Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the Normative Aging Study

Background

Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case?Ccontrol studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case?Ccontrol studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear.

Methods

In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing.

Results

Individuals with low LINE-1 methylation (Conclusion These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.     

The role of <Emphasis Type="Italic">LINE</Emphasis>-<Emphasis Type="Italic">1</Emphasis> methylation in predicting survival among colorectal cancer patients: a meta-analysis

Background

The prognostic value of long interspersed nucleotide element-1 (LINE-1) methylation in patients with colorectal cancer (CRC) remains uncertain. We have therefore performed a meta-analysis to elucidate this issue.

Methods

The PubMed and Web of Science databases were searched for studies published up to 30 June 2016 which reported on an association between LINE-1 methylation and overall survival (OS), disease-free survival (DFS), or cancer-specific survival (CSS) among CRC patients. The reference lists of the identified studies were also analyzed to identify additional eligible studies. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using the fixed-effects or the random-effects model. Stratification analysis and meta-regression analysis were performed to detect the source of heterogeneity. Analyses of sensitivity and publication bias were also carried out.

Results

Thirteen independent studies involving 3620 CRC patients were recruited to the meta-analysis. LINE-1 hypomethylation was found to be significantly associated with shorter OS (HR 2.92, 95% CI 2.20–3.88, p < 0.001) and DFS (HR 2.18, 95% CI 1.46–3.27, p < 0.001), as well as unfavorable CSS (HR 1.96, 95% CI 1.35–2.85, p < 0.001). No heterogeneity was found among the studies evaluating the associations between LINE-1 hypomethylation and OS or DFS, with the exception being CSS. Moreover, meta-regression analysis suggested that one of the contributors to between-study heterogeneity on the association between LINE-1 methylation and CSS was statistical methodology. The subgroup analysis suggested that the association in studies using the Cox model statistical method (HR 2.76, 95% CI 1.90–4.01, p < 0.001) was stronger than that in studies using the Log-rank test (HR 1.41, 95% CI 1.07–1.87, p = 0.015).

Conclusions

The results of this meta-analysis suggest that LINE-1 methylation is significantly associated with the survival of CRC patients and that it could be a predictive factor for CRC prognosis.

     

Prognostic value of tropomyosin-related kinases A,B, and C in gastric cancer

Purpose

Tropomyosin-related kinase (Trk) receptors play critical roles in tumor development and are considered attractive targets for cancer therapy. We investigated correlations of the expression of TrkA, TrkB, and TrkC with clinicopathological features and outcomes in gastric cancer.

Methods

Tumor samples were obtained from 221 patients with gastric cancer who underwent gastrectomy between 2003 and 2007. The expression of TrkA, TrkB, and TrkC was analyzed using immunohistochemical staining. The relationship of their expression to clinicopathological factors and outcomes was assessed.

Results

High expression of TrkA, TrkB, or TrkC was significantly associated with histopathology (p = 0.022, p < 0.001, and p < 0.001). High expression of TrkA was significantly correlated with variables related to tumor progression, including lymph node metastasis (p = 0.024) and distant metastasis or recurrence (p < 0.001). Distant metastasis or recurrence was found in a significantly higher proportion of patients with high expression of TrkC than in those with low expression (p = 0.036). High expression of TrkA was significantly associated with poorer relapse-free survival (RFS) in univariate analysis (p = 0.001). High expression of TrkA or TrkC was significantly associated with poorer disease-specific survival (DSS) in univariate analysis (p < 0.001 and p = 0.008). In multivariate analysis, TrkA was an independent predictor of RFS [hazard ratio (HR), 2.294; 95 % confidence interval (CI), 1.309–4.032; p = 0.004] and DSS (HR, 2.146; 95 % CI, 1.195–3.861; p = 0.011). Expression of TrkB was not associated with RFS or DSS in univariate analysis.

Conclusions

Our results demonstrated that TrkA expression was associated with tumor progression and poor survival, and was an independent predictor of poor outcomes in gastric cancer patients.

     

Epigenetic status of LINE-1 predicts clinical outcome in early-stage rectal cancer

Background:

We evaluated the clinical prognostic value of methylation of two non-coding repeat sequences, long interspersed element 1 (LINE-1) and Alu, in rectal tumour tissues. In addition to DNA methylation, expression of histone modifications H3K27me3 and H3K9Ac was studied in this patient cohort.

