Cic edizioni internazionali
Reviews in Oncology

Beyond trastuzumab: what does it?

Review, 5 - 14
Tag this article
Enhanced HTML Full text PDF
Human epidermal growth factor receptor 2 (HER-2) gene amplification or protein overexpression occurs in 20% to 25% of breast tumors, often leading to an aggressive disease course and poor clinical outcomes. Successful targeting of HER-2-positive tumors in preclinical models with trastuzumab has translated to the clinic.
Overexpression of the HER-2 represents a biological subclass of breast cancer (BC) with distinct molecular alterations, clinical behavior, and response to systemic therapy. Trastuzumab is a monoclonal antibody directed against HER-2 which has revolutionized the management of both early and advanced BC. It may exert its anti-cancer effects through inhibition of intracellular signaling, up regulation of p27, impaired angiogenesis, induction of immune-mediated destruction, and blockade of cleavage of the extracellular domain of HER-2. In spite of its robust clinical activity, most women with metastatic HER-2 overexpressing BC eventually progress on trastuzumab therapy. Possible mechanisms of resistance include: altered receptor antibody interaction, PTEN loss and enhanced Akt signaling, p27 loss, signaling through other receptors.
Preclinical experiments, clinical experience with the use of trastuzumab beyond progression, and a recent phase III clinical trial with Lapatinib, a dual EGFR/HER-2 tyrosine kinase inhibitor, demonstrate that the HER-2 signaling axis remains an important therapeutic target even after progression on trastuzumab. A variety of novel strategies are currently in development to exploit this pathway following the onset of resistance, such as receptor antibodies, sheddase inhibitors, signal transduction inhibitors, heat shock protein inhibitors, proteasome inhibitors, anti-angiogenic agents, and immunostimulatory therapies, either as single agents or in combination with trastuzumab. Rational clinical trial design, with attention to appropriate patient selection and prospective collection of biological material, is needed to ensure that the new generation of anti-HER-2 targeted therapies realizes its promise in the treatment of trastuzumab-resistant disease.

Vol. 3 (No. 1) 2015 January - December

  1. Pregnancy in breast cancer survivors: safety and feasibility
    Stani S.C., Sini V.
    doi: 10.11138/rio/2015.1.5.105
Last Viewed articles: la lista degli ultimi x visitati.
  1. Beyond trastuzumab: what does it?
    Malaguti P., Vari S., Pellegrini D., Fabi A., Cognetti F.