Advancing precision oncology in metastatic colorectal cancer: The food and drug administration approval of foundation one liquid CDx as a companion diagnostic a correspondence

Dear Editor,

Colorectal cancer (CRC) is the third most commonly diagnosed and the second most mortality-causing cancer worldwide. ¹ Colorectal cancer develops through genetic and epigenetic changes that activate oncogenes, decrease tumor suppressor genes, and cause the disease to develop characteristic cancer traits. Mutation accumulation is fueled by genomic and epigenomic instability, which drives malignant transformation via aggressive cell selection and clonal growth. ² BRAF mutations, particularly the V600E mutation, are observed in approximately 10% of colorectal cancer (CRC) patients. These mutations are more common in females, often found in right-sided tumors, and associated with advanced stage, mucinous histology, defective mismatch repair, and the serrated adenoma pathway. Compared to normal CRCs, patients with BRAF-mutated CRCs experience a worsened prognosis and demonstrate resistance to conventional treatment approaches. ³

BRAF-mutated colorectal cancer (CRC) poses treatment challenges due to chemotherapy resistance. Combination therapies involving BRAF, MEK, and EGFR inhibitors are being explored, while further research targets Wnt and immunotherapy. In 2020, the FDA approved Encorafenib in combination with Cetuximab, as the first and the only treatment regimen for adult mCRC patients with a BRAF V600E mutation based on the BEACON CRC (NCT02928224) trial. This Phase 3 trial showed improved overall survival in patients with BRAF mutation, making it an important therapeutic advancement. ⁴ The approved CRC combination therapy combines both effects of the BRAF inhibitor (Encorafenib) with the epidermal growth factor receptor inhibitor EFGR (Cetuximab) in patients with the BRAF V600E mutation CRC. ⁴ Encorafenib acts to inhibit the activity of mutated BRAF proteins by blocking the abnormal signaling pathway in cancer cells, while Cetuximab acts as a monoclonal antibody that targets the overexpressed EFGR in CRC. Since the BRAF inhibition results in a rapid release of feedback-suppressed (EGFR)–mediated MAPK signaling, combining both drugs will synergistically inhibit tumor growth in BRAF V600E–mutant CRC. ⁵

A significant recent advancement is the FDA approval of FoundationOne Liquid CDx on June 2023, a blood-based liquid biopsy test, as a companion diagnostic for determining the eligibility of patients with BRAF-V600E metastatic CRC (mCRC) for this combination therapy. ⁶ Utilizing targeted high throughput hybridization-based capture technology, FoundationOne Liquid CDx is a qualitative next-generation sequencing-based in vitro diagnostic test capable of identifying and reporting gene substitutions, insertions and deletions, rearrangements, and copy number variations across 324 genes. It harnesses circulating cell-free DNA (cfDNA) extracted from anticoagulated peripheral whole blood plasma, collected in specialized FoundationOne tubes specifically designed for cfDNA analysis. ⁷ This vital companion diagnostics tool offers oncologists a validated, non-invasive genomic testing option for patients with metastatic solid tumors, with demonstrated efficacy as a companion diagnostic in prostate cancer (Olaparib and rucaparib), breast cancer (Alpelisib), and solid tumors (Entrectinib). ⁷ By aiding in the identification of specific mutations, FoundationOne Liquid CDx enables patients with mCRC BRAF V600E to benefit from expedited treatment initiation, particularly valuable for those unable to undergo tumor biopsy [6]. This regulatory milestone brings newfound hope to patients with BRAF-mutated CRC, offering them an approved treatment option tailored to their specific cancer type, coupled with a blood-based companion diagnostic.

Despite recent advances, the suggested revolutionary approach's dependence on circulating cell-free DNA (cfDNA) poses hurdles due to variable DNA fragment levels. False positive results, ambiguity in non-detection cases, and high costs necessitate the development of more sensitive, accessible, and cost-effective companion diagnostics for the timely diagnosis and personalized management of BRAF V600E-mutated metastatic colorectal cancers (mCRC). It is critical to address these restrictions through technological integration and artificial intelligence, as well as to investigate alternative biofluids and prioritize safety, accessibility, and cost. Large-scale research and clinical trials are required to establish clinical relevance, standardization, and consistent and reliable results.