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Trastuzumab, a humanized monoclonal antibody against the HER-2 receptor, was the first targeted therapy for HER-2 positive breast cancer. The treatment of HER-2 positive breast cancer in monotherapy, but mainly in combination with cytostatics trastuzumab, showed significant efficacy and increased the time to progression/relapse and overall survival. On the other hand, despite it being administered to only a selected patient population, the response rate varies in range and duration due to the primary or acquired tumor resistance to trastuzumab. Several mechanisms contributing to the drug resistance are presumed and overcoming strategies are in development. In connection with the drug resistance there are the mechanisms of trastuzumab's action on tumor cells and the search for feasible biomarkers in order to predict the response of trastuzumab-based targeted therapies. Furthermore, we present here the actual possibilities to overcome primary or acquired trastuzumab resistance.

Breast cancer is the second most common type of cancer in women after skin cancer. Between 15 to 25% of breast cancers are characterized by overexpression of human epidermal growth factor receptor 2 (HER-2). HER-2 overexpression has been associated with more aggressive tumor phenotype, poor prognosis and shortened survival. Humanized monoclonal antibody trastuzumab was the first targeted therapy against HER-2 used in clinical practice. Trastuzumab has significantly improved the prognosis of HER-2 overexpressing breast cancer, is effective as a single agent or in combination with chemotherapy, has proven efficacy in the treatment of metastatic breast cancer and also in adjuvant and neoadjuvant setting. Despite trastuzumab success in treatment, several important questions are still not clearly answered. The most discussed issues are the optimal selection of patients with regard to HER-2 testing, combination of trastuzumab with anthracyclines, comparison of the efficacy of trastuzumab in combination with different chemotherapy regimens, the ideal scheduling of trastuzumab administration, the duration of treatment, especially in adjuvant therapy, continuation of trastuzumab treatment beyond disease progression and after development of brain metastasis. Trastuzumab is generally well tolerated and the clinically most important adverse effect is potential for congestive heart failure, therefore careful cardiac monitoring is required for all patients receiving this therapy. Aim of this article is to summarize the results of clinical trials with trastuzumab and refer to some issues concerning trastuzumab administration and toxicity.

Backgrounds: Neoadjuvant concomitant chemoradiotherapy has become a standard treatment of locally advanced rectal adenocarcinomas (LARA). It leads to shrinkage of the tumor mass and subsequently to an increase in complete resections (R0 resections), increasing a feasibility of sphincter-sparing intervention avoiding colostomy. It is based on concurrent application of fluoropyrimidines (5-fluorouracil, capecitabine) and radiotherapy (45 - 50,4 Gy). It shows less acute toxicity and improves local control rate in comparison to adjuvant treatment. Unfortunately, neoadjuvant chemoradiotherapy is not beneficial for all patients. The treatment response ranges from a complete pathological remission (pCR, ypT0ypN0) to a resistance. It is reported that cca 15 percent of patients with advanced rectal cancer show pCR which is indicative of improved long-term prognosis., Design: The following is a review of the significance of neoadjuvant concomitant chemoradiotherapy in the treatment algorithm of patients with LARA and summary of potentional clinical-pathological and molecular markers of response prediction to neoadjuvant therapy. The most important clinical studies concern serum tumor markers levels, clinical lymph node classification. The components of the carcinogenic pathways are explored, including oncogenes, tumor supressor genes, microsatellite instability (MSI) and potentional markers involved in apoptosis, angiogionesis, proliferation as well as metastasis and invasion, are reviewed. Finally, the role of specific enzymes associated with the metabolism of fluoropyrimidines are examined., Conclusions: No one marker has been consistently identified as clinically applicable. Studies designed to determine the potentional markers are hampered by various techniques as well as tumor heterogenity and recent scientific approach--studying individual molecular markers. Gene expression profiling analysis of multiple genes from the same tumor is becoming reality. We suppose that this assessment will lead in future in finding combination of markers for predicting prognosis and response to therapy in rectal cancer.

Background: Neoadjuvant concomitant chemoradiotherapy has become a standard treatment of locally advanced rectal adenocarcinomas (LARA). It can reduce tumor volume, thus increases a feasibility of sphincter-sparing surgery, shows less acute toxicity, improves local control rate. It is based on fluoropyrimidines (5-fluorouracil, capecitabine) with concurrent radiotherapy. The aim of the study was to evaluate the capability of gene expression method to identify nonresponders (NR) pretherapeutically., Methods and Results: 17 patients with LARA, clinical stage II, III according to IUCC were enrolled into our pilot study. Response to therapy was determined clinically by transrectal ultrasonography and CT/MRI before and after therapy and histopathologically by TRG (tumor regression grade) according to Mandard. Patients with TRG 1-2 were included to responders group (R) and patients with TRG 4-5 composed NR group. Gene expression levels of 440 genes were obtained by low-density oligonucleotide microarrays. Gene expression data analysis based on SAM (Significance Analysis of Microarrays) and t-test methods identified 8 genes (RB1, RBBP4, HYOUI, JUNB, MDM4, CANX, MMP2, TCF7L2) significantly upregulated in NR., Conclusions: Validation of identified changes on the mRNA level (Real-Time PCR) and on protein level (immunohistochemistry) is ongoing. We suggest that low-density oligonucleotide microarray technology could contribute to individualize the therapy of patients with LARA.