HER2 Therapies for Patients with mCRC
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HER2 (human epidermal growth factor receptor 2) is a protein receptor found in all human cells and is responsible for controlling cell growth and repair. When the HER2 gene acquires mutations which cause it to be amplified or overexpressed in the cell, it promotes the growth and metastasis of different cancers, including colorectal cancer.
Treatments for metastatic colorectal cancer (mCRC) have improved significantly over the past two decades – novel targeted therapies that target specific subtypes of mCRC, such as BRAFV600E and microsatellite instability high (MSI-H) have helped to improve disease outcomes for many patients. HER2 gene amplification is one of the latest molecular subtypes of mCRC that is currently under investigation.
Microsatellite instability high (MSI-H): a biomarker that describes the condition of a tumour having a high likelihood of developing mutations, resulting from impaired DNA mismatch repair (MMR). A tumour that is MSI-H is characterized by a high number of mutations. This biomarker is present in about 5% of CRCs and is a predictor for positive response to immunotherapy.
HER2 amplification is present in about 5% of patients with RAS/BRAF wild type mCRC. HER2 amplification tends to be more commonly associated with patients whose primary tumours originate on the left-side of the colon and tends to also be more associated with a higher frequency of lung and brain metastases. While a patient’s HER2 status is not likely to have a strong impact on disease outcomes in patients with MCRC, studies suggest that HER2 amplification is associated with resistance to anti-EGFR targeted therapies, such as cetuximab and panintumumab.
Trastuzumab detuxtecan (T-DXd) is a targeted therapy that is composed of two drugs joined together – tratuzumab (Herceptin), a targeted therapy that blocks the effect of mutated HER2 – and deruxtecan (Enhertu), a chemotherapy agent that targets rapidly dividing cancer cells. Together, the two drugs form what is referred to as an antibody-drug conjugate. T-DXd has shown impressive results against HER2-amplified mCRC in several studies, most importantly the DESTINY-CRC01 study. The National Comprehensive Cancer Network (NCCN) guidelines now recommend this treatment in combination with other targeted therapies for RAS/BRAF wild type, HER2-amplified mCRC. However, it is still recommended that patients who have this subtype of mCRC to consider clinical trials whenever possible.
Take away message:
Since HER2 amplifications are rare in patients with mCRC, advances in the treatment for this subset of patients are unlikely to occur at a rapid pace. However, its therapeutic importance justifies routine biomarker testing, and numerous trials are currently underway to investigate the combination of HER2-directed therapies with first- or second-line chemotherapy for mCRC patients.
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Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3(99):99ra86.
 National Comprehensive Cancer Network. Colon Cancer v3.2021. Accessed December 17, 2021. https://www.nccn.org/patients/guidelines/content/PDF/colon-patient.pdf