Citations

Multiple testing and its impact on the type I and type II error rates are frequently discussed in the statistical and biomedical literature. The Bonferroni adjustment is one of the most widely used approaches, yet it suffers from poor statistical performance when there are correlated test statistics. For example, it is criticized to be too conservative. Nonetheless, part of the strong appeal of the Bonferroni approach is the straightforward implementation and relatively intuitive explanation. In this manuscript, a novel adaptation to the traditional Bonferroni approach that accounts for correlated data is proposed. A simple correction factor based on intraclass correlation is applied to the standard Bonferroni method to overcome the shortcomings of the standard Bonferroni adjustment yet maintains its advantages. The method is motivated by an early phase clinical trial examining the effect of a study medication on marijuana craving, which is commonly quantified into four correlated constructs. A detailed simulation study demonstrated that the proposed approach is statistically sound and appropriate for a wide range of common settings. Copyright © 2012 John Wiley & Sons, Ltd.

Abstract The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole-genome sequencing (WGS) on 4 purified tumor samples and patient germline DNA drawn over a 5-year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse, and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single-nucleotide variants (SNVs) on WGS comprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors, suggesting the presence of multiple independent, yet related, clones at diagnosis that rose and fell in dominance. Five newly acquired SNVs, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. This longitudinal WGS characterization of the natural history of a high-risk myeloma patient demonstrated tumor heterogeneity at diagnosis with shifting dominance of tumor clones over time and has also identified potential mutations contributing to myelomagenesis as well as transformation from myeloma to overt extramedullary disease such as sPCL.

Abstract Combinations of bortezomib (V) and dexamethasone (D) with either lenalidomide (R) or cyclophosphamide (C) have shown significant efficacy. This randomized phase 2 trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM). Patients received V 1.3 mg/m2 (days 1, 4, 8, 11) and D 40 mg (days 1, 8, 15), with either C 500 mg/m2 (days 1, 8) and R 15 mg (days 1-14; VDCR), R 25 mg (days 1-14; VDR), C 500 mg/m2 (days 1, 8; VDC) or C 500 mg/m2 (days 1, 8, 15; VDC-mod) in 3-week cycles (maximum 8 cycles), followed by maintenance with V 1.3 mg/m2 (days 1, 8, 15, 22) for four 6-week cycles (all arms) ≥ very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively); the corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%, respectively. Common adverse events included hematologic toxicities, peripheral neuropathy, fatigue, and gastrointestinal disturbances. All regimens were highly active and well tolerated in previously untreated MM, and, based on this trial, VDR and VCD-mod are preferred for clinical practice and further comparative testing. No substantial advantage was noted with VDCR over the 3-drug combinations. This trial is registered at www.clinicaltrials.gov (NCT00507442).

Glioblastoma, the most common primary malignant cancer of the brain, is characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. These traits cause glioblastomas to be highly resistant to current therapies with a resultant poor prognosis. Although aberrant oncogenic signaling driven by signature genetic alterations, such as EGF receptor (EGFR) gene amplification and mutation, plays a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here, we report that EGFRvIII (also known as ΔEGFR and de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in human glioblastoma, promotes tumorigenesis through Src family kinase (SFK)-dependent phosphorylation of Dock180, a guanine nucleotide exchange factor for Rac1. EGFRvIII induces phosphorylation of Dock180 at tyrosine residue 722 (Dock180 Y722 ) and stimulates Rac1-signaling, glioblastoma cell survival and migration. Consistent with this being causal, siRNA knockdown of Dock180 or expression of a Dock180 Y722F mutant inhibits each of these EGFRvIII-stimulated activities. The SFKs, Src, Fyn, and Lyn, induce phosphorylation of Dock180 Y722 and inhibition of these SFKs by pharmacological inhibitors or shRNA depletion markedly attenuates EGFRvIII-induced phosphorylation of Dock180 Y722 , Rac1 activity, and glioblastoma cell migration. Finally, phosphorylated Dock180 Y722 is coexpressed with EGFRvIII and phosphorylated Src Y418 in clinical specimens, and such coexpression correlates with an extremely poor survival in glioblastoma patients. These results suggest that targeting the SFK-p-Dock180 Y722 -Rac1 signaling pathway may offer a novel therapeutic strategy for glioblastomas with EGFRvIII overexpression.

