Abstract
Molecular heterogeneity in metastatic breast cancer presents multiple clinical challenges in accurately characterizing and treating the disease. Current diagnostic approaches offer limited ability to assess heterogeneity that exists among multiple metastatic lesions throughout the treatment course. We developed a precision oncology platform that combines serial biopsies, multi-omic analysis, longitudinal patient monitoring, and molecular tumor boards, with the goal of improving cancer management through enhanced understanding of the entire cancer ecosystem within each patient. We describe this integrative approach using comprehensive analytics generated from serial-biopsied lesions in a metastatic breast cancer patient. The serial biopsies identified remarkable heterogeneity among metastatic lesions that presented clinically as discordance in receptor status and genomic alterations with mixed treatment response. Based on our study, we highlight clinical scenarios, such as rapid progression or mixed response, that indicate consideration for repeat biopsies to evaluate intermetastatic heterogeneity (IMH), with the objective of refining targeted therapy. We present a framework for understanding the clinical significance of heterogeneity in breast cancer between metastatic lesions utilizing multi-omic analyses of serial biopsies and its implication for effective personalized treatment.
Highlights
Heterogeneity in breast cancer can be observed across metastatic lesions within an individual patient and can even be seen within a singular lesion[1,2]
Reports suggest that estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) changes following neoadjuvant treatment or throughout tumor progression is a potential indicator of poor prognosis when taken into consideration with the tumor’s original receptor status[6,11,12,13]
At not be performed on this specimen. Her initial presentation, she was treated with bilateral mastectomies and right axillary lymph node dissection, adjuvant Characterization of heterogeneity in receptor status and anthracycline/taxane based chemotherapy, and endocrine therapy intrinsic subtype with tamoxifen
Summary
Heterogeneity in breast cancer can be observed across metastatic lesions (intermetastatic heterogeneity [IMH]) within an individual patient and can even be seen within a singular lesion (intratumoral heterogeneity)[1,2]. Phylogenetic analysis of metastatic breast the IRB-approved observational study, “Molecular Mechanisms of Tumor Evolution and Resistance to Therapy” (MM-TERT)[31], within cancer within individual patients has indicated that two modes of the precision oncology SMMART-program at Oregon Health and disease progression exist, one in which all metastases are Science University, Knight Cancer Institute This program aims to monoclonal, sharing a common metastatic origin, and another benefit individual patients by identifying potential actionable in which multiple metastases arise from different subclones within biology through multi-omic analysis of serial metastatic biopsies the primary tumor[26], leading to molecularly heterogeneous to guide novel precision combination therapies. To comprehensively characterize tumor biopsy tissue, clinical assays were performed within the OHSU Knight Diagnostic Laboratories that are CLIA-licensed/CAP-accredited, including IHC (ER, PR, HER2, AR, and PD-L1), a targeted next-generation sequencing (NGS) panel covering 125 genes (GeneTrails© Comprehensive Solid Tumor Panel), whole transcriptomic sequencing (Illumina TruSeq RNA exome), and a multiplex protein analysis of
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