Methods:

LINE-1 and Alu methylation were assessed in DNA extracted from formalin-fixed paraffin-embedded tissues. A pilot (30 tumour and 25 normal tissues) and validation study (189 tumour and 53 normal tissues) were performed. Histone modifications H3K27me3 and H3K9Ac were immunohistochemically stained on tissue microarrays of the study cohort.

Results:

In early-stage rectal cancer (stage I-II), hypomethylation of LINE-1 was an independent clinical prognostic factor, showing shorter patient survival (P=0.014; HR: 4.6) and a higher chance of tumour recurrence (P=0.001; HR: 9.6). Alu methylation did not show any significant correlation with clinical parameters, suggesting an active role of LINE-1 in tumour development. Expression of H3K27me3 (silencing gene expression) and H3K9Ac (activating gene expression) in relation to methylation status of LINE-1 and Alu supported this specific role of LINE-1 methylation.

Conclusion:

The epigenetic status of LINE-1, but not of Alu, is prognostic in rectal cancer, indicating an active role for LINE-1 in determining clinical outcome.     

Prognostic and predictive significance of long interspersed nucleotide element-1 methylation in advanced-stage colorectal cancer

Background

Hypomethylation of Long Interspersed Nucleotide Element-1 (LINE-1) is associated with worse prognosis in colorectal cancer (CRC). However, little is known about the relevance of this marker for the prognosis and response to chemotherapy of metastatic and recurrent (advanced-stage) CRC. Our aim was therefore to investigate whether tumor LINE-1 hypomethylation correlates with patient survival and with response to 5-fluorouracil (5-FU)/ oxaliplatin (FOLFOX) chemotherapy in advanced-stage CRC.

Methods

The study included 40 CRC patients who developed metastasis or local recurrence after surgery and subsequently underwent FOLFOX therapy. Progression-free and overall survival were estimated using the Kaplan-Meier method. LINE-1 methylation levels in formalin-fixed and paraffin-embedded primary tumor tissues were measured by MethyLight assay and correlated with patient survival. In vitro analyses were also conducted with human colon cancer cell lines having different LINE-1 methylation levels to examine the effects of 5-FU and oxaliplatin on LINE-1 activity and DNA double-strand-breaks.

Results

Patients with LINE-1 hypomethylation showed significantly worse progression-free (median: 6.6 vs 9.4 months; P?=?0.02) and overall (median: 16.6 vs 23.2 months; P?=?0.01) survival following chemotherapy compared to patients with high methylation. LINE-1 hypomethylation was an independent factor for poor prognosis (P?=?0.018) and was associated with a trend for non-response to FOLFOX chemotherapy. In vitro analysis showed that oxaliplatin increased the LINE-1 score in LINE-1-expressing (hypomethylated) cancer cells, thereby enhancing and prolonging the effect of 5-FU against these cells. This finding supports the observed correlation between tumor LINE-1 methylation and response to chemotherapy in CRC patients.

Conclusions

Tumor LINE-1 hypomethylation is an independent marker of poor prognosis in advanced-stage CRC and may also predict non-response to combination FOLFOX chemotherapy. Prospective studies are needed to optimize the measurement of tumor LINE-1 methylation and to confirm its clinical impact, particularly as a predictive marker.

     

Prognosis of gastric carcinoma patients aged 85 years or older who underwent surgery or who received best supportive care only

Background

There is controversy regarding strategies for treating very elderly patients with gastric carcinoma. We aimed to assess survival after surgery in very elderly patients according to their clinical characteristics.

Methods

Gastric cancer patients aged ≥85 years were retrospectively reviewed. There were no significant differences in clinical characteristics between 58 patients with curative resection (OP group) and 32 patients with best supportive care alone (BSC group) in cancer stage IA–IIIC and with a performance status of 0–3.

