Metastatic Colorectal Cancer and Treatment Challenges
Colorectal cancer (CRC) is estimated to be the third most prevalent cause of cancer death in both men and women in the United States in 2021. (1) While some patients are diagnosed with localized disease and cured with appropriate treatments, most patients who are diagnosed with de novo or recurrent advanced disease face a life-limiting illness. Median overall survival (OS) in metastatic CRC (mCRC) continues to increase over time, largely due to improving systemic therapies, but more therapies are still needed. For the majority of patients with mCRC, even initially effective systemic therapies become intolerable or cancer resistance to chemotherapy develops.
In the last decade, the identification of actionable genomic alterations in mCRC has led to the FDA approval of several effective therapeutic regimens targeting these alterations (see below). Still, even guideline-aligned biomarker testing for alterations such as RAS, BRAF, and microsatellite instability high (MSI-H)/mismatch repair deficiency (dMMR) in mCRC remains suboptimal, (2) highlighting the need for more streamlined testing. Once therapeutic resistance develops, recognition of this is necessary and new therapeutic options are needed. This article will describe currently established and actionable genomic alterations in mCRC, emerging targets, and a novel clinical trial platform designed to optimize therapeutic selection for patients with mCRC.
Next-Generation Sequencing Utilizing Tumor Tissue and/or Blood
The identification of actionable genomic alterations in tumors such as mCRC was once performed by Sanger DNA sequencing of tumor DNA that was extracted from fixed paraffin-embedded tumor tissue, but this has now been replaced by next-generation sequencing (NGS), which allows for larger-scale and automated genome sequencing. Multiple commercial vendors, such as Foundation One, Caris, and Tempus, among others, provide comprehensive tumor molecular profiling. However, utilizing NGS data from a tumor biopsy of 1 anatomic location at 1 time point may be insufficient to treat patients with mCRC, as we recognize that there can be spatial tumor heterogeneity (between the primary tumor and metastatic lesions) and temporal tumor heterogeneity (when targeted therapies exert pressure for certain mutations to disappear and new mutations to evolve). (3,4) The invasiveness of serial tissue biopsies and the turnaround time of 2 to 4 weeks for NGS analysis can both be limitations for clinical use. Thus, the development of blood-based NGS testing as a method to analyze circulating tumor DNA (ctDNA) has been a welcome one. This allows clinicians to identify the prominent actionable genomic alterations from the patient's cancer as a whole, and to monitor the dynamic changes in the molecular profile serially as the patient progresses from one treatment to another. (5) The FoundationOne Liquid CDX test (Foundation Medicine, Inc, Cambridge, MA) is now FDA approved as a companion test for multiple biomarkers, including BRCA1 and BRCA2 genes in ovarian cancer for rucaparib (Rubraca) treatment, ALK rearrangements in non-small cell lung cancer (NSCLC) for alectinib (Alecensa) treatment, PIK3CA mutations in breast cancer for alpelisib (Piqray) treatment, and BRCA1 and BRCA2 and ATM mutations in prostate cancer for olaparib (Lynparza) treatment. The Guardant360 CDX (Guardant Health, Redwood...