444
关键词：
Address Adjuvant Therapy Aftercare Archives Biological Assay Biological Markers Biopsy Blood Tests Blood Volume Blood specimen Clinical Clinical Data Clinical Trials Complement DNA DNA analysis Detection Detection of Minimal Residual Disease Diagnostic Disease Disease Progression Disease-Free Survival Drops Early treatment Enrollment Ensure Estrogen receptor positive Excision Goals Histopathology Image In complete remission Individual Literature Malignant Neoplasms Measures Metastatic breast cancer Methods Microscopic Molecular Monitor Mutate Mutation Neoadjuvant Therapy No Evidence of Disease Operative Surgical Procedures Outcome Paraffin Embedding Pathologic Patients Performance Phase Phenotype Plasma Postoperative Period Process Prognostic Marker Radiology Specialty Recurrence Reproducibility Residual Neoplasm Residual Tumors Sampling Sensitivity and Specificity Signal Transduction Somatic Mutation Specificity Testing Therapeutic Tissues Tumor Cell Line Tumor Tissue Validation advanced breast cancer aggressive therapy base cancer cell circulating biomarkers clinically relevant design digital exome sequencing follow-up improved improved outcome malignant breast neoplasm overtreatment personalized medicine portability preservation prognostic value prospective response survival outcome treatment optimization treatment planning treatment response tumor tumor DNA

项目摘要

PROJECT SUMMARY Patients with early and locally advanced breast cancer (ELABC) are treated with a combination of pre- operative (neoadjuvant) therapy, surgical resection and post-operative (adjuvant) therapy. In recent years, overall survival for ELABC has improved to ~90% at 5 years. However, to achieve this goal, patients are often over-treated due to lack of effective biomarkers. For example, a majority of patients who receive adjuvant therapy are already cured after surgery and derive no further benefit. Similarly, almost a third of patients treated with neoadjuvant therapy are found to have pathological Complete Response upon surgery (no evidence of tumor upon histopathology), suggesting that the surgery could have been safely omitted. An effective biomarker for minimal residual disease (MRD) can help personalize treatment plans and reduce over- treatment, while preserving outcomes in patients with breast cancer. Recent literature shows post-operative detection of circulating tumor DNA (ctDNA) can identify recurrence, months before it is recognized on imaging. However, due to lack of sensitivity of current methods and limited blood sample volumes, ctDNA signal often drops below limit of detection. Current approaches for ctDNA analysis do not have adequate sensitivity to detect residual disease during and after completion of treatment. To address this gap, we have developed TARgeted DIgital Sequencing (TARDIS), an approach for multiplexed analysis of several patient-specific mutations in ctDNA. In this application, we propose to first analytically validate TARDIS for ctDNA detection and then clinically validate this approach as a biomarker for treatment monitoring and residual disease detection in early and locally advanced breast cancer. In the UH2 analytical validation phase, we will assess analytical sensitivity, specificity, accuracy, precision and reproducibility of TARDIS using reference material, tumor cell line dilutions and plasma samples from patients with breast cancer. In the UH3 clinical validation phase, we will measure baseline ctDNA detection rates in patients with early and locally advanced breast cancer, evaluate whether ctDNA levels after neoadjuvant treatment are predictive of pathological Complete Response and evaluate the prognostic value of ctDNA detection after surgical resection for disease-free survival. Our goal is to enable greater precision in treatment of patients with early and locally advanced breast cancer. Once validated, ctDNA analysis and monitoring will complement existing diagnostic approaches such as imaging and histopathology to help optimize management of patients with early and locally advanced breast cancer.

项目总结