Results

Overall survival (OS) was significantly better in the OP group than in the BSC group in females [hazard ratio (HR) 0.27, 95 % confidence interval (CI) 0.12–0.57, P < 0.001] but not in males (HR 0.71, 95 % CI 0.35–1.49, P = 0.35). OS was significantly better in the OP group in patients aged 85–89 years (HR 0.44, 95 % CI 0.25–0.78, P = 0.006) but not in patients aged ≥90 years (HR 0.47, 95 % CI 0.12–1.66, P = 0.24). OS was significantly better in the OP group in patients with stage IB–IIIC cancer (HR 0.29, 95 % CI 0.14–0.58, P < 0.001) but not in patients with stage IA cancer (HR 0.52, 95 % CI 0.21–1.27, P = 0.15).

Conclusions

Females, patients aged 85–89 years, and patients with stage IB–IIIC cancer had significantly better OS with surgery than without. For males, patients aged ≥90 years, or stage IA patients, the decision to perform surgery should be carefully made, and BSC might be an optimal strategy.     

A single-center analysis of the survival benefits of adjuvant gemcitabine chemotherapy for biliary tract cancer

Background

Surgical resection is the only curative treatment of biliary tract cancer (BTC). However, the prognosis of BTC remains unsatisfactory. The aim of this study is to evaluate the benefits of adjuvant gemcitabine chemotherapy for BTC.

Methods

We performed a historical cohort study that involved 198 patients who underwent R0 surgical resection. Patients who underwent major hepatectomy were administered biweekly intravenous gemcitabine at a dose of 800 mg/m². Otherwise, patients were administered intravenous gemcitabine at a dose of 1,000 mg/m² in 3 weekly infusions, which were followed by a 1-week pause. The primary outcome was overall survival. The hazard ratio (HR) of adjuvant chemotherapy was estimated by propensity score-stratified Cox regression that was adjusted for confounders.

Results

Forty patients received adjuvant chemotherapy. The HR of adjuvant chemotherapy was 0.47 [95 % confidence interval (CI) 0.28–0.95; P = 0.03]. Subgroup analysis showed that the survival benefits were possibly modified by lymph node positivity (HR 0.19; 95 % CI 0.07–0.58; interaction, P = 0.22), stage III (HR 0.11; 95 % CI 0.02–0.50; interaction, P < 0.01), intrahepatic cholangiocarcinoma (ICC) (HR 0.09; 95 % CI 0.01–0.67; interaction, P = 0.05), and poorly differentiated tumor (HR 0.16; 95 % CI 0.03–0.85; interaction, P = 0.13).

Conclusions

Adjuvant gemcitabine chemotherapy for BTC may be effective, particularly for patients with stage III and ICC.     

Serum integrin-linked kinase (sILK) concentration and survival in non-small cell lung cancer: a pilot study

Background

Integrin-linked kinase (ILK) is an intracellular signaling protein critically involved in cellular growth and motility. In non-small cell lung cancer (NSCLC), increased ILK expression has been associated with decreased recurrence-free and overall survival. Recently, ILK has also been detected in the serum of NSCLC patients.

Objective

To assess the prognostic impact of preoperative serum ILK (sILK) concentration on overall survival in surgically amenable NSCLC.

Patients and methods

Preoperative sILK was quantified by ELISA in 50 newly diagnosed NSCLC patients. After surgery, patients were followed-up for a median interval of 2.5 years.

Results

Serum ILK concentrations ranged from 0 to 2.44 ng/ml. Mean sILK was around 2.3 times higher in the 16 patients who died as compared to the 34 patients who survived (1.04 vs. 0.45 ng/ml, p = 0.001). In univariate time-to-event analysis, increased sILK was associated with adverse survival [Hazard ratio (HR): 4.03, 95 % CI: 2.00–8.13, p < 0.001]. This association prevailed after multivariable adjustment for several clinical, demographic, and laboratory parameters (HR: 3.85, 95 % CI: 1.53–9.72, p = 0.004).

Conclusions

Serum ILK shows potential as a novel strong and independent prognostic marker for postoperative survival in surgically amenable NSCLC.     

Long-term oncologic outcomes of robotic gastrectomy for gastric cancer compared with laparoscopic gastrectomy

Background

Initial experiences with robotic gastrectomy (RG) for gastric cancer have demonstrated favorable short-term outcomes, suggesting that RG is an effective alternative to laparoscopic gastrectomy (LG). However, data on long-term survival and recurrence after RG for gastric cancer have yet to be reported. The objective of this study was to assess long-term outcomes after RG compared with LG.

