[Role of predictive pathology in oncology--example of new therapies targeting EGFR].
New cancer-specific therapies are based on specific molecular alterations of malignant tumors which are targeted by small inhibitory molecules or specific antibodies. During the development of these agents potential molecular targets are characterized for their expression and importance for pathogenesis and clinical course of the disease. Frequently the assumption is made that the degree of expression of the target protein or the molecular alteration of the target gene allows a prediction if a certain patient will profit from the therapy against this specific protein or not. The first example was that breast cancer patients with overexpression and/or amplification of Her-2 respond to a Her-2-specific antibody (Herceptin) therapy. The expression or activation of the Epidermal Growth Factor Receptor (EGFR, Her-1) are altered in many epithelial tumours and clinical studies indicate that they have important roles in tumor aetiology and progression. Several EGFR-specific monoclonal antibodies and specific tyrosine kinase inhibitors were developed in the last years. Cetuximab is approved for the treatment of metastatic colorectal cancer and advanced squamous cell carcinoma of the head and neck and is investigated in numerous trials for other tumors. The expression of EGFR in the tumor was a prerequisite for the therapy in the first trials, giving the pathologist a central role in treatment decision. However, recent data clearly demonstrate that the degree of EGFR expression does not correlate with therapy response. Therefore a therapy should be not denied to a individual patient solely because of lack of EGFR expression in the tumor. Tyrosine kinase inhibitors (e. g. Gefitinib, Erlotinib) are effective in the treatment of non small cell lung cancer and also investigated in ongoing trials in many cancer types. The correlation of therapy response with both specific molecular alterations (EGFR tyrosine kinase domain mutations) and clinicopathological features (Asian ethnicity, women, non-smokers, bronchioloalveolar differentation) is a good example of the potential role of predictive molecular pathology in the future.
Hartmann
Arndt
A
Institut für Pathologie, Universität Regensburg.
D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human