Abstract Purpose: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). Experimental Design: HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3–4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. Results: Overall, 17% of EACs were HER2 positive (i.e., IHC3+ or IHC2+ with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barrett's esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1–2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (Pinteraction = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35–0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. Conclusions: HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival. Clin Cancer Res; 18(2); 546–54. ©2012 AACR.

Purpose Symptoms and complications of metastatic colorectal cancer (mCRC) differ by metastatic sites. There is a paucity of prospective survival data for patients with peritoneal carcinomatosis colorectal cancer (pcCRC). We characterized outcomes of patients with pcCRC enrolled onto two prospective randomized trials of chemotherapy and contrasted that with other manifestations of mCRC (non-pcCRC). Methods A total of 2,095 patients enrolled onto two prospective randomized trials were evaluated for overall survival (OS) and progression-free survival (PFS). A Cox proportional hazard model was used to assess the adjusted associations. Results The characteristics of the pcCRC group (n = 364) were similar to those of the non-pcCRC patients in median age (63 v 61 years, P = .23), sex (57% males v 61%, P = .23), and performance status (Eastern Cooperative Oncology Group performance status 0 or 1 94% v 96%, P = .06), but differed in frequency of liver (63% v 82%, P < .001) and lung metastases (27% v 34%, P = .01). Median OS (12.7 v 17.6 months, hazard ratio [HR] = 1.3; 95% CI, 1.2 to 1.5; P < .001) and PFS (5.8 v 7.2 months, HR = 1.2; 95% CI, 1.1 to 1.3; P = .001) were shorter for pcCRC versus non-pcCRC. The unfavorable prognostic influence of pcCRC remained after adjusting for age, PS, liver metastases, and other factors (OS: HR = 1.3, P < .001; PFS: HR = 1.1, P = .02). Infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, and fluorouracil as a first-line treatment among pcCRC (HR for OS = 0.62, P = .005) and non-pcCRC patients (HR = 0.66, P < .001). Conclusion pcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations of mCRC. Future trials for mCRC should consider stratifying on the basis of pcCRC status.

A two‐stage model for evaluating both trial‐level and patient‐level surrogacy of correlated time‐to‐event endpoints has been introduced, using patient‐level data when multiple clinical trials are available. However, the associated maximum likelihood approach often suffers from numerical problems when different baseline hazards among trials and imperfect estimation of treatment effects are assumed. To address this issue, we propose performing the second‐stage, trial‐level evaluation of potential surrogates within a Bayesian framework, where we may naturally borrow information across trials while maintaining these realistic assumptions. Posterior distributions on surrogacy measures of interest may then be used to compare measures or make decisions regarding the candidacy of a specific endpoint. We perform a simulation study to investigate differences in estimation performance between traditional maximum likelihood and new Bayesian representations of common meta‐analytic surrogacy measures, while assessing sensitivity to data characteristics such as number of trials, trial size, and amount of censoring. Furthermore, we present both frequentist and Bayesian trial‐level surrogacy evaluations of time to recurrence for overall survival in two meta‐analyses of adjuvant therapy trials in colon cancer. With these results, we recommend Bayesian evaluation as an attractive and numerically stable alternative in the multitrial assessment of potential surrogate endpoints. Copyright © 2011 John Wiley & Sons, Ltd.

Abstract Despite recent advances in targeted treatments for multiple myeloma, optimal molecular therapeutic targets have yet to be identified. To functionally identify critical molecular targets, we conducted a genome-scale lethality study in multiple myeloma cells using siRNAs. We validated the top 160 lethal hits with four siRNAs per gene in three multiple myeloma cell lines and two non-myeloma cell lines, cataloging a total of 57 potent multiple myeloma survival genes. We identified the Bcl2 family member MCL1 and several 26S proteasome subunits among the most important and selective multiple myeloma survival genes. These results provided biologic validation of our screening strategy. Other essential targets included genes involved in RNA splicing, ubiquitination, transcription, translation, and mitosis. Several of the multiple myeloma survival genes, especially MCL1, TNK2, CDK11, and WBSCR22, exhibited differential expression in primary plasma cells compared with other human primary somatic tissues. Overall, the most striking differential functional vulnerabilities between multiple myeloma and non–multiple myeloma cells were found to occur within the 20S proteasome subunits, MCL1, RRM1, USP8, and CKAP5. We propose that these genes should be investigated further as potential therapeutic targets in multiple myeloma. Cancer Res; 72(3); 757–68. ©2011 AACR.