Methods

We retrospectively evaluated 313 and 524 patients who underwent RG or LG, respectively, for gastric cancer between July 2005 and December 2009. We compared long-term outcomes using the entire and a propensity-score matched cohort.

Results

The entire cohort analysis revealed no statistically significant differences in 5-year overall survival(OS) or relapse-free survival(RFS) (p = 0.4112 and p = 0.8733, respectively): 93.3% [95% confidence interval (CI) 89.9–95.6] and 90.7% (95% CI, 86.9–93.5) after RG and 91.6% (95% CI 88.9–93.7) and 90.5% (95% CI 87.6–92.7) after LG, respectively; hazard ratios for death and recurrence in the robotic group were 0.828 (95% CI, 0.528–1.299; p = 0.4119) and 0.968 (95% CI, 0.649–1.445; p = 0.8741), respectively. The propensity-matched cohort analysis demonstrated no statistically significant differences for 5-year OS or RFS (p = 0.5207 and p = 0.2293, respectively): 93.2% and 90.7% after RG and 94.2% and 92.6% after LG, respectively; hazard ratios for death and recurrence in the robotic group were 1.194 (95% CI, 0.695–2.062; p = 0.5214) and 1.343 (95% CI, 0.830–2.192; p = 0.2321), respectively.

Conclusion

The potential technical superiority of robotic system over laparoscopy did not improve oncological outcomes after gastrectomy. Long-term oncological outcomes were not different between RG and LG. Nevertheless, robotic applications in minimally invasive gastric cancer surgery may be an oncologically safe alternative.

     

Early gastric cancer: diagnosis, staging, and clinical impact. Evaluation of 530 patients. New elements for an updated definition and classification

Background

The prevention and early diagnosis of gastric cancer permit clinicians to discover the tumor in the initial phase, during which time it can be completely eradicated, endoscopically or surgically. Since Murakami gave the definition of early gastric cancer (EGC) in 1971, many authors have identified various subtypes of EGC with different morphological characteristics and clinical behaviour.

Methods

We evaluated retrospectively 530 patients: the median follow-up time was 10.4 months (range 0.3–29.2). All tumors were classified according to the macroscopic and microscopic criteria proposed by the Japanese Society of Gastroenterology and Endoscopy and Lauren, respectively. The infiltrative growth pattern was evaluated according to Kodama’s classification. Only tumor-related death was considered as an endpoint of interest for the survival analysis.

Results

The overall survival rates of our patients were 94 % (95 % CI, 92–96) and 90 % (95 % CI, 87–93) at 5 and 10 years, respectively. Only 44 patients (8.3 %) died of the disease. Kodama’s type (p < 0.0001), lymph node status, both for number and pathological stage according to the 7th Edition of TNM (p < 0.0001), and depth of infiltration (p = 0.0006) were significant prognostic factors in univariate analysis. The multivariate analysis identified Kodama’s PENA type (HR, 3.91; 95 % CI, 2.08–7.33; p < 0.0001) and lymph node status for more than three positive nodes versus negative nodes (HR, 12.78; 95 % CI, 5.37–30.43; p < 0.0001) as the only independent prognostic factors in our series.

Conclusion

Lymph node status, especially when more than three lymph nodes are involved, is the most important prognostic factor in EGC. However, it is also important to evaluate the infiltrative growth pattern of the cancers in their early phase according to Kodama’s classification, considering PEN A type lesions to be more aggressive than the other EGC types. Then, we propose new elements for an updated definition and classification of EGC, with an important clinical impact on the treatment of patients.     

Prognostic factors affecting survival in metastatic soft tissue sarcoma: an analysis of 110 patients

Background

Data on treatment outcome and prognostic factors in patients with metastatic soft tissue sarcoma (STS) are limited in the literature.

Methods

A total of 119 patients with metastatic STS treated between June 2003 and December 2012 were analyzed for treatment outcome and prognostic factors.

