Friday, April 26, 2024
4/26/2024
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.
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