Serum markers in small cell lung cancer: opportunities for improvement

Lung cancer is one of the leading causes of death from malignancy worldwide. In particular small cell lung cancers, which comprise about 15-20% of all lung cancers, are extremely aggressive and cure rates are extremely low. Therefore, new treatment modalities are needed and detection at an early stage of disease, as well as adequate monitoring of treatment response is essential in order to improve outcome. In this respect, the use of non-invasive tools for screening and monitoring has gained increasing interest and the clinical applicability of reliable, tumor-related substances that can be detected as tumor markers in easily accessible body fluids is subject of intense investigation. Some of these indicators, such as high LDH levels in serum as a reflection of the disease, have been in use for a long time as a general tumor marker. To allow for improved monitoring of the efficacy of new therapeutic modalities and for accurate subtyping, there is a strong need for specific and sensitive markers that are more directly related to the biology and behavior of small cell lung cancer. In this review the current status of these potential markers, like CEA, NSE, ProGRP, CK-BB, SCC, CgA, NCAM and several cytokeratins will be critically analyzed with respect to their performance in blood based assays. Based on known cleavage sites for cytoplasmic and extracellular proteases, a prediction of stable fragments can be obtained and used for optimal test design. Furthermore, insight into the synthesis of specific splice variants and neo-epitopes resulting from protein modification and cleavage, offers further opportunities for improvement of tumor assays. Finally, we discuss the possibility that detection of SCLC related autoantibodies in paraneoplastic disease can be used as a very early indicator of SCLC.