Results

Median age was 37 years (range 2–72 years) with a male to female ratio of 1.5:1. Most common histologic subtypes were synovial sarcoma (36 %) and leiomyosarcoma (16 %). Median tumor size was 12 cm (range 1.6–30 cm). Twenty-four (20 %) patients were treated with multimodality therapy and 80 % patients received systemic chemotherapy alone. At a median follow-up of 10 months (range 1–66 months), the 2-year EFS and OS were 10 and 19 %, respectively, with a median EFS and OS of 6 and 10 months, respectively. Univariate analysis identified albumin ≤4 g/dl (p = 0.001), histologic subtypes other than synovial sarcoma (p = 0.02), non-extremity tumors (p = 0.03) and single modality treatment (p = 0.03) as factors predicting poor EFS; however, for OS, hemoglobin ≤10 g/dl (p = 0.02), tumor size >10 cm (p = 0.01) and single modality treatment (p = 0.04) were identified as poor prognostic factors. Multivariate analysis identified only serum albumin ≤4 g/dl (p = 0.002, HR 0.47, 95 % CI 0.29–0.75) associated with poor EFS; however, for OS, hemoglobin ≤10 g/dl (p = 0.009, HR 0.49, 95 % CI 0.29–0.83), tumor size >10 cm (p = 0.003, HR 2.11, 95 % CI 1.28–3.47) and single modality treatment (p = 0.01, HR 0.47, 95 % CI 0.25–0.86) emerged as poor prognostic factors.

Conclusions

Serum albumin, tumor size, hemoglobin and treatment modality affect survival in metastatic STS.

     

Prognosis of patients with advanced gastric cancer by HER2 status and trastuzumab treatment

Background

The purpose of this study was to evaluate the impact of human epidermal growth factor receptor 2 (HER2) status and trastuzumab treatment on the prognosis of patients with advanced gastric cancer (AGC).

Methods

We retrospectively analyzed 364 AGC patients who received systemic chemotherapy. To evaluate the impact of trastuzumab exposure during any type of chemotherapy, our analysis used time-varying covariates to avoid a possible lead-time bias.

Results

Among the 364 patients, 58 (15.9 %) were HER2-positive. The median overall survival of the HER2-positive patients treated with trastuzumab (n = 43) was significantly longer than that of the HER2-negative patients [n = 306; 24.7 vs. 13.9 months, with an adjusted hazard ratio (HR) of 0.58; 95 % confidence interval (CI), 0.36–0.95; P = 0.03]. Notably, 22 patients continued with trastuzumab beyond the date of progression. By contrast, the HER2-positive patients not treated with trastuzumab (n = 15) showed survival similar to that of the HER2-negative patients (13.5 vs. 13.9 months, with an adjusted HR of 1.04; 95 % CI, 0.52–2.11; P = 0.91). According to the multivariate analysis, exposure to trastuzumab was independently associated with a better prognosis (HR 0.56; 95 % CI; 0.33–0.93; P = 0.026).

Conclusions

Recent HER2-positive AGC patients have a better prognosis than HER2-negative patients, particularly when treated with trastuzumab.     

Anthracycline-based triplets do not improve the efficacy of platinum-fluoropyrimidine doublets in first-line treatment of advanced gastric cancer: real-world data from the AGAMEMON National Cancer Registry

Background

Although anthracycline-based triplets are one of the most widely used schedules to treat advanced gastric cancer (AGC), the benefit of including epirubicin in these therapeutic combinations remains unknown. This study aims to evaluate both the efficacy and tolerance of triplets with epirubicin vs. doublets with platinum-fluoropyrimidine in a national AGC registry.

Methods

Patients with AGC treated with polychemotherapy without trastuzumab at 28 hospitals in Spain between 2008 and 2016 were included. The effect of anthracycline-based triplets against doublets was evaluated by propensity score matching (PSM) and Cox proportional hazards (PH) regression.

