<i>BRAF</i>-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape

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Abstract

BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAF ^V600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAF ^V600E -mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAF ^V600E-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.

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Mutational Landscape of Metastatic Cancer Revealed from Prospective Clinical Sequencing of 10,000 Patients

Ahmet Zehir, Ryma Benayed, Ronak H Shah … (2017)

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically-defined tumor types, coupled with an expanding portfolio of molecularly-targeted therapies, demands flexible and comprehensive approaches to profile clinically significant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative utilizing a comprehensive assay, MSK-IMPACT, through which we have compiled matched tumor and normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel non-coding alterations, and mutational signatures that were shared among common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

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Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer

Thierry André, Kai-Keen Shiu, Tae Won Kim … (2020)

Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.

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AACR Project GENIE: Powering Precision Medicine through an International Consortium

(2017)

The AACR Project GENIE is an international data-sharing consortium focused on generating an evidence base for precision cancer medicine by integrating clinical-grade cancer genomic data with clinical outcome data for tens of thousands of cancer patients treated at multiple institutions worldwide. In conjunction with the first public data release from approximately 19,000 samples, we describe the goals, structure, and data standards of the consortium and report conclusions from high-level analysis of the initial phase of genomic data. We also provide examples of the clinical utility of GENIE data, such as an estimate of clinical actionability across multiple cancer types (>30%) and prediction of accrual rates to the NCI-MATCH trial that accurately reflect recently reported actual match rates. The GENIE database is expected to grow to >100,000 samples within 5 years and should serve as a powerful tool for precision cancer medicine.Significance: The AACR Project GENIE aims to catalyze sharing of integrated genomic and clinical datasets across multiple institutions worldwide, and thereby enable precision cancer medicine research, including the identification of novel therapeutic targets, design of biomarker-driven clinical trials, and identification of genomic determinants of response to therapy. Cancer Discov; 7(8); 818-31. ©2017 AACR.See related commentary by Litchfield et al., p. 796This article is highlighted in the In This Issue feature, p. 783.