Tumor biomarkers: PSA and beyond.

Laboratory medicine plays an increasingly important role in the management of cancer patients (1, 2) . In none of the tumors has the advent of biomarkers changed the treatment in a more fundamental way than the introduction of prostate specifi c antigen (PSA) which has virtually transformed the management of prostate cancer. Prostate cancer represents a major public health problem. The last decade has witnessed a hitherto unprecedented progress in the treatment of pro state cancer, including surgical therapy, radiation therapy or systemic treatment. In the case of prostate cancer, laboratory medicine has contributed not only to an early diagnosis, but had an equally important impact on the management of the tumor during the entire course of the disease. In fact, the introduction of PSA has likely changed the course of the treatment of this tumor to the extent that we now distinguish between the ‘ pre-PSA era ’ and the ‘ PSA era ’ . The assessment of the disease course and the effect of therapy in patients with prostate cancer are currently based largely on serial PSA measurements. In patients after the radical therapy of the primary tumor, detection of a sustained rise of PSA is the basis for the diagnosis of relapse, termed biochemical relapse, and leads to the institution of therapy even if there is no evidence of a tumor on the imaging studies. Early diagnosis that results from the widespread use of PSA in the screening allowed more patients with localized tumors to be treated with local treatments, i.e., surgery or radiation therapy. Major progress has been achieved in the systemic treatment of prostate cancer. While metastatic pro state cancer still remains an incurable disease, anticancer therapies may prolong the patient survival, sometimes for several years. Hormonal therapy based on either surgical or medical androgen deprivation has been the mainstay of the treatment of metastatic prostate cancer for decades. Metastatic prostate cancer progressing despite castration levels of androgens, may respond to second-line hormonal therapies, however, these responses tend to be of short duration. Cytoxic chemotherapy has been offered to patients with a tumor progressing despite hormonal therapy. In 2004 two large clinical trials with docetaxel have been published proving that chemotherapy actually prolongs survival in metastatic prostate cancer (3, 4) . Duration of response to docetaxel is, again, limited. More recently, two new agents, carbazitaxel (5) and abiraterone (6) , were shown to prolong survival in patients with metastatic castration-resistant prostate cancer progressing after docetaxel. Carbazitaxel is another cytotoxic agent that in a randomized trial signifi cantly prolonged survival in patients with metastatic castration-resistant prostate cancer failing docetaxel (5) . Abiraterone is a hormonal agent that also prolonged survival in patients with metastatic castrationresistant prostate cancer after the failure of docetaxel (6) . In addition, the administration of autologous dendritic cells has been shown to prolong survival in patients with metastatic castration-resistant prostate cancer (7) . The introduction of these new therapies obviously results in new requirements for laboratory testing to assess the effi cacy or to monitor the toxi city of the treatment. PSA is a member of kallikrein and kallikrein-related peptidases (KLK) family of proteases that is the focus of a review in the present issue of Clinical Chemistry and Laboratory Medicine (CCLM ) (8) . KLK genes are clustered on the long arm of chromosome 19 and share exon/intron organization and similarity of protein sequences (8) . KLK family comprises 15 homologous, single-chain proteases that are expressed by glandular epithelial cells and participate in a range of physiological and pathological processes, including semen liquefaction, skin desquamation, tooth maturation and also tumor progression (8) . PSA (or KLK3) is currently the best characterized KLK family member and only KLK protease that is widely used as a biomarker. As outlined above, the utilization of PSA as a biomarker in the management of patients with prostate cancer represents a unique situation across the entire spectrum of malignant tumors. Circulating PSA is mostly complexed with α 1 -antichymotrypsin, α 2 -macroglobulin or α 1 -protease inhibitor (complexed PSA), while unbound PSA that is referred to as free PSA comprises of single-chain nonclipped forms called intact PSA. Differential information may be derived from measuring total PSA and free PSA as the elimination differs between complexed PSA and free PSA. Serial PSA measurement or correlation with other clinical parameters led to the introduction of concepts of PSA velocity, PSA density or PSA doubling time. Importantly, the expression of PSA is under the control of androgen receptor (9) . Thus, the changes of PSA concentrations in patients treated with hormonal therapy may be associated with the reduction of tumor mass with different kinetics compared to cytotoxic chemotherapy. Despite the fact that the decrease of PSA concentration is usually less dramatic after cytotoxic chemotherapy compared to hormonal treatment, the change of PSA concentration is an established surrogate endpoint in patients with castration-resistant prostate cancer treated with docetaxel (10) . However, the daily clinical practice has taught us that the changes of serum PSA concentrations must be interpreted with caution as a phenomenon of