EGFR and KRAS mutations in lung carcinoma: molecular testing by using cytology specimens

BACKGROUND:

The aim of this study was to validate clinical utilization of routinely prepared cytology specimens for molecular testing to detect EGFR or KRAS mutations in lung cancer.

METHODS:

From September 2009 to April 2010, the authors collected 209 cytology specimens from patients with lung cancer at the MD Anderson Cancer Center Department of Pathology. The specimens included 99 cases of endobronchial ultrasound‐guided (EBUS) fine‐needle aspiration (FNA), 67 cases of computed tomography (CT)‐guided FNA, 27 cases of body fluid, 10 cases of ultrasound‐guided of superficial FNA, and 6 cases of other cytology specimens. DNA sequencing for EGFR exons 18‐21 and KRAS codons 12, 13, and 61 was performed.

RESULTS:

The overall specimen insufficiency rate was low (6.2%). EBUS (4%) and body‐fluid cases (3.7%) showed lower insufficiency rates than the other cases. Similar insufficiency rates were observed in smears (6.1%) and cell‐block sections (6.4%). EGFR mutations were detected in 19.4% (34 of 175) of nonsmall cell lung carcinoma (NSCLC) with a significantly higher frequency in adenocarcinoma (29%, 29 of 100) than in nonadenocarcinoma (7%, 5 of 75, P = .002). KRAS mutations were detected in 23.6% (41 of 174) of NSCLCs with no statistical differences between adenocarcinoma (26%, 26 of 102) and nonadenocarcinoma (21%, 17 of 72, P = .86). Higher frequencies of EGFR mutations in exons 19 and 21 (65%) than in exons 18 and 20 were detected.

CONCLUSIONS:

Our findings support clinical utilization of routinely prepared cytology specimens, including EBUS, CT/US. FNAs and body fluid specimens, as a reliable source for molecular testing to detect EGFR or KRAS mutations in patients with NSCLC. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

BRAF Mutation is associated with early stage disease and improved outcome in patients with low‐grade serous ovarian cancer

BACKGROUND:

Low‐grade serous (LGS) ovarian cancer is a chemoresistant disease that accounts for 10% of serous ovarian cancers. Prior studies have reported that 28% to 35% of serous borderline (SB)/LGS ovarian tumors harbor a BRAF mutation, suggesting that BRAF inhibitors may be a rational therapeutic approach for this disease. In the current study, the authors sought to determine whether BRAF or KRAS mutation status was associated with disease stage and/or histology in patients with SB and LGS ovarian cancer.

METHODS:

Genetic profiles were constructed for 75 SB and LGS ovarian tumors to determine BRAF and KRAS mutation status. The incidence and identity of BRAF and KRAS mutations were defined, and the results were correlated with disease stage, response to treatment, and overall survival.

RESULTS:

Of 75 samples examined, 56 tumors (75%) had SB histology, and 19 tumors (25%) had LGS histology. Fifty‐seven percent of tumors harbored either a KRAS mutation (n = 17) or a BRAF mutation (a valine‐to‐glutamate substitution at residue 600 [V600E]; n = 26). The BRAF V600E mutation was associated significantly with early disease stage (stage I/II; P < .001) and SB histology (P = .002). KRAS mutations were not associated significantly with disease stage or histology. Of the 22 patients (29%) who required chemotherapy, 20 had tumors with wild‐type KRAS/BRAF, 2 had KRAS mutant tumors, and none had tumors that harbored a BRAF mutation. All patients with BRAF tumors remained alive at a median follow‐up of 3.6 years (range, 1.9–129.3 months).

CONCLUSIONS:

V600E BRAF mutations were present in 35% of patients who had SB/LGS ovarian cancers. The presence of the BRAF V600E mutation in SB/LGS ovarian cancer was associated with early stage disease and improved prognosis. The authors concluded that patients with SB/LGS ovarian cancer who require systemic therapy are unlikely to have BRAF mutant tumors. Cancer 2013. © 2012 American Cancer Society.     

Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma

BACKGROUND:

Gemcitabine (2′,2′‐difluorodeoxycytidine) administration after resection of pancreatic cancer improves both disease‐free survival (DFS) and overall survival (OS). Deoxycytidine kinase (dCK) mediates the rate‐limiting catabolic step in the activation of gemcitabine. The authors of this report studied patient outcomes according to the expression of dCK after a postoperative gemcitabine‐based chemoradiation regimen.

METHODS:

Forty‐five patients with resected pancreatic adenocarcinoma received adjuvant gemcitabine based‐therapy in the context of multicenter phase 2 studies. Their tumors were evaluated retrospectively for dCK protein expression by immunohistochemistry. A composite score based on the percentage of dCK‐positive cancer cells and the intensity of staining was generated, and the results were dichotomized at the median values.

RESULTS:

The median follow‐up was 19.95 months (95% confident interval [CI], 3.3‐107.4 months). The lymph node (LN) ratio and dCK protein expression were significant predictors of DFS and OS in univariate analysis. On multivariate analysis, dCK protein expression was the only independent prognostic variable (DFS: hazard ratio [HR], 3.48; 95% CI, 1.66‐7.31; P = .001; OS: HR, 3.2; 95% CI,1.44‐7.13; P = .004).

