Kaplan-Meier Analysis Of Overall Survival Research Articles

Prognostic Validity of a Novel American Joint Committee on Cancer Staging Classification for Pancreatic Neuroendocrine Tumors

The American Joint Committee on Cancer (AJCC) staging manual (seventh edition) has introduced its first TNM staging classification for pancreatic neuroendocrine tumors (NETs) derived from the staging algorithm for exocrine pancreatic adenocarcinomas. This classification has not yet been validated. Patients with pancreatic NETs treated at the H. Lee Moffitt Cancer Center between 1999 and 2010 were assigned a stage (I to IV) based on the new AJCC classification. Kaplan-Meier analyses for overall survival (OS) were performed based on age, race, histologic grade, incidental diagnosis, and TNM staging (European Neuroendocrine Tumors Society [ENETS] v AJCC) using log-rank tests. Survival time was measured from time of initial diagnosis to date of last contact or date of death. Multivariate modeling was performed using Cox proportional hazards regression. Weighted Cohen's κ coefficient was computed to evaluate the agreement of ENETS and AJCC classifications. We identified 425 patients with pancreatic NETs. On the basis of histopathologic grade, 5-year survival rates for low-, intermediate-, and high-grade tumors were 75%, 62%, and 7%, respectively (P < .001). When using the ENETS classification, 5-year OS rates for stages I, II, III, and IV were 100%, 88%, 85%, and 57%, respectively (P < .001). Subsequently, using the AJCC classification, 5-year OS rates for stages I, II, III, and IV were 92%, 84%, 81%, and 57%, respectively (P < .001). Both the novel AJCC classification and the ENETS classification were highly prognostic for survival. The AJCC TNM classification for pancreatic NETs is prognostic for OS and can be adopted in clinical practice.

Abstract LB-144: I-kappa-B kinase (IKK)ε expression in pancreatic ductal adenocarcinoma

Abstract I-kappa-B-kinase (IKKε) is a serine/threonine protein kinase that belongs to the IKK kinase family. Recent studies have shown that IKKε functions as a breast and ovarian cancer oncogene. Here we demonstrate frequent overexpression of IKKε in pancreatic ductal adenocarcinoma (PDA). We immunohistochemically evaluated 78 PDA using the avidin-biotin-peroxidase method and the anti-IKKε, rabbit polyclonal antibody. Elevated IKKε reactivity (IHC score 4–9) was observed in 64.1 % (50/78) PDAs, but in 0% (0/113) of non neoplastic pancreatic ductal epithelium (NMP) (p &amp;lt; 0.001). Kaplan-Meier analysis of overall survival (OS) revealed that patients with high IKKε-IHC scores (4–9) had a significantly shorter survival than that of patients with low IKKε -IHC scores (0–3) (Log-rang test p = 0.023), independent of either tumor stage or grade. These data indicate that deregulation of IKKε is a common event in PDA and might play an important role in the pathogenesis of this deadly disease. In addition, IKKε could serve as a prognostic marker and potential therapeutic target for PDA intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-144. doi:10.1158/1538-7445.AM2011-LB-144

Updated Survival Analyses after Prolonged Follow-Up of the Phase 2, Multicenter CREST Study of Bortezomib in Relapsed or Refractory Multiple Myeloma.

