Modest Improvement in Overall Survival for Patients With Metastatic Pancreatic Cancer

OBJECTIVES: Patients with pancreatic adenocarcinoma often present with distant metastatic disease. We aimed to assess whether improvements in survival of clinical trials translated to a population-based level. METHODS: The US Surveillance, Epidemiology, and End Results registry was queried. Adult patients with distant metastatic adenocarcinoma of the pancreas were included from 1988 to 2008. Overall survival was analyzed using Kaplan-Meier curves as well as multivariable-adjusted Cox proportional hazards models. RESULTS: In total, 32,452 patients were included. Mean age was 67.6 (SD: 11.7) years, and 15,341 (47.3%) were female. Median overall survival was 3 months (95% confidence interval [CI], 3-3 months), which increased from 2 (CI, 2-2) months in 1988 to 3 (CI, 3-4) months in 2008. After adjustment for multiple covariates, the hazard ratio (HR) decreased by 0.977 per year (CI, 0.975-0.980). In multivariable-adjusted survival analyses, tumor location in the pancreatic body/tail (HR, 1.10), male sex (HR, 1.09), increasing age (HR, 1.016), African American ethnicity (HR, 1.16), nonmarried civil status (HR, 1.18), and absence of radiotherapy (HR, 1.41) were associated with worse survival (P < 0.001 for all predictors). CONCLUSIONS: The improvement in overall survival over the past 2 decades among patients with metastatic pancreatic adenocarcinoma is modest and disappointing. More effective therapeutic strategies for advanced disease are desperately needed.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019)

BACKGROUND Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa-the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)-includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.

Loss of tumor suppressor mir-203 mediates overexpression of LIM and SH3 Protein 1 (LASP1) in high-risk prostate cancer thereby increasing cell proliferation and migration

Several studies have linked overexpression of the LIM and SH3 domain protein 1 (LASP1) to progression of breast, colon, liver, and bladder cancer. However, its expression pattern and role in human prostate cancer (PCa) remained largely undefined. Analysis of published microarray data revealed a significant overexpression of LASP1 in PCa metastases compared to parental primary tumors and normal prostate epithelial cells. Subsequent gene-set enrichment analysis comparing LASP1-high and -low PCa identified an association of LASP1 with genes involved in locomotory behavior and chemokine signaling. These bioinformatic predictions were confirmed in vitro as the inducible short hairpin RNA-mediated LASP1 knockdown impaired migration and proliferation in LNCaP prostate cancer cells. By immunohistochemical staining and semi-quantitative image analysis of whole tissue sections we found an enhanced expression of LASP1 in primary PCa and lymph node metastases over benign prostatic hyperplasia. Strong cytosolic and nuclear LASP1 immunoreactivity correlated with PSA progression. Conversely, qRT-PCR analyses for mir-203, which is a known translational suppressor of LASP1 in matched RNA samples revealed an inverse correlation of LASP1 protein and mir-203 expression. Collectively, our results suggest that loss of mir-203 expression and thus uncontrolled LASP1 overexpression might drive progression of PCa.

Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons.

BACKGROUND Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown. OBJECTIVE We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients. METHODS We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes. RESULTS We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation-related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients. CONCLUSION We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations.

Disruption of tumor suppressor gene Hint1 leads to remodeling of the lipid metabolic phenotype of mouse liver

A lipidomic and metabolomic investigation of serum and liver from mice was performed to gain insight into the tumor suppressor gene Hint1. A major reprogramming of lipid homeostasis was found in both serum and liver of Hint1-null (Hint(-/-)) mice, with significant changes in the levels of many lipid molecules, as compared with gender-, age-, and strain-matched WT mice. In the Hint1(-/-) mice, serum total and esterified cholesterol were reduced 2.5-fold, and lysophosphatidylcholines (LPCs) and lysophosphatidic acids were 10-fold elevated in serum, with a corresponding fall in phosphatidylcholines (PCs). In the liver, MUFAs and PUFAs, including arachidonic acid (AA) and its metabolic precursors, were also raised, as was mRNA encoding enzymes involved in AA de novo synthesis. There was also a significant 50% increase in hepatic macrophages in the Hint1(-/-) mice. Several hepatic ceramides and acylcarnitines were decreased in the livers of Hint1(-/-) mice. The changes in serum LPCs and PCs were neither related to hepatic phospholipase A2 activity nor to mRNAs encoding lysophosphatidylcholine acetyltransferases 1-4. The lipidomic phenotype of the Hint1(-/-) mouse revealed decreased inflammatory eicosanoids with elevated proliferative mediators that, combined with decreased ceramide apoptosis signaling molecules, may contribute to the tumor suppressor activity of Hint1.

High tumor budding stratifies breast cancer with metastatic properties.

Tumor budding refers to single or small cluster of tumor cells detached from the main tumor mass. In colon cancer high tumor budding is associated with positive lymph nodes and worse prognosis. Therefore, we investigated the value of tumor budding as a predictive feature of lymph node status in breast cancer (BC). Whole tissue sections from 148 surgical resection specimens (SRS) and 99 matched preoperative core biopsies (CB) with invasive BC of no special type were analyzed on one slide stained with pan-cytokeratin. In SRS, the total number of intratumoral (ITB) and peripheral tumor buds (PTB) in ten high-power fields (HPF) were counted. A bud was defined as a single tumor cell or a cluster of up to five tumor cells. High tumor budding equated to scores averaging >4 tumor buds across 10HPFs. In CB high tumor budding was defined as ≥10 buds/HPF. The results were correlated with pathological parameters. In SRS high PTB stratified BC with lymph node metastases (p ≤ 0.03) and lymphatic invasion (p ≤ 0.015). In CB high tumor budding was significantly (p = 0.0063) associated with venous invasion. Pathologists are able, based on morphology, to categorize BC into a high and low risk groups based in part on lymph node status. This risk assessment can be easily performed during routine diagnostics and it is time and cost effective. These results suggest that high PTB is associated with loco-regional metastasis, highlighting the possibility that this tumor feature may help in therapeutic decision-making.

