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A feasibility trial of functional precision cancer medicine to inform treatment selection in metastatic breast cancer

功能性精准癌症医学的可行性试验，为转移性乳腺癌的治疗选择提供信息

基本信息

批准号：
10436097
负责人：
Christos Vaklavas
金额：
$ 17.94万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436097
关键词：
Biologic Characteristic Biological Biological Assay Biopsy Clinical Clinical Treatment Clinical Trials Complex Disease remission Double-Blind Method Drug Screening ERBB2 gene Ecosystem Endocrine Enrollment Exhibits Generations Genes Genomics Genotype Gold Grant Heterogeneity Histology Institutional Review Boards Lead Malignant Neoplasms Mammary Neoplasms Metastatic breast cancer Modeling Molecular Mutation Neoplasm Metastasis Newly Diagnosed Organoids Patients Perception Performance Pharmaceutical Preparations Physicians Preclinical Drug Evaluation Progression-Free Survivals Proteins Quality of life Recommendation Recurrence Research Resources Selection for Treatments Seminal Series Site Testing Therapeutic Time Woman actionable mutation base clinical efficacy clinical investigation clinical practice clinical predictors clinically relevant combinatorial design effective therapy exhaust feasibility trial genomic profiles high risk hormone receptor-positive human disease improved inhibitor therapy insight malignant breast neoplasm mutant patient derived xenograft model patient population personalized medicine precision genomic medicine precision medicine precision oncology preclinical evaluation pressure relapse prediction resistance mechanism response therapy resistant tool treatment response tumor

项目摘要

Title: A feasibility trial of functional precision cancer medicine to inform treatment selection in metastatic breast cancer. In metastatic breast cancer, with the notable exception of the HER2 paradigm, the promise of the genomic “precision medicine” in which mutant driver genes in a patient’s tumor are identified and the encoded proteins are targeted with therapeutic inhibitors, has not been fully realized. Mutations alone, particularly those identified in gene panels, are insufficiently informative to guide treatment selection. Tumors, especially metastases, grow in complex ecosystems and exhibit striking heterogeneity and plasticity that allow them to evolve dynamically under a series of pressures. To overcome this limitation, we have now established a Functional Precision Oncology (FPO) platform, whereby patient derived xenografts (PDX) and organoids (PDO) are established from tumors obtained from patients with breast cancer. These models retain faithfully the complex molecular and biologic characteristics of the originating tumors and, to that end, can predict clinical responses more reliably. Organoids are amenable to medium-throughput drug screening and drug “hits” have been validated in PDXs, which currently constitute the gold standard for preclinical drug evaluation. We integrate drug profiling results with genomic studies to gain insights into determinants of treatment response or resistance and create genotype – drug response correlations. We leverage this platform in the context of an ongoing clinical trial in early-stage breast cancer, not only to generate patient-derived models, but also identify patients at high risk of metastatic recurrence. In the trial proposed herein (FORESEE: Functional precision oncology for metastatic breast cancer: a feasibility trial, NCT04450706), we aim to systematically analyze the performance of this platform and gain insights on the clinical activity of the proposed treatments in metastatic breast cancer. We establish PDOs directly from biopsies of metastatic sites and perform PDO-based drug screens in women with metastatic breast cancer, either newly diagnosed triple negative or hormone receptor-positive and Her2-negative who have exhausted endocrine mono- and combinatorial therapies. With Aim 1, we will assess how often our PDO- focused FPO pipeline leads to a treatment recommendation within 12 weeks. With Aim 2, we will assess how often our FPO pipeline and concurrent commercial (gold standard) testing lead to treatment recommendations and how often these recommendations overlap. The clinical efficacy of treatment selection informed by our FPO assays will be captured (Aim 3). Collectively, these studies will investigate whether our PDO-based FPO pipeline can be meaningfully incorporated in an investigational clinical practice and provide preliminary insights of impact that can inform the design of a larger study.

题目：功能性精准肿瘤医学为治疗选择提供依据的可行性试验