Investigational ErbB-2 tyrosine kinase inhibitors for the treatment of breast cancer

ABSTRACT

Introduction: ErbB2 overexpression and/or gene amplification is present in 20% of all breast cancers and characterizes an aggressive form of this disease. Despite the availability of several active drugs that have yielded substantial survival improvements, most patients with ErbB2-positive metastatic disease will develop tumor progression, either because of primary or acquired resistance. Therefore, research has focused on drugs that can more efficiently interfere with ErbB2 and with other members of the epidermal growth factor receptor family.

Areas covered: This review focuses on those investigational drugs that inhibit ErbB2 tyrosine kinase activity (TKIs) for treating breast cancer.

Expert opinion: ErbB-targeting TKIs show encouraging activity in patients with ErbB-positive tumors that are resistant to conventional ErbB-therapies (mostly trastuzumab), confirming pre-clinical observations. Efficient interference with the ErbB-network signaling implies also a potential use in ErbB2-normal tumors, where the phenotype is sustained by ErbB-aberrant signaling. Finally, early data suggests that ErbB-targeting TKIs could be active in treating patients with activating ErbB2 mutations. Ongoing and future research efforts should elucidate what is, according to the peculiarities of these compounds, their positioning in the treatment of women with breast cancer.

KEYWORDS:

• Breast cancer
• ErbB1
• ErbB2
• ErbB3
• ErbB4
• tyrosine-kinase inhibitors

Article highlights.

• Currently registered drugs targeting the ErbB2 receptors have significantly improved the outlook of women with BC bearing ErbB2 overexpression

• Resistance to these compounds is mediated by several mechanisms, including increased aberrant signaling through ErbB2 and other members of the ErbB family of receptors

• The clinical activity of lapatinib, the first TK-inhibitor against ErbB1 and ErbB2 in the clinic, prompted studies aimed at establishing newer compounds that could more efficiently target the TK-activity of ErbB receptors

• Initial clinical experience with two irreversible, pan-ErbB inhibitors (afatinib and neratinib) appears promising in patients resistant to prior ErbB-targeting conventional strategies

• A variety of compounds that are reversible or irreversible, selective or pan-ErbB TKIs are currently under investigation and clinical results are pending

• For a full appreciation of the advantage of ErbB2-targeting TKIs compared to other anti-ErbB2 strategies, biomarker studies are eagerly awaited

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Financial and conflicting interests disclosure

The authors are supported by the Italian Ministry of Health and the Italian Association for Cancer Research (AIRC). F Montemurro is member of the speakers’ bureau of Hoffmann La Roche and Novartis. G Zucchini is supported by the FPRC (ONLUS) fondi 5 mille 2012 Ministero della Salute while A Nuzzo is supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) Investigator Grant IG-2013 Ref. 14,451. 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 apart from those disclosed.