HER2-Targeted Therapies in Metastatic Colorectal Cancer
Summary
Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor whose amplification or overexpression drives tumour cell proliferation and survival. In metastatic colorectal cancer (mCRC), HER2 alterations occur in a subset of patients, often in a RAS/BRAF wild-type background, and are implicated in resistance to anti-EGFR agents. Targeted strategies include dual monoclonal antibody blockade, antibody–drug conjugates and combination regimens with pathway inhibitors. Recent advances have centred on precise patient selection, using tissue and liquid biopsies to confirm HER2 status, and on optimising combinations to overcome adaptive resistance. These developments bear global significance by expanding personalised treatment options and improving outcomes in a disease that remains a major cause of cancer mortality worldwide.
Research from Nature Portfolio
Final analysis of a phase 2 trial of trastuzumab deruxtecan in HER2-positive mCRC reported an objective response rate of 45.3% in patients with high HER2 expression, median progression-free survival of 6.9 months and overall survival of 15.5 months, establishing antibody–drug conjugates as an active approach. Separately, a circulating tumour DNA-guided phase 2 study demonstrated that pertuzumab plus trastuzumab achieved confirmed response rates of approximately 30% in both tissue- and ctDNA-confirmed HER2-amplified mCRC, and showed that early ctDNA dynamics can stratify responders, highlighting the utility of liquid biopsy for treatment selection and monitoring.
HER2-Targeted Therapies in Metastatic Colorectal Cancer publication trend
The graph below shows the total number of articles in her2-targeted therapies in metastatic colorectal cancer across all publications each year (not limited to Nature Index journals).
Technical terms
HER2: A receptor tyrosine kinase involved in cell growth signalling, encoded by the ERBB2 gene.
Antibody–drug conjugate: A targeted therapy linking a monoclonal antibody to a cytotoxic payload.
Circulating tumour DNA (ctDNA): Fragments of tumour-derived DNA detected in plasma, used for non-invasive genotyping.
Objective response rate (ORR): The proportion of patients with tumour size reduction meeting predefined criteria.
Progression-free survival (PFS): The interval during which a patient’s disease does not worsen.
Overall survival (OS): The duration from treatment start to death from any cause.
Immunohistochemistry (IHC): A technique using antibodies to detect protein expression in tissue sections.
In situ hybridisation (ISH): A method for visualising specific DNA or RNA sequences within tissue samples.
PI3K/AKT pathway: A signalling cascade promoting cell growth and survival, often co-activated with HER2.
References
- Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nature Communications (2023).
- Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial. Nature Medicine (2021).
- HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials. The Journal of Pathology (2016).
- Molecular profiling of metastatic colorectal tumors using next-generation sequencing: A single-institution experience. Oncotarget (2017).
- HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer. Oncotarget (2015).
- PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells. Gut (2021).
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