Background: The initial report of the CREST phase 2 study (Br J Haematol 2004; 127:165–72) demonstrated the substantial activity of bortezomib (VELCADE®, Vc) at two different dose levels in patients with relapsed or refractory multiple myeloma (MM). Here, we provide an updated analysis of overall survival (OS) after prolonged follow-up (median >5 years).Methods: 54 patients were enrolled to receive Vc 1.0 mg/m2 (n=28) or 1.3 mg/m2 (n=26) on days 1, 4, 8, and 11 of a 21-day cycle, for up to 8 cycles. Dexamethasone (dex) 20 mg on the day of and day after each Vc dose was added for 16 (57%) patients in the 1.0 mg/m2 group and 12 (46%) patients in the 1.3 mg/m2 group, upon suboptimal response to Vc alone. A total of 17 (31%) patients continued to receive Vc ± dex in an extension study, 12 (43%) from the 1.0 mg/m2 and 5 (19%) from the 1.3 mg/m2 groups. Patients received a median of 3 (range, 1–7) prior regimens. Median time from diagnosis to first Vc dose was 2 years. In the 1.0 and 1.3 mg/m2 groups, respectively, mean age was 64 vs 60 years, 50% vs 35% of patients were male, 54% vs 65% had IgG MM, 58% vs 48% had β2-microglobulin ≥4 mg/L, and 29% vs 48% had abnormal cytogenetics. Response rate (CR+PR, EBMT criteria) to Vc alone was 30% vs 38%, and to Vc ± dex was 37% vs 50% in the 1.0 and 1.3 mg/m2 groups. OS from first dose of Vc in each dose group was analyzed using the Kaplan-Meier method.Results: Median OS in the 1.0 and 1.3 mg/m2 groups was 26.8 months and 60.0 months, after median follow-up of 61 and 65 months, respectively (Figure). In the 1.0 mg/m2 group, 21 (75%) patients have died; the 1- and 2-year OS rates were 82% and 54%, respectively. In the 1.3 mg/m2 group, only 14/26 (54%) patients have died; 1- and 2-year OS rates were 81% and 69%, respectively.Conclusions: Vc ± dex was active in relapsed or refractory MM at both the 1.0 mg/m2 and 1.3 mg/m2 dose levels and was associated with notable OS, particularly in patients treated with the approved Vc dose of 1.3 mg/m2. The difference in OS between dose groups suggests that the higher dose of Vc is more active. Figure. Kaplan-Meier analyses of OS in patients who received Vc 1.0 mg/m2 (n=28) or 1.3 mg/m2 (n=26). [Display omitted]

Elevated serum ras level predicts decreased survival in patients with hematologic malignancies

6562 Background: Ras is a GDP/GTP binding G protein that acts as a molecular switch converting signals from the cell membrane to the nucleus to regulate cell proliferation, differentiation, and protein synthesis. Activation of ras oncogenes has been identified in a variety of cancers, including 30% of acute myelogenous leukemia patients. The purpose of our study was to evaluate serum ras levels and correlate with survival in hematologic cancer patients. Methods: A novel ras p21 ELISA (Oncogene Science/Bayer Diagnostics, Cambridge, MA) employing two monoclonal antibodies reactive with H, K, and N ras was utilized to quantify total ras levels in serum obtained from patients with various hematologic malignancies including acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and chronic lymphocytic leukemia (CLL). Results: The total leukemia patient group consisted of 52 patients. At the 75th percentile serum ras cutpoint (524 pg/ml) 11/52 patients were defined as elevated for serum ras. From this patient group, 38 patients had clinical followup available and were included in the Kaplan-Meier analysis of overall survival. Patients with elevated serum ras (&gt;524 pg/ml) had significantly shorter overall survival compared to those without (median OS 205 vs. 677 days) (p= 0.04). In a multivariate analysis including serum ras level and type of leukemia, serum ras level remained a significant independent variable for shorter overall survival (p=0.004). Within leukemia subtypes 2/18 AML, 4/9 CML, 3/7 ALL, and 0/4 CLL patients had elevated serum ras levels. Conclusions: Leukemia patients with elevated serum ras levels had a significantly shorter overall survival. Serum ras should be evaluated as a potential biomarker in larger leukemia trials, especially for response to treatment with inhibitors of the ras signaling pathway. [Table: see text]

