Skin toxicity and quality of life in patients with metastatic colorectal cancer during first-line panitumumab plus FOLFIRI treatment in a single-arm phase II study

Background: Integument-related toxicities are common during epidermal growth factor receptor (EGFR)-targeted therapy. Panitumumab is a fully human monoclonal antibody targeting the EGFR that significantly improves progression-free survival when added to chemotherapy in patients with metastatic colorectal cancer who have wild-type (WT) KRAS tumours. Primary efficacy and tolerability results from a phase II single-arm study of first-line panitumumab plus FOLFIRI in patients with metastatic colorectal cancer have been reported. Here we report additional descriptive tolerability and quality of life data from this trial. Methods: Integument-related toxicities and quality of life were analysed; toxicities were graded using modified National Cancer Institute Common Toxicity Criteria. Kaplan-Meier estimates of time to and duration of first integument-related toxicity were prepared. Quality of life was measured using EuroQoL EQ-5D and EORTC QLQ-C30. Best overall response was analysed by skin toxicity grade and baseline quality of life. Change in quality of life was analysed by skin toxicity severity. Results: 154 patients were enrolled (WT KRAS n = 86; mutant KRAS n = 59); most (98%) experienced integument-related toxicities (most commonly rash [42%], dry skin [40%] and acne [36%]). Median time to first integument-related toxicity was 8 days; median duration was 334 days. Overall, proportionally more patients with grade 2+ skin toxicity responded (56%) compared with those with grade 0/1 (29%). Mean overall EQ-5D health state index scores (0.81 vs. 0.78), health rating scores (72.5 vs. 71.0) and QLQ-C30 global health status scores (65.8 vs. 66.7) were comparable at baseline vs. safety follow-up (8 weeks after completion), respectively and appeared unaffected by skin toxicity severity. Conclusions: First-line panitumumab plus FOLFIRI has acceptable tolerability and appears to have little impact on quality of life, despite the high incidence of integument-related toxicity

Predominance of CIN versus MSI in the development of rectal cancer at young age

BACKGROUND: Development of proximal and distal colorectal cancers involve partly different mechanisms associated with the microsatellite instability (MSI) and the chromosomal instability (CIN) pathways. Colorectal cancers in patients under 50 years of age represent about 5% of the total number of tumors and have been associated with an increased frequency of MSI tumors. However, MSI and CIN may play different roles in the development of colon cancer and rectal cancer, and we have specifically investigated their contribution to the development of rectal cancer at young age. METHODS: Thirty rectal cancers diagnosed before the age of 50 were characterized for DNA-ploidy, MSI, mutations of KRAS and CTNNB1 and immunohistochemical expression of p53, β-catenin and of the mismatch repair (MMR) proteins MLH1 and MSH2. RESULTS: DNA aneuploidy was detected in 21/30 tumors, KRAS mutations in 6 tumors, no mutations of CTNNB1 were detected but immunohistochemical staining for β-catenin showed nuclear staining in 6 tumors, and immunohistochemical expression of p53 was detected in 18 tumors. MSI was detected in 3/30 tumors, all of which showed and immunohistochemical loss of staining for the MMR protein MSH2, which strongly indicates a phenotype associated with hereditary nonpolyposis colorectal cancer (HNPCC). CONCLUSIONS: MSI occurs only in a small fraction of the tumors from young patients with rectal cancer, but when present it strongly indicates an underlying HNPCC-causing mutation, and other mechanisms than HNPCC thus cause rectal cancer in the majority of young patients

