Chapter 085. Neoplasms of the Lung (Part 4) Inherited Predisposition to Lung Cancer While an inherited predisposition to develop lung cancer is not common, several features suggest a potential for familial association. People with inherited mutations in RB (patients with retinoblastomas living to adulthood) and p53 (Li- Fraumeni syndrome) genes may develop lung cancer. First-degree relatives of lung cancer probands have a two- to threefold excess risk of lung cancer or other cancers, many of which are not smoking-related. An as yet unidentified gene in chromosome region 6q23 was found to segregate in families at high risk of developing lung cancer of all histologic types. Finally, certain polymorphisms of the P450 enzyme system (which metabolizes carcinogens) or chromosome fragility (mutagen sensitivity) genotypes are associated with the development of lung cancer. The use of any of these inherited differences to identify persons at very high risk of developing lung cancer would be useful in early detection and prevention efforts. Therapy Targeted at Molecular Abnormalities A detailed understanding of the molecular pathogenesis should be applicable to new methods of early diagnosis, prevention, and treatment of lung cancer. Two examples of this translation involve EGFR and vascular endothelial growth factor (VEGF). EGFR belongs to the ERBB (HER) family of protooncogenes, including EGFR (ERBB1), Her2/neu (ERBB2), HER3 (ERBB3), and HER4 (ERBB4), cell-surface receptors consisting of an extracellular ligand- binding domain, a transmembrane structure, and an intracellular tyrosine kinase (TK) domain. The binding of ligand to receptor activates receptor dimerization and TK autophosphorylation, initiating a cascade of intracellular events, leading to increased cell proliferation, angiogenesis, metastasis, and a decrease in apoptosis (Chap. 80). Overexpression of EGFR protein or amplification of the EGFR gene has been found in as many as 70% of NSCLCs. Activating/oncogenic mutations (usually a missense or a small deletion mutation) in the TK domain of EGFR have been identified. These are found most commonly in women, East Asians, patients who have never smoked, and those with adenocarcinoma and BAC histology. This is also the group of patients who are most likely to have dramatic responses to drugs that inhibit TK activation [tyrosine kinase inhibitors (TKIs)]. EGFR mutations are almost never found in cancers other than lung cancer, nor in lung cancers that have KRAS mutations. These EGFR mutations, often associated with amplification of the EGFR gene, usually confer sensitivity of these lung cancers to EGFR TKIs (such as gefitinib or erlotinib), resulting in clinically beneficial tumor responses that unfortunately are still not permanent. In many cases the development of EGFR TKI resistance is associated with the development of another mutation in the EGFR gene (T790M mutation), or amplification of the c-met oncogene. However, other drugs with EGFR TKI activity are in development to which the lung cancers with these resistance mutations will respond as are drugs targeting c-met or its pathways. The discovery of EGFR mutation/amplification driving lung cancer growth and the dramatic response of these tumors to oral EGFR TKI therapy has prompted a widespread search for other drugs "targeted" against oncogenic changes in lung cancer. An important example of another such target is VEGF, which, while not mutated, is inappropriately produced by lung cancers and stimulates tumor angiogenesis (Chap. 80). VEGF is often overexpressed in lung cancer, and the resulting increase in tumor microvessel density correlates with poor prognosis. A monoclonal antibody to the VEGF ligand, bevacizumab, has significant antitumor effects when used with chemotherapy in lung cancer (see below). Molecular Profiles Predict Survival and Response Just as the presence of EGFR TK domain mutations and amplification is an excellent predictor of response to EGFR TKIs, molecular predictors of response to standard chemotherapy and other new targeted agents are being sought. Lung cancers can be molecularly typed at the time of diagnosis to yield information that predicts survival and defines agents to which the tumor is most likely to respond. One example is the identification of alterations in lung cancer DNA repair pathways that may predict resistance to chemotherapy. Patients whose tumors exhibit low activity of the excision-repair-cross complementation group 1 (ERCC1) proteins typically have a worse prognosis as they are unable to repair DNA adducts in the tumor. However, retrospective analysis shows that when treated with cisplatin, patients with tumors expressing low levels of ERCC1 activity appear to do better, as they are unable to repair DNA adducts caused by cisplatin, while patients with high ERCC1 activity actually do worse with cisplatin-based chemotherapy. Although these protein or gene expression "signatures" have yet to be validated in large prospective studies, it is possible that such information will allow future therapy to be tailored to the characteristics of each patient's tumor. Mass spectroscopy-based proteomic studies have identified unique protein patterns in the serum of patients, one of which allows for early diagnosis, while another can predict sensitivity or resistance to drugs. However, such methods have not been validated and may be difficult to implement in a patient care setting. . Chapter 085. Neoplasms of the Lung (Part 4) Inherited Predisposition to Lung Cancer While an inherited predisposition to develop lung cancer is not common, several. cancers other than lung cancer, nor in lung cancers that have KRAS mutations. These EGFR mutations, often associated with amplification of the EGFR gene, usually confer sensitivity of these lung. genotypes are associated with the development of lung cancer. The use of any of these inherited differences to identify persons at very high risk of developing lung cancer would be useful in