Result

A total of 1002 patients were included (doublets, n = 653; anthracycline-based triplets, n = 349). The multivariable Cox PH regression failed to detect significantly increased OS in favor of triplets with anthracyclines: HR 0.90 (95% CI, 0.78–1.05), p = 0.20035. After PSM, the sample contained 325 pairs with similar baseline characteristics. This method was also unable to reveal an increase in OS: 10.5 (95% CI, 9.7–12.3) vs. 9.9 (95% CI, 9.2–11.4) months, HR 0.91 (CI 95%, 0.76–1.083), and (log-rank test, p = 0.226). Response rates (42.1 vs. 33.1%, p = 0.12) and PFS (HR 0.95, CI 95%, 0.80–1.13, log-rank test, p = 0.873) were not significantly higher with epirubicin-based regimens. The triplets were associated with greater grade 3–4 hematological toxicity, and increased hospitalization due to toxicity by 68%. The addition of epirubicin is viable, but 23.7% discontinued treatment because of adverse effects or patient decision.

Conclusion

Anthracyclines added to platinum-fluoropyrimidine doublets did not improve the response rate or survival outcomes in patients with AGC but entailed greater toxicity.

     

Correlation of toxicity and efficacy with pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD) (Caelyx®)

Purpose

Pegylated liposomal doxorubicin (PLD) is used to treat patients with breast and gynecological cancers. In order to optimize treatment with PLD, we assessed the prognostic and predictive factors for efficacy of PLD.

Methods

Seventeen patients treated with PLD 30 or 40 mg/m² underwent pharmacokinetic sampling during the first cycle of treatment. PLD exposure was calculated. An univariate analysis was performed with the variables: hand–foot syndrome, mucositis, rash, neutropenia, age, tumor type, number of previous therapies, ECOG performance status and progression-free survival (PFS). Candidate variables with p ≤ 0.1 were selected for the multivariate analysis.

Results

Based on the results of the multivariate analysis, the PLD exposure (log AUC) was higher in patients who experienced rash (p = 0.002) and mucositis (p = 0.001) compared to those who did not have these adverse events. The development of hand–foot syndrome was significantly related to a lower risk of disease progression (HR 0.1; 95 % CI 0.02–0.64). Patients with an ECOG status of 0 had a longer PFS than the patients with an ECOG status of 1 (HR 5.4; 95 % CI 1.3–22.8). Moreover, PLD exposure (ln AUC) was also positively related to PFS (HR 0.001; 95 % CI 0.00–0.42).

Conclusions

The extent of the exposure to PLD was correlated with more adverse events and longer PFS. This has important clinical implications, since dose reductions or interruptions might thus negatively affect treatment outcomes. More attention should be paid to preventive and supportive measures of adverse events of PLD to keep the exposure to PLD as high as possible.     

Increased expression of α5β1-integrin is a prognostic marker for patients with gastric cancer

Objective

The study was to evaluate the association of expression level of α5β1-integrin with clinicopathologic features and prognosis in gastric cancer (GC).

Methods

The expression of α5β1-integrin in normal gastric mucosa and GC tissue was detected with immunohistochemistry. The level of α5 and β1 mRNA in GC tissues and non-neoplastic tissues was evaluated in 48 paired cases by quantitative real-time polymerase chain reaction (qRT-PCR). Survival analysis by the Kaplan–Meier method was performed to assess prognostic significance.

Results

The α5β1-integrin expression was detected in 68.3 % (127/186) GC samples, and there was a significant difference on their positive expression rate between GC tissue and normal gastric mucosa (P < 0.001). The positive expression rate of α5β1-integrin in patients with poor histologic differentiation (P = 0.001), lymph node metastasis (P < 0.001), and recurrence (P < 0.001) group was heightened. Using Kaplan–Meier analysis, a comparison of survival curves of low versus high expresser of α5β1-integrin revealed a highly significant difference in human GC tissue (P = 0.002), which suggested that overexpression of α5β1-integrin is associated with a worse prognosis. Multivariate analyses showed that α5β1-integrin expression was independent risk factor predicting overall survival [Hazard ratio (HR) 1.594, 95 % confidence interval (CI) 1.236–2.408, P = 0.006] and disease-free survival [HR 3.952, 95 % CI 1.676–9.861, P = 0.003] in GC.

Conclusions

The α5β1-integrin promotes angiogenesis and associates with lymph node metastasis, vascular invasion and poor prognosis of GC. The current study shows that α5β1-integrin may be an independent prognostic factor for GC patients.     