Spotlight

Abd El-Rehim et al., pp. 340–350 Breast cancer, a complex disease, cannot be completely assessed by currently available clinical methods. Novel molecular markers have been identified that may better address the molecular and genetic events underlying the disease. A panel of these new biomarkers has now been examined in a comprehensive British study of a large series of invasive breast cancer. Abd El-Rehim and colleagues tested the expression profiles of 25 candidate proteins by immunohistochemistry in tissue microarray sections of nearly 2,000 women with breast cancer. Using hierarchical clustering and artificial neural networks, the authors identified 6 main clusters of biomarkers. Hormone receptors, the epidermal growth factor c-erbB-2, cytokeratins 5/6 and 18, mucin1, the tumor suppressors p53 and BRCA1 and the cell adhesion molecule E-cadherin were the driving key markers and the most important discriminators among different clusters. The authors characterized the cancer cases into 6 groups. Whereas groups 1 and 2 were strongly positive for cytokeratin 18 and hormone receptors, group 3 showed strong expression of c-erbB-2 and mucin1. Group 4 was dominated by strong expression of c-erbB-2, p53 and nuclear BRCA1, whereas group 5 was characterized by strong p53 expression and the absence of hormone receptors and group 6 by the abundance of c-erbB-2 and E-cadherin. The authors found marked differences between the 6 groups with respect to tumor grade, size and lymph node stage. Importantly, the molecular clustering was highly significantly associated with overall survival and disease-free intervals. Mortality was highest in patients whose tumors were classified as group 5, followed by patients in groups 3 and 6. These results suggest a more complex classification system is needed for clinical and prognostic management of breast cancer. 1 Kaplan-Meier analysis of overall survival in different clusters of invasive breast cancer. Hoglund et al., pp. 401–406 Systematic analysis of of karyotypic evolution in epithelial tumors has identified a number of conserved features, including: (1) acquisition of chromosomal imbalance in a preferred order; (2) the presence of distinct cytogenetic pathways characterized either by gain or loss; and (3) conformity of the number of acquired chromosomal changes to a power law distribution. Hoglund and colleagues have proposed a model of stepwise acquisition of aberrations that faithfully reproduces the power law distribution to explain the observed distribution of the number of aberrations per tumor. In this report, the same group has analyzed the accumulated cytogenetic data on karyotypic evolution in Ewing tumors and synovial sarcomas. Both tumors are frequently characterized by the presence of the balanced translocations t(11;22) and t(X;18). In Ewing tumors, the authors identified +8, +12, +1q and 16q− as important secondary changes to t(11;22). By principal component analysis, a major karyotypic pathway characterized by gains and a minor one characterized by losses were identified. In synovial sarcomas, the karyotypic evolution was less clear. A power law distribution of the number of acquired aberrations was identified for both tumors. Ewing tumors and synovial sarcomas differ from other malignancies with balanced translocations resulting in fusion genes. These observations are consistent with the model that chromosomal changes observed in these two tumors may develop through mechanisms similar to those observed in epithelial tumors, in contrast to hematological malignancies, which are characterized by balanced translocations with gene fusions. Becher et al., pp. 451–457 Laryngeal cancer (mostly squamous cell carcinoma) is the second most frequent cancer of the respiratory system and generally carries a favorable prognosis. The two major risk factors identified are cigarette smoking and high alcohol consumption, particularly in combination. Some occupational risk factors have also been linked to laryngeal cancer, including exposure to asbestos, mineral coal products, mineral oils, fossil fuels, ionizing radiation and others. However, no conclusive evidence has been provided so far. In this issue, Becher and colleagues have analyzed occupational risk in a cohort of 257 cases of laryngeal cancer in Germany. Job-specific questionnaires for selected jobs known to be associated with carcinogenic exposure were used to ascertain exposure to potential carcinogens in all members of the cohort. A strong effect of polycyclic aromatic hydrocarbons was noted for laryngeal cancer risk after adjusting for smoking and alcohol and a clear dose-response effect was found for exposure duration. These findings are further supported by the risk associated with occupations in which exposure to polycyclic aromatic hydrocarbons is likely, such as road and building construction, where workers are exposed to asphalt. These observations firmly establish polycyclic aromatic hydrocarbons as an independent risk factor for laryngeal carcinoma.

Elevated Expression of CKS1B at 1q21 Is Highly Correlated with Short Survival in Myeloma.

The variability in survival among patients with myeloma can range from months to >10 years. Patients at highest risk are best identified by the presence or absence of an abnormal karyotype found by conventional cytogenetics. However, this test only accounts for ~15% of the variability in outcome. Thus, many patients who present with no cytogenetic abnormalities experience rapid relapse and early death. To better define high-risk disease and also potentially identify specific genetic mechanisms that give rise to this poor survival, we analyzed the gene expression patterns in freshly isolated plasma cells from 40 newly diagnosed myeloma patients who were then treated with high-dose therapy and tandem stem cell transplants. Patients were separated into two groups of 20. Those in the “short-survival” group all died within 900 days of therapy initiation due to disease progression. Patients in the “long-survival” group had all survived >1453 days since therapy initiation. RNA from plasma cells was labeled and hybridized to the U133Plus2.0 microarray containing ~33,000 genes. The expression value was transformed by the log base 2 and each sample was normalized to give a mean of 0 and a variance of 1. Chi-square analyses and t-tests were performed to identify genes whose expression patterns were unique to each group. Kaplan-Meier analysis of overall survival using expression level quartiles was used to demonstrate links to outcome. A total of 1770 probe sets were significantly differentially expressed between the two groups (P <.05). A total of 1025 (58%) of the probe sets were up-regulated in the short-survival group. The chromosomal map positions of all 1770 probe sets were determined; 19% mapped to chromosome 1. Of the 1770 probe sets, 84 demonstrating a >2-fold difference in expression were further analyzed with Kaplan-Meier survival analyses. In this test, 18 probe sets representing 17 genes were highly significant (P <.0001). Of the 17 genes identified, 10 map to chromosome 1; all 4 genes from the p arm were down-regulated while all 6 genes from the q arm were up-regulated in the short-survival group. We have previously demonstrated that jumping 1q and amplification of genes from 1q21 represent common genetic lesions in myeloma. We then examined by FISH, BCL2 and IL-6R showed highly variable over-expression in patient subsets, unrelated to outcome. CKS1B, an evolutionarily conserved protein that interacts genetically and physically with cyclin-dependent kinases and promotes mitosis, is located very near the 1q21 amplification and is over-expressed in myelomas with a short survival. Using FISH analysis with probes specific for these genes, we will determine if over-expression is due to gene amplification. Given the important role of CKS1B in controlling mitosis and the emerging role of D-type cyclins in myelomagenesis, this gene represents a strong candidate for a gene whose over-expression, possibly as a result of gene amplification, may impart a highly aggressive phenotype on malignant plasma cells.

