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Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical Implications
Mohamed A Gouda1, Blessie E Nelson1, Lars Buschhorn2
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Abstract:
Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAFV600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High). Herein, we have used data from AACR project GENIE to explore the clinico-genomic landscape of these alterations. AACR GENIE is a publicly accessible registry of genomic data from multiple collaborating cancer centers. Current database (version 13.0) includes sequencing data of 168,423 samples collected from patients with different cancers. We were able to identify BRAFV600E, RET fusions, NTRK fusions, and high TMB in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples, respectively. In this article, we describe the distribution of those tissue-agnostic targets among different cancer types. In addition, we summarize the current prospect on the biology of these alterations and evidence on approved drugs, including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib combination.
Insights
Precision oncology advances with tissue-agnostic cancer therapies targeting biomarkers like BRAFV600E mutations and high tumor mutation burden (TMB). This study explores their distribution across various cancer types, aiding targeted treatment strategies.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Biomarker-driven therapies have transformed oncology, enabling treatments effective across diverse cancer types.
- Tissue-agnostic targets, identified through understanding tumor biology, have led to pan-cancer therapeutic approvals.
- Five key molecular biomarkers (BRAFV600E, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High)) have FDA tissue-agnostic approval.
Purpose of the Study:
- To investigate the clinico-genomic landscape of FDA-approved tissue-agnostic targets.
- To analyze the distribution of specific biomarkers (BRAFV600E, RET fusions, NTRK fusions, high TMB) across various cancer types.
- To summarize the biological insights and approved therapies for these pan-cancer targets.
Main Methods:
- Utilized data from the AACR Project GENIE registry (version 13.0), encompassing 168,423 patient samples.
- Analyzed genomic data to identify the prevalence of BRAFV600E mutations, RET fusions, NTRK fusions, and high TMB.
- Reviewed existing literature on the biology of these alterations and the efficacy of associated targeted therapies and immunotherapies.
Main Results:
- BRAFV600E mutations, RET fusions, NTRK fusions, and high TMB were identified in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples, respectively.
- Detailed the distribution patterns of these tissue-agnostic targets across different cancer types.
- Compiled information on approved drugs, including pembrolizumab, dostarlimab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib.
Conclusions:
- The study provides a comprehensive overview of the clinico-genomic landscape for key tissue-agnostic cancer biomarkers.
- Understanding the prevalence and distribution of these targets is crucial for optimizing precision oncology strategies.
- This analysis supports the clinical application of targeted therapies and immunotherapies across a broad spectrum of cancers based on specific molecular alterations.
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