Adiposity,post-diagnosis weight change,and risk of cardiovascular events among early-stage breast cancer survivors

Purpose

We hypothesized different Overall Survival (OS) in metastatic breast cancer (MBC) after relapse vs de novo presentation.

Methods

We identified women in British Columbia with MBC diagnosed between 01/2001 and 12/2009. OS from MBC was calculated for relapsed vs de novo cohorts in 3 subgroups, based on hormone receptors (HR) and HER2 status. Age at MBC, disease-free interval (DFI), de novo vs relapsed, year of MBC diagnosis, and systemic treatment were entered into univariable and multivariable analyses.

Results

We identified 3645 pts with known HR of which 2796 had known HER2. Median follow-up was 91 months. Median OS was longer for de novo vs relapsed MBC: HR+/HER2- 34 versus 23 months (mos) (p < 0.0001), HR?/HER2- (TN) 11 versus 8 mos (p = 0.02), HER2+ 29 versus 15 mos (p < 0.0001). For TN disease, no variable independently discriminated a group with increased risk of death. For both the HR +/HER2- and the HER2 + groups, relapsed vs de novo status (HzR 1.4 [95% CI 1.2–1.5; p < 0.0001], and HzR 1.6 [95% CI 1.4–1.9; p < 0.0001], respectively) and age >50 (HzR 1.2 [95% CI 1.1–1.4; p = 0.001] and HzR 1.3 [95% CI 1.1–1.5; p = 0.01], respectively) were associated with increased risk of death on multivariable analysis.

Conclusion

These data provide information that may guide discussions about prognosis between physicians and patients with MBC. In addition, it highlights the importance of stratifying for initial stage at diagnosis in future MBC therapeutic trials.

     

Subtype-specific prognostic impact of different immune signatures in node-negative breast cancer

Background

The role of different subtypes of immune cells is still a matter of debate.

Methods

We compared the prognostic relevance for metastasis-free survival (MFS) of a B-cell signature (BS), a T-cell signature (TS), and an immune checkpoint signature (CPS) in node-negative breast cancer (BC) using mRNA expression. Microarray-based gene-expression data were analyzed in six previously published cohorts of node-negative breast cancer patients not treated with adjuvant therapy (n = 824). The prognostic relevance of the individual immune markers was assessed using univariate analysis. The amount of independent prognostic information provided by each immune signature was then compared using a likelihood ratio statistic in the whole cohort as well as in different molecular subtypes.

Results

Univariate Cox regression in the whole cohort revealed prognostic significance of CD4 (HR 0.66, CI 0.50–0.87, p = 0.004), CXCL13 (HR 0.86, CI 0.81–0.92, p < 0.001), CD20 (HR 0.76, CI 0.64–0.89, p = 0.001), IgκC (HR 0.81, CI 0.75–0.88, p < 0.001), and CTLA-4 (HR 0.67, CI 0.46–0.97, p = 0.032). Multivariate analyses of the immune signatures showed that both TS (p < 0.001) and BS (p < 0.001) showed a significant prognostic information in the whole cohort. After accounting for clinical-pathological variables, TS (p < 0.001), BS (p < 0.05), and CPS (p < 0.05) had an independent effect for MFS. In subgroup analyses, the prognostic effect of immune cells was most pronounced in HER2+ BC: BS as well as TS showed a strong association with MFS when included first in the model (p < 0.001).

Conclusion

Immune signatures provide subtype-specific additional prognostic information over clinical-pathological variables in node-negative breast cancer.

     

Is extracapsular tumour spread a prognostic factor in patients with early breast cancer?

Background

This study searched for extra capsular tumour spread (ECS) as a prognostic factor for recurrence in terms of Disease Free Survival (DFS) and Overall Survival (OS).

Patients and methods

For this study, from a retrospective database of the Doubs cancer registry, 823 eligible women with node positive breast cancer treated from February 1984 to November 2000 were identified. The following factors were evaluated: ECS, numbers of involved nodes, histological tumour grade, tumour size, status of estrogen and progesterone receptors, and age of patient. A Cox proportional hazards method was used to search for significant factors related to OS and DFS length.