Rectal Cancer - Tumor Biology and Prognostic Markers

Colorectal cancer is one of our most common malignancies and the second leading cause of cancer death worldwide. About 1/3 of the tumors are located in the rectum. Treatment advances such as the introduction of the standardized surgical technique total mesorectal excision (TME), pre-operative radiotherapy, and adjuvant chemotherapy have reduced the previously high local recurrence rates and improved survival in rectal cancer patients, but despite these advances about 40% of the patients still die from disseminated disease. Rectal cancer evolves through an accumulation of genetic alterations in the tumor cells, and although multiple such changes have been characterized, the molecular markers have not yet gained widespread clinical use. The prognostic markers currently available fail to identify patients at risk for tumor recurrencies, which implies a need for refined prognostic tools. This thesis focuses on analysis of different molecular events in rectal cancer with correlations to prognosis. Papers I-II evaluate the novel serological markers suPAR and TIMP-1 analyzed in pre-treatment plasma samples from patients with rectal cancer. High suPAR and TIMP-1 values were associated with shorter survival and these markers may thus be of potential prognostic use. In paper III, we evaluated the tissue microarray technique (TMA) for immunohistochemistry (IHC) using the markers p53 and Ki-67. Good quality staining was obtained and TMA could reproduce the results obtained from whole-tissue sections. Paper IV presents IHC tumor profiling using TMA in rectal cancer with correlations to prognosis using the markers Ki-67, p53, Bcl-2, EGFR, ß-catenin, E-cadherin, MLH1, and MSH2. The cell adhesion molecules ß-catenin and E-cadherin significantly correlated with metastatic disease, whereas the other markers did not. In paper V, we studied 30 cancers from patients younger than 50 years at diagnosis with respect to molecular alterations associated with the microsatellite instability (MSI) and the chromosomal instability (CIN) pathways for colorectal cancer development. We found that microsatellite stable (MSS), aneuploid tumors with increased expression of p53 and ß-catenin predominate also among young rectal cancer patients. Only 10% of the tumors displayed MSI, all of which showed loss of expression for MSH2, which suggests presence of a mutation associated with hereditary nonpolyposis colorectal cancer (HNPCC). In summary, this thesis presents confirmatory data on the plasma levels of suPAR and TIMP-1 as presumptive prognostic markers in rectal cancer. In addition, we have demonstrated that the TMA-technique allows high-throughput immunostaining in rectal cancer. A TMA-based molecular profiling demonstrated that aberrant expression patterns frequently occur, and that the expression of the cell-adhesion proteins ß-catenin and E-cadherin correlated with clinical outcome. Finally, the 5% of the rectal cancers that occur in young patients predominantly develop through the CIN pathway, whereas MSI is found in a small, HNPCC-related subset of the tumors. Hence, other mechanisms than defective MMR and HNPCC cause rectal cancer in the majority of young patients

Evaluation of the tissue microarray technique for immunohistochemical analysis in rectal cancer.

BACKGROUND: Immunohistochemical staining for tumor-associated proteins is widely used for the identification of novel prognostic markers. Recently, a tissue-conserving, high-throughput technique, tissue microarray, has been introduced. This technique uses 0.6-mm tissue core biopsy specimens, 500 to 1000 of which are brought into a new paraffin array block, which can be sectioned up to 100 times. METHODS: We evaluated the tissue microarray technique for immunohistochemical analysis in 20 rectal cancers. Immunohistochemical staining was performed for the proliferation marker Ki-67 and the tumor suppressor protein p53 in whole tissue sections and in tissue core biopsy specimens. RESULTS: The whole tissue sections were assessed by counting all cells in 10 high-power fields (x40), which resulted in a mean fraction of Ki-67-expressing tumor cells of 0.81 (range, 0.54-1.0). p53 expression assessed in whole tissue sections showed nuclear staining in 15 (75%) of 20 rectal carcinomas. For the tissue microarray technique, a median of 3 (range, 3-5) 0.6-mm tissue core biopsy specimens were studied from each of the 20 tumor specimens. The tissue microarray method gave a mean Ki-67 expression of 0.85 (range, 0.50-1.0) in tumor cell nuclei and showed p53 protein expression in the same 15 of 20 tumors as in the whole tissue sections. CONCLUSION: We conclude that the tissue microarray technique for immunohistochemical staining in rectal cancer yields staining of good quality and expression data for Ki-67 and p53 comparable to those obtained with whole tissue staining. The feasibility of tissue microarray thus enables time- and tissue-preserving studies of multiple markers in large tumor series

Preoperative plasma soluble urokinase plasminogen activator receptor as a prognostic marker in rectal cancer patients. An EORTC-receptor and Biomarker Group collaboration

