Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from early-phase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients.
COBISS.SI-ID: 2108539
The mechanisms underlying the favourable prognosis of androgen receptor (AR) expression in breast cancer are unknown. METHODS: The associations between the 21-gene recurrence score (RS), AR, grade, mitotic score, Ki-67 and estrogen receptor (ER) and progesterone receptor (PgR) expression were explored in sequential women with lymph node-negative, ER-positive and HER2-negative breast cancer. Statistical significance of this exploratory study was defined as p(0.10. RESULTS: Analysis comprised 70 women. Most tumours had high AR expression (97% had scores )3). Median RS was 15 (range 1-53). AR expression showed a minimally significant positive correlation with ER (R=0.37), but no correlation with Ki-67 (R=-0.18). In univariable analysis, AR (p=0.01), ER (p(0.001) and PgR (p(0.001) had significant negative associations with RS. Ki-67 (p=0.16), grade (p=0.40) and mitotic score (p=0.23) showed no association with RS. Multivariable analysis showed similar associations. CONCLUSIONS: AR is associated with lower RS, but not with Ki-67.
COBISS.SI-ID: 2054779
Abstract. Analysis of the immunoglobulin % light chain (IGK) gene is an alternative method for B-cell clonality assessment in the diagnosis of mature B-cell proliferations in which the detection of clonal immunoglobulin heavy chain (IGH) gene rearrangements fails. The aim of the present study was to evaluate the added value of standardized BIOMED-2 assay for the detection of clonal IGK gene rearrangements in the diagnostic setting of suspected B-cell lymphomas. With this purpose, 92 specimens from 80 patients with the final diagnosis of mature B-cell lymphoma (37 specimens), mature T-cell lymphoma (26 specimens) and reactive lymphoid proliferation (29 specimens) were analyzed for B-cell clonality. B-cell clonality analysis was performed using the BIOMED-2 IGH and IGK gene clonality assays. The determined sensitivity of the IGK assay was 67.6%, while the determined sensitivity of the IGH assay was 75.7%. The sensitivity of combined IGH+IGK assay was 81.1%. The determined specificity of the IGK assay was 96.2% in the group of T-cell lymphomas and 96.6% in the group of reactive lesions. The determined specificity of the IGH assay was 84.6% in the group of lymphomas and 86.2% in the group of reactive lesions. The comparison of GeneScan (GS) and heteroduplex pretreatment-polyacrylamide gel electrophoresis (HD-PAGE) methods for the analysis of IGK gene rearrangements showed a higher efficacy of GS analysis in a series of 27 B-cell lymphomas analyzed by both methods. In the present study, we demonstrated that by applying the combined IGH+IGK clonality assay the overall detection rate of B-cell clonality was increased by 5.4%. Thus, we confirmed the added value of the standardized BIOMED-2 IGK assay for assessment of B-cell clonality in suspected B-cell lymphomas with inconclusive clinical and cyto/histological diagnosis.
COBISS.SI-ID: 1938299
Background Osteosarcoma patients are commonly treated with cisplatin-based preoperative and postoperative chemotherapy. Cisplatin binds to DNA and forms both intrastrand and interstrand crosslinks, inhibiting DNA replication. Glutathione-S-transferases (GSTs) participate in cisplatin detoxification, while several independent DNA repair mechanisms repair cisplatin-induced lesions. The aim of our study was to investigate the influence of genetic variability of DNA repair mechanisms and GSTs on efficacy and toxicity of cisplatin-based chemotherapy in osteosarcoma patients. Methods A total of 66 osteosarcoma patients were genotyped for ERCC1, ERCC2, NBN, RAD51, XRCC3, and GSTP1 polymorphisms, as well as GSTM1 and GSTT1 gene deletion. We determined the influence of polymorphisms on survival and treatment outcome using Cox regression and logistic regression. Results Carriers of at least one polymorphic ERCC2 rs1799793 allele had longer event-free survival (EFS) (P = 0.006; hazard ratio (HR) = 0.28; 95% confidence interval (CI) = 0.11-0.70). Polymorphic GSTP1 rs1138272 allele was associated with both shorter EFS and OS (P = 0.005; HR = 3.67; 95%CI = 1.47-9.16; and P = 0.004; HR = 3.52; 95%CI = 1.51-8.22, respectively). Compared to the reference NBN CAA haplotype, NBN CGA haplotype was associated with shorter EFS (P = 0.001; HR = 4.12; 95%CI = 1.77-9.56). Conclusions Our results suggest that DNA repair polymorphisms and GST polymorphisms could be used as predictive factors for cisplatin-based chemotherapy in osteosarcoma patients and could contribute to treatment personalization.
COBISS.SI-ID: 31771353
Background. Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) play a key role in tumour invasion and metastasis. High levels of both proteolytic enzymes are associated with poor prognosis in breast cancer patients. The purpose of this study was to evaluate the correlation between traditional prognostic factors and uPA and PAI-1 expression in primary tumour of breast cancer patients. Patients and methods. 606 primary breast cancer patients were enrolled in the prospective study in the Department of gynaecological oncology and breast oncology at the University Medical Centre Maribor between the years 2004 and 2010. We evaluated the traditional prognostic factors (age, menopausal status, tumour size, pathohistological type, histologic grade, lymph node status, lymphovascular invasion and hormone receptor status), together with uPA and PAI-1. We used Spearman%s rank correlation, Mann Whitney U test and X2 test for statistical analysis. Results. Our findings indicate a positive correlation between uPA and tumour size (p ( 0.001), grade (p ( 0.001), histological type (p ( 0.001), lymphovascular invasion (p = 0.01) and a negative correlation between uPA and hormone receptor status (p ( 0.001). They also indicate a positive correlation between PAI-1 and tumour size (p = 0.004), grade (p ( 0.001), pathohistological type (p ( 0.001) and negative correlation between PAI-1 and hormone receptor status (p = 0.002). Conclusions. Our study showed a relationship between uPA and PAI-1 and traditional prognostic factors. Their role as prognostic and predictive factors remains to be further evaluated.
COBISS.SI-ID: 1979259