Clinical Significance of Cytogenetic Findings at Diagnosis and in Remission in Childhood and Adult Acute Lymphoblastic Leukemia: Experience from India

We report cytogenetic findings in 114 patients of acute lymphoblastic leukemia (ALL), which includes 78 children ( ≤15 years) and 36 adults (16–60 years). Chromosome aberrations were detected in 109 (95%) cases. A lower frequency of hyperdiploidy (15%) in children and a higher frequency of hypodiploidy both in children (38.4%) and adults (44.4%) were found, in contrast to literature. Translocations were detected in one third of adult and pediatric cases. The incidence of t(9;22) was comparatively low in adults (7.7%). Frequency of t(1;19) was also low in overall ALL cases. Various other recurrent abnormalities such as del(6q), abn(11q23), i(9p), abn(12p13), del(7q), and i(17q) were seen in our cases; a striking difference in the incidence of del(6q) (41%) and abn(11q23) (30%) was found in our series versus reported literature. Ploidy distribution indicated association of pseudo- and hypodiploidy with B-lineage, and hypodiploidy with T-lineage in children. The occurrence of del(6q) was more frequent in pediatric ALL with highly aberrant pattern and also with lymphadenopathy. Abn(11q23) was found to be early-B and pre-B specific. Kaplan-Meier analysis of overall survival revealed prognostic value of sex, FAB, immunophenotype, and cytogenetic findings. Females and T-ALL patients had a better prognosis, whereas males and B-ALL patients had poor outcome in overall and pediatric age groups. Prognostic evaluation of cytogenetics indicated translocations as an independent high-risk predictor in childhood ( P < 0.008) and adult ALL ( P < 0.01). Childhood ALL with t(8;14) and t(4;11) and adults with t(9;22) had poor survival. Cytogenetics of remission marrows demonstrated disappearance of abnormal clones in 31.4%, and expansion in normal clones in 50% of patients. Persistence of original clones and development of new clones were observed in 20% and 33% of patients, respectively; whereas karyotype evolution was identified in 10% of patients. The prognostic significance of cytogenetic findings at diagnosis, and differential cytogenetic response in so-called clinical remission in our study indicated the utmost need for more intensive therapy for eradication of resistant clones, and necessity of sequential cytogenetic follow-up in these patients for identification of minimal residual disease.

90K IS A SERUM MARKER OF POOR-PROGNOSIS IN NON-HODGKINS-LYMPHOMA PATIENTS

Monoclonal antibody SP-2, which binds to a 90,000 daltons tumor-associated antigen termed 90K, was generated by mouse immunization with proteins released by human breast cancer cells into the culture medium (Iacobelli et al: Cancer Res 46: 3005-3010, 1986). Elevated 90K levels have been previously reported in the serum of patients with various malignancies. We investigated whether the circulating levels of 90K antigen might be related to prognosis of patients with Non-Hodgkin's Lymphomas (NHL). Serum samples were obtained from 50 apparently healthy blood donors and 81 patients with NHL. Circulating serum 90K concentrations (U/ml) were determined by a solid-phase immunoradiometric assay (IRMA) by a two-step procedure. Serum 90K levels were significantly higher in patients with NHL than in healthy controls (p=0.004). The Kaplan-Meier analysis of overall survival showed that patients with 90K-negative (serum 90K levels less than or equal to 16 U/ml) survived longer than patients with 90K-positive sera (less than or equal to 16 U/ml) (p=0.004). Multivariate regression analysis revealed that serum levels of LDH and 90K were the two independent prognostic variables for predicting overall survival. We propose that an elevated 90K antigen level in sera is a predictor of poor prognosis in NHL.