Background and aims: Since approximately 30% of patients with Dukes' stage B colorectal cancer will experience disease recurrence within five years of primary treatment, current staging of patients with early colorectal cancer apparently fails to adequately predict patient outcome. It has previously been shown that the preoperative plasma concentration of soluble urokinase plasminogen activator receptor (suPAR) is associated with the survival of patients with early colorectal cancer. In this study we sought to confirm the independent prognostic value of suPAR in rectal cancer. Methods: suPAR was retrospectively determined by two different versions of a suPAR ELISA in preoperatively collected plasma samples from a Swedish (n=354) and a Danish (n=255) cohort of rectal cancer patients. Results: In both cohorts the suPAR concentration was significantly higher in Dukes' stage D patients than in Dukes' stage A-C patients (p < 0.0001). Among Dukes' stage A-C patients, no differences in median suPAR values were seen. In univariate analysis, continuous suPAR was found to be associated with survival (p < 0.0001 in both cohorts). Of particular interest was that similar results were obtained for Dukes' stage A and B patients when analyzed separately. In multivariate analysis, continuous suPAR was found in both cohorts to be independent of Dukes' stage. Conclusions: This study confirms that the preoperative concentration of plasma suPAR contains independent prognostic information on patients with rectal cancer. This result was independent of the two different versions of an in-house suPAR ELISA used to perform the analyses. The next step. in the evaluation of suPAR as a prognostic parameter in rectal cancer will be to launch an appropriately dimensioned prospective study where the benefit of applying preoperative plasma suPAR measurement to clinical decision-making regarding adjuvant therapy is assessed

Low expression of CysLT(1)R and high expression of CysLT(2)R mediate good prognosis in colorectal cancer

Colorectal cancer is the third most common cancer type in the western world. in search of new treatment possibilities, the inflammation mediators, know as cysteinyl leukotrienes (CysLTs), have been shown to regulate intestinal epithelial cell survival and proliferation via the CysLT(1)R, and cell differentiation via the CysLT(2)R. These results prompted us to investigate the significance of CysLT(1)R and CysLT(2)R expression in colorectal cancer tissue for patient survival. The CysLT(1)R, CysLT(2)R, beta-catenin and Bcl-xL protein expression levels were evaluated by immunohistochemistry in a tissue microarray of 329 colorectal patients. We found that high nuclear expression of CysLT(1)R is associated with a poor prognosis, whereas high nuclear expression of CysLT(2)R is associated with a good prognosis. We also observed that patients with colorectal tumours characterised by high CysLT(1)R but low CysLT(2)R nuclear expression had the lowest survival expectancy, whereas patients with colorectal tumours characterised by low CysLT(1)R but high CysLT(2)R nuclear expression had the best survival expectancy. Interestingly, beta-catenin as a single prognostic marker did not exhibit any prognostic value. However, in patients with tumours characterised by a high CysLT(1)R nuclear expression, an elevated beta-catenin nuclear expression had a significantly prognostic value. In conclusion these data indicate that nuclear expressions of CysLTRs are potential prognostic indicators of colorectal cancer. (C) 2009 Elsevier Ltd. All rights reserved

The influence of in vitro fitness defects on pneumococcal ability to colonize and to cause invasive disease

Abstract Background Streptococcus pneumoniae is a genetically diverse major human pathogen, yet a common colonizer of the nasopharynx. Here we analyzed the influence of defects affecting in vitro growth rate, on the ability of S. pneumoniae to colonize and to cause invasive disease in vivo. Results Of eleven different clinical isolates one serotype 14 carrier isolate showed a significantly longer generation time as compared to other isolates, and was severely attenuated in mice. To directly investigate the impact of growth rate on virulence, a panel of mutants in five non-essential housekeeping genes was constructed in the virulent TIGR4 background by insertion-deletion mutagenesis. Three of these mutants (ychF, hemK and yebC) were, to different degrees, growth defective, and showed a reduced invasiveness in an intranasal murine challenge model that correlated to their in vitro growth rate, but remained capable of colonizing the upper airways. The growth defect, as well as virulence defect of the hemK insertion-deletion mutant, was mediated by polarity effects on the downstream yrdC gene, encoding a probable chaperone in ribosome assembly. Conclusion We conclude that large fitness defects are needed to completely prevent pneumococci from causing invasive disease after intranasal challenge. However, even severe growth defects still allow pneumococci to persistently colonize the upper airways.</p