Heterogeneous clinical and pathological landscapes of HER2 positive colorectal cancer

ABSTRACT

Introduction: Metastatic (m) colorectal cancer (CRC) can be divided into specific subgroups under the ‘one gene, one drug’ paradigm of precision medicine. Progress of targeted therapy in mCRC patients significantly improved the overall survival rate, notably by therapy targeting of EGFR signaling in RAS wild-type mCRC patients. Activation of the HER2 pathway is an important mechanism of resistance for anti-EGFR therapy.

Area covered: Inhibition of HER2 with monoclonal antibodies and/or tyrosine kinase inhibitors induces tumor responses in partial HER2-positive CRC refractory to standard systemic therapy. This manuscript aimed to provide an overall insight of the HER2 expression pattern and highlighted specific clinicopathological and molecular features involved in mCRC. In addition, we summarize preclinical and clinical trials in HER2-positive mCRC.

Expert opinion: The status and progression of HER2-positive gastric cancer and breast cancer and anti-HER2 therapy have been reported widely. However, the understanding of HER2-positive CRC models which may guide future therapeutic decision-making is poor. Therefore, it is essential to summarize the existing research to extract similarity and difference among various studies.

KEYWORDS:

• Colorectal cancer
• erbb2
• clinicopathological features
• targeted therapy
• precision medicine

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• HER2 status of tumor samples can be assessed by IHC, FISH and NGS comprehensively.

• The prevalence of HER-2 amplification and mutation varied in CRC based on the differences in examination methods and objective criteria.

• HER2 positive CRC patients exit heterogeneous clinical and pathological features.

• Several preclinical studies revealed that the HER2-amplified colorectal PDX model could respond to various HER2-targeted therapies alone or in combination.

• A number of published and ongoing clinical trials of anti-HER2 targeted therapy in Her-2 positive mCRC showed effective survival outcomes, which should be further validated by more large-scale randomized controlled trial.

• The activation of HER2-dependent intracellular signaling demonstrates as a mechanism of resistance to anti-EGFR therapies in preclinical and clinical models of mCRC.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China (81972280), the Natural Science Foundation of Shanghai (19ZR1441800), Outstanding Clinical Discipline Project of Shanghai Pudong (PWYgy2018-02) and Shanghai ‘Rising Stars of Medical Talent’ Youth Development Program (yyxx201901).