Human DMTF1β antagonizes DMTF1α regulation of the p14(ARF) tumor suppressor and promotes cellular proliferation

The human DMTF1 (DMP1) transcription factor, a DNA binding protein that interacts with cyclin D, is a positive regulator of the p14ARF (ARF) tumor suppressor. Our earlier studies have shown that three differentially spliced human DMP1 mRNAs, α, β and γ, arise from the human gene. We now show that DMP1α, β and γ isoforms differentially regulate ARF expression and promote distinct cellular functions. In contrast to DMP1α, DMP1β and γ did not activate the ARF promoter, whereas only β resulted in a dose-dependent inhibition of DMP1α-induced transactivation of the ARF promoter. Ectopic expression of DMP1β reduced endogenous ARF mRNA levels in human fibroblasts. The DMP1β- and γ-isoforms share domains necessary for the inhibitory function of the β-isoform. That DMP1β may interact with DMP1α to antagonize its function was shown in DNA binding assays and in cells by the close proximity of DMP1α/β in the nucleus. Cells stably expressing DMP1β, as well as shRNA targeting all DMP1 isoforms, disrupted cellular growth arrest induced by serum deprivation or in PMA-derived macrophages in the presence or absence of cellular p53. DMP1 mRNA levels in acute myeloid leukemia samples, as compared to granulocytes, were reduced. Treatment of acute promyelocytic leukemia patient samples with all-trans retinoic acid promoted differentiation to granulocytes and restored DMP1 transcripts to normal granulocyte levels. Our findings imply that DMP1α- and β-ratios are tightly regulated in hematopoietic cells and DMP1β antagonizes DMP1α transcriptional regulation of ARF resulting in the alteration of cellular control with a gain in proliferation.

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06)

BACKGROUND Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, number NCT00544700.

Prognostic Relevance of Palliative Primary Tumor Removal in 37,793 Metastatic Colorectal Cancer Patients: A Population-Based, Propensity Score-Adjusted Trend Analysis

OBJECTIVE To assess whether palliative primary tumor resection in colorectal cancer patients with incurable stage IV disease is associated with improved survival. BACKGROUND There is a heated debate regarding whether or not an asymptomatic primary tumor should be removed in patients with incurable stage IV colorectal disease. METHODS Stage IV colorectal cancer patients were identified in the Surveillance, Epidemiology, and End Results database between 1998 and 2009. Patients undergoing surgery to metastatic sites were excluded. Overall survival and cancer-specific survival were compared between patients with and without palliative primary tumor resection using risk-adjusted Cox proportional hazard regression models and stratified propensity score methods. RESULTS Overall, 37,793 stage IV colorectal cancer patients were identified. Of those, 23,004 (60.9%) underwent palliative primary tumor resection. The rate of patients undergoing palliative primary cancer resection decreased from 68.4% in 1998 to 50.7% in 2009 (P < 0.001). In Cox regression analysis after propensity score matching primary cancer resection was associated with a significantly improved overall survival [hazard ratio (HR) of death = 0.40, 95% confidence interval (CI) = 0.39-0.42, P < 0.001] and cancer-specific survival (HR of death = 0.39, 95% CI = 0.38-0.40, P < 0.001). The benefit of palliative primary cancer resection persisted during the time period 1998 to 2009 with HRs equal to or less than 0.47 for both overall and cancer-specific survival. CONCLUSIONS On the basis of this population-based cohort of stage IV colorectal cancer patients, palliative primary tumor resection was associated with improved overall and cancer-specific survival. Therefore, the dogma that an asymptomatic primary tumor never should be resected in patients with unresectable colorectal cancer metastases must be questioned.

Non-metastatic castrate-resistant prostate cancer: a call for improved guidance on clinical management.

BACKGROUND Guidelines on the clinical management of non-metastatic castrate-resistant prostate cancer (nmCRPC) generally focus on the need to continue androgen deprivation therapy and enrol patients into clinical trials of investigational agents. This guidance reflects the lack of clinical trial data with established agents in the nmCRPC patient population and the need for trials of new agents. AIM To review the evidence base and consider ways of improving the management of nmCRPC. CONCLUSION Upon the development of castrate resistance, it is essential to rule out the presence of metastases or micrometastases by optimising the use of bone scans and possibly newer procedures and techniques. When nmCRPC is established, management decisions should be individualised according to risk, but risk stratification in this diverse population is poorly defined. Currently, prostate-specific antigen (PSA) levels and PSA doubling time remain the best method of assessing the risk of progression and response to treatment in nmCRPC. However, optimising imaging protocols can also help assess the changing metastatic burden in patients with CRPC. Clinical trials of novel agents in nmCRPC are limited and have problems with enrolment, and therefore, improved risk stratification and imaging may be crucial to the improved management. The statements presented in this paper, reflecting the views of the authors, provide a discussion of the most recent evidence in nmCRPC and provide some advice on how to ensure these patients receive the best management available. However, there is an urgent need for more data on the management of nmCRPC.