Her2-neu: a target in lung cancer?

In addition to the steady flow of new cytotoxic drugs for lung cancer during the last decade, the elegant concept of targeted agents has in recent years become a source of optimism and pitfalls. Among all the targets, Her2-neu is a typical example of how preclinical data can be translated into clinical progress. Her2-neu in breast cancer: the ideal model Erb-B2 (Her2-neu) is a 185 kDa glycoprotein with tyrosine kinase activity. This protein is a member of the ErbB receptor family that also includes ErbB1 (EGFr), ErbB3 and ErbB4. The implication of Her2-neu in mammary carcinogenesis has been shown in vitro [1] and in vivo [2]. Since then, most of the studies focusing on ErbB2 have been carried out in breast cancer. In this model, it has been shown that ErbB2 overexpression was associated with poor prognosis in some subsets of patients [3, 4] and with tamoxifen resistance [5]. Since ErbB2 overexpression was involved in mammary carcinogenesis, the idea has emerged that its inhibition could lead to tumor regression. Monoclonal anti-ErbB2 antibodies have been developed in this setting. Preclinical studies that tested anti-Her2-neu antibodies have shown that (i) injection of mono-clonal anti-Her2neu antibodies induce tumor regressions in mice and (ii) the anti-Her2neu antibody induces tumor cell growth inhibition in vitro. Following these data, a humanized monoclonal antibody directed against Her2-neu (trastuzumab) has been tested in clinical trials. The pivotal trial was published in the New England Journal of Medicine in 2001 [6]. This randomized trial compared anthracycline-or taxane-based chemotherapy versus the same chemotherapy plus trastuzumab. The results showed that the addition of trastuzumab increased response rates (50% versus 34%), time to progression (7.4 versus 4.6 months) and overall survival (25 versus 20 months). Some technical and logistical considerations must be put forward. This trial included patients presenting weak to moderate Her2-neu overexpression (coded as 2+) and more than moderate Her2-neu overexpression (3+) in >10% of tumor cells while 70–80% of tumors were coded 3+. This restriction allowed the recruitment of 469 patients during a 2-year period. Encouraged by these exciting data, investigators have looked at potential indications of trastuzumab in other cancers, including non-small-cell lung cancer (NSCLC). Her2-neu in lung cancer: is the mammalian model adequate in bronchial tumors? Some studies have shown that a small subset of NSCLC over-express Her2-neu. Nevertheless, the exact percentage of Her2-neu overexpression in NSCLC is difficult to assess since papers report overexpression rates ranging …