HER2-targeted therapy: an emerging strategy in advanced colorectal cancer

ABSTRACT

Introduction: Colorectal cancer (CRC) is one of the most common malignant tumors; it is a focus of research globally, but the identification of clinically actionable oncogenic drivers remains elusive. Human epidermal growth factor receptor 2 (HER2) activation is present in approximately 5% of CRC and has acquired resistance to epidermal growth factor receptor (EGFR)-targeted therapy. Early clinical trials suggest an emerging role for personalized HER2-targeted therapy in a subset of metastatic CRC.

Areas covered: This manuscript reviews the relevance of HER2 activation in CRC and its potential role as a target for therapy. A literature search was conducted in June 2018 of MEDLINE and EMBASE databases for published preclinical and clinical studies; abstracts of international cancer meetings (AACR, ASCO, and ESMO) were also reviewed.

Expert opinion: HER2 is activated in a small but relevant proportion of CRC patients (particularly left-side, RAS wild-type, anti-EGFR resistant tumors). Dual HER2 blockade with monoclonal antibodies (mAbs) (trastuzumab and pertuzumab) or the combination of mAbs with tyrosine kinase inhibitors (trastuzumab and lapatinib) induces durable tumor responses in about one-third of HER2-positive CRC refractory to standard systemic therapy. Although immature, these results are remarkable and anticipate an expanding role for HER2 as a therapeutic target in CRC.

KEYWORDS:

• Colorectal cancer
• HER2 amplification
• overexpression
• mutation
• personalized therapy
• prognostic and predictive biomarker
• EGFR resistance
• mAbs

Article highlights

• The clinical management of advanced CRC has substantially changed over the last decades determining significant improvements of patients’ survival. However, most drugs (cytotoxic agents and antiangiogenics) are still employed in molecularly unselected tumors and are not effective in a significant proportion of patients.

• At present, RAS mutations, to exclude EGFR-targeted therapy, and MSI, to select patients for immunotherapy, are the only clinically validated biomarkers to assist physicians in the selection of more personalized and effective therapies. In this context, the identification of a clinically actionable oncogenic driver is a relevant step forward.

• HER2 activation by amplification or mutation is present in about 5% of CRC and has been involved in primary and acquired resistance to EGFR-targeted therapy.

• Encouraging recently reported clinical trials have shown that dual HER2 blockade with mAbs (trastuzumab and pertuzumab) or the combination of mAbs with TKIs (trastuzumab and lapatinib) induces durable tumor responses in about one-third of HER2-positive mCRC patients’ refractory to standard systemic therapy. Although yet immature, these results are remarkable and anticipate an expanding role for HER2 as a therapeutic target in CRC.

• Many other HER2-targeted strategies are being actively explored, including novel TKIs, antibody-drug conjugates, vaccines, donor-derived NK cells, and anti-HER2 CAR-modified T cells. Small randomized trials are also underway to compare dual HER2 blockade to more standard chemotherapy-based treatment approaches (irinotecan and cetuximab) in RAS wild-type, HER2-positive mCRC patients. The results of these trials shall help elucidate the optimal strategy and timing of HER2-targeted treatment in these patients.

• Efforts to standardize HER2 assessment in CRC are warranted

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Declaration of interest

R Garcia-Carbonero has disclosed personal and/or research funding from Ipsen, Novartis, Pfizer, Adacap, Roche, Sanofi-Aventis, Merck, M.S.D., Amgen, Bayer, Servier and Bristol-Myers Squibb. The authors have no other 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.

Additional information

Funding

This paper was not funded