Results

In the multivariate analysis, factors related to DFS length were found to be: tumour grade (aHR 0.76, 95 % CI 0.61–0.96, p = 0.02), ECS status (aHR 0.7, 95 % CI 0.49–0.96, p = 0.03), progesterone (PgR) status (aHR 0.63, 95 % CI 0.44–0.85 p = 0.008), number of nodes involved (aHR 0.75, 95 % CI 0.56–1, p = 0.05). The multivariate analysis for OS found as significant factors: tumour grade (aHR 0.76, 95 % CI 0.61–0.95; p = 0.02) and PgR status (aHR 0.8, 95 % CI 0.56–0.99, p = 0.02).

Conclusions

This study might suggest taking into account ECS status in the adjuvant decision-making process.     

Genetic polymorphism of cytochrome P450 (CYP) 1A1, CYP1A2, and CYP2E1 genes modulate susceptibility to gastric cancer in patients with Helicobacter pylori infection

Background

Activity of cytochrome P450 (CYP), a polymorphic carcinogen-activating enzyme, is exaggerated following Helicobacter pylori infection. We studied the role of CYP2E1, CYP1A2 (rs762551), and CYP1A1 (rs4646903) polymorphisms in association with H. pylori infection in gastric carcinogenesis.

Methods

Genotyping of CYP2E1 (96-bp insertion), CYP1A2 (164A to C), and CYP1A1 (3801C to T) was carried out in 88, 76, 53, and 170 patients with gastric cancer (GC), functional dyspepsia (FD), peptic ulcer (PU), and healthy controls (HC), respectively. Serum IgG antibody (all subjects), rapid urease test, and histology (GC, FD, and PU patients) were used to test for H. pylori.

Results

CYP2E1 gene polymorphism was more common among patients with GC than HC and PU [48/88 (54.5 %) vs. 67/170 (39.4 %); OR 1.9, 95 % CI 1.1–3.2, p = 0.016) and [PU 18/53 (34 %); OR 2.3 (1–4.7), p = 0.02]. CYP1A2 CC or CT genotypes was lower among patients with GC than HC [50/88 (56.8 %) vs. 120/170 (70.6 %); OR 0.54 (0.31–0.92), p = 0.023]. CYP1A1 polymorphism and CYP1A1–CYP1A2 haplotypes were comparable among different groups. CYP2E1 was also more common in patients with GC than HC and PU in the absence of H. pylori [33/60 (55 %) vs. 19/52 (36.5 %); OR 4 (1.5–11.4), p = 0.007 and PU 7/22 (31.8 %); OR 3.4 (1–11.6), p = 0.05]. CYP1A1 (CT + TT) was more common in patients with GC than PU in presence of H. pylori [17/26 (65.4 %) vs. 11/29 (38 %); OR 3.0 (1.03–9.3), p = 0.045].

Conclusions

The presence of CYP2E1 (96-bp insertion) is associated with increased risk of GC even in absence of H. pylori. CYP1A2 CC or CT is associated with reduced risk of GC.     

Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer

Purpose

The aim of this study was to evaluate efficacy and safety of gemcitabine plus S-1 (GS) combination chemotherapy in patients with unresectable pancreatic cancer.

Methods

Patients were randomly assigned to receive GS (oral S-1 60 mg/m² daily on days 1–15 every 3 weeks and gemcitabine 1,000 mg/m² on days 8 and 15) or gemcitabine (1,000 mg/m² on days 1, 8, and 15 every 4 weeks). The primary endpoint was progression-free survival (PFS).

Results

One hundred and one patients were randomly assigned. PFS was significantly longer in the GS arm with an estimated hazard ratio (HR) of 0.65 (95 % CI 0.43–0.98; P = 0.039; median 5.3 vs 3.8 months). Objective response rate (ORR) was also better in the GS arm (21.6 vs 6 %, P = 0.048). Median survival was 8.6 months for GS and 8.6 months for GEM (HR 0.93; 95 % CI 0.61–1.41; P = 0.714). Grade 3–4 neutropenia (44 vs 19.6 %, P = 0.011) and thrombocytopenia (26 vs 8.7 %, P = 0.051) were more frequent in the GS arm.

Conclusions

GS therapy improved PFS and ORR with acceptable toxicity profile in patients with unresectable pancreatic cancer.