HER2-positive male breast cancer: an update

Abstract

Although rare, male breast cancer (MBC) remains a substantial cause for morbidity and mortality in men. Based on age frequency distribution, age-specific incidence rate pattern, and prognostic factor profiles, MBC is considered similar to postmenopausal breast cancer (BC). Compared with female BC (FBC), MBC cases are more often hormonal receptor (estrogen receptor/progesterone receptor [ER/PR]) positive and human epidermal growth factor receptor 2 (HER2) negative. Treatment of MBC patients follows the same indications as female postmenopausal with surgery, systemic therapy, and radiotherapy. To date, ER/PR and HER2 status provides baseline predictive information used in selecting optimal adjuvant/neoadjuvant therapy and in the selection of therapy for recurrent or metastatic disease. HER2 represents a very interesting molecular target and a number of compounds (trastuzumab [Herceptin®; F. Hoffmann-La Roche, Basel, Switzerland] and lapatinib [Tykerb®, GlaxoSmithKline, London, UK]) are currently under clinical evaluation. Particularly, trastuzumab, a monoclonal antibody which selectively binds the extracellular domain of HER2, has become an important therapeutic agent for women with HER2-positive (HER2+) BC. Currently, data regarding the use of trastuzumab in MBC patients is limited and only few case reports exist. In all cases, MBC patients received trastuzumab concomitantly with other drugs and no severe toxicity above grade 3 was observed. However, MBC patients that would be candidate for trastuzumab therapy (ie, HER2+/ER+ or HER2+/ER- MBCs) represent only a very small percentage of MBC cases. This is noteworthy, when taking into account that trastuzumab is an important and expensive component of systemic BC therapy. Since there is no data supporting the fact that response to therapy is different for men or women, we concluded that systemic therapy in MBC should be considered on the same basis as for FBC. Particularly in male patients, trastuzumab should be considered exclusively for advanced disease or high-risk HER2+ early BCs. On the other hand, lapatinib (Tykerb), a novel oral dual tyrosine kinase inhibitor that targets both HER2 and epidermal growth factor receptor, may represent an interesting and promising therapeutic agent for trastuzumab-resistant MBC patients.

Keywords: lapatinib; target therapy; trastuzumab.

Figure 1

HER family receptors. Epidermal growth factor family (ErbB) receptors are characterized by an extracellular domain (ECD), consisting of two Leu-rich ligand-binding subdomains (LR) and two Cys-rich subdomains (CR), a α-helical transmembrane domain and a intracellular domain (ICD), comprising the catalytic protein tyrosine kinase subdomain (PTK) and multiple regulatory tyrosine residues which become phosphorylated on receptor activation. The crosses on the human epidermal growth factor receptor 2 (HER2) ligand-binding domains indicate their lack of functionality and on HER3 protein tyrosine kinase subdomain indicate that it is catalytically inactive.

Figure 2

HER2 pathway. Ligand binding to the extracellular domain of human epidermal growth factor receptor (HER1/3/4) stabilizes the formation of active HER2 heterodimers. Transphosphorylation of tyrosine residues within the intracellular domains results in kinase domains activation. Phosphorylation creates binding sites for adaptor or effector proteins (SOS and PI3K) that activate mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-Akt pathways. These pathways result downstream in transcription of genes driving cell proliferation, migration, differentiation, and apoptosis.

Figure 3

Mechanisms of action of trastuzumab. A) Trastuzumab may cause immune activation by recruiting natural killer (NK) cells, leading to cancer cells lysis. B) Trastuzumab may physically block either human epidermal growth factor receptor 2 (HER2) homodimerization or heterodimerization with other HER family partners. C) Trastuzumab may inhibit the shedding of HER2 extracellular domain, preventing the formation of p95. D) Trastuzumab may reduce the signaling from downstream pathways by the internalization and degradation of HER2.

Figure 4

Proposed algorithm for the treatment of operable male breast cancer. Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; CT, chemotherapy; HT, hormonal therapy. Note: ¹T ≥ 1 cm/N+; Levels of evidence, there is insufficient evidence to support the use of trastuzumab in early male breast cancer.

Figure 5

Proposed algorithm for the treatment of locally advanced (inoperable) male breast cancer. Abbreviations: LABC, locally advanced breast cancer; CT, chemotherapy; HT, hormonal therapy; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2. Note: ¹HER2-positive tumors; ²ER positive and/or PR positive; Levels of evidence, there is insufficient evidence to support the use of trastuzumab or neoadjuvant CT in male breast cancer setting.