CONCLUSIONS:

dCK protein expression was identified as an independent and strong prognostic factor in patients with resected pancreatic adenocarcinoma who received adjuvant gemcitabine therapy. The authors concluded that it deserves prospective evaluation as a predictive biomarker for patient selection. Cancer 2010. © 2010 American Cancer Society.     

Improved survival for fallopian tube cancer

BACKGROUND.

Fallopian tube cancers are rare neoplasms. These malignancies are thought to behave biologically and clinically like ovarian cancer. The purpose of this study was to compare the clinical behavior and outcome of fallopian tube and ovarian cancer.

METHODS.

The Surveillance, Epidemiology, and End Results database was reviewed to identify women with tumors of the fallopian tube (FT) and ovary (OV) diagnosed between 1988 and 2004. Demographic and clinical data were compared, and the impact of tumor site on survival was analyzed using Cox models and the Kaplan‐Meier method.

RESULTS.

A total of 55,825 patients were identified, 1576 (3%) with FT and 54,249 (97%) with OV cancer. FT patients were more likely to present with early stage tumors (P < .001). Among FT patients, 47% had stage I/II tumors compared with 29% of OV cancers. In an adjusted Cox model of all patients, cancer‐specific mortality was 48% lower in FT patients (hazard ratio, 0.52; 95% confidence interval [CI], 0.48‐0.56) compared with OV cancer. Among patients with FT tumors, advanced age and stage were independent predictors of decreased survival. When stratified by stage, survival was similar for stage I and II tumors, but stage III and IV FT patients had an improved survival. The 5‐year survival for stage III FT cancer was 54% (95% CI, 48%‐60%), compared with 30% (95% CI, 29%‐31%) for OV.

CONCLUSIONS.

Fallopian tube cancers present earlier and at advanced stage have a better overall survival than primary ovarian malignancies. Future clinical trials should recognize the possible distinct clinical behavior of fallopian tube cancers. Cancer 2008. © 2008 American Cancer Society.     

Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer

BACKGROUND.

Pancreatic cancer is a multifactorial disease with metastasis‐prone and therapy‐resistant nature. The authors hypothesized that genetic variants of glutathione S‐transferase (GST) affect detoxification of carcinogens and anticancer agents in the human pancreas and, thus, the risk and survival of pancreatic cancer.

METHODS.

Genotypes of GSTM1, GSTT1, and GSTP1 were determined in 352 patients with pancreatic ductal adenocarcinoma and in a control group of 315 healthy, non‐Hispanic whites (frequency‐matched by age and sex). Survival analysis was performed in a subset of 290 patients. Epidemiological and clinical information was obtained. A multiple unconditional logistic regression model, a Cox proportional hazards model, and log‐rank tests were used for statistical analysis.

RESULTS.

No significant main effects of any of 3 GST genes on the risk of pancreatic cancer were observed. Subgroup analysis showed that older individuals (aged ≥62 years) who carried the GSTP1*C (¹⁰⁵Val‐¹¹⁴Val) containing genotype tended to have a reduced risk compared with younger individuals who carried the non‐*C genotype (for sex and pack‐years of smoking, the adjusted odd ratio was 0.54; 95% confidence interval [95% CI], 0.29–1.02). In a survival analysis of 138 patients who received 5‐flurorouracil, patients who carried the GSTP1*C containing genotype had a significantly longer survival than patients who carried the non‐*C genotype (multivariate hazard ratio, 0.45; 95% CI, 0.22–0.94).

CONCLUSIONS.

The GSTP1*C variant conferred a possible protective effect against pancreatic cancer in older individuals and a significant survival advantage in patients who received 5‐florouracil. The current findings must be confirmed before further inferences can be made. Cancer 2007 © 2007 American Cancer Society.     

Human pancreatic cancer fusion 2 (HPC2) 1‐B3: A novel monoclonal antibody to screen for pancreatic ductal dysplasia

BACKGROUND.

Pancreatic ductal adenocarcinoma is rarely detected early enough for patients to be cured. The objective of the authors was to develop a monoclonal antibody to distinguish adenocarcinoma and precancerous intraductal papillary mucinous neoplasia (IPMN) from benign epithelium.

METHODS.

Mice were immunized with human pancreatic adenocarcinoma cells and monoclonal antibodies were screened against a panel of archived pancreatic tissue sections, including pancreatitis (23 cases), grade 1 IPMN (16 cases), grade 2 IPMN (9 cases), grade 3 IPMN (13 cases), and various grades of adenocarcinoma (17 cases). One monoclonal antibody, human pancreatic cancer fusion 2 (HPC2) 1‐B3, which specifically immunostained adenocarcinoma and all grades of IPMN, was isolated. Subsequently, HPC2 1‐B3 was evaluated in a retrospective series of 31 fine‐needle aspiration (FNA) biopsies from clinically suspicious pancreatic lesions that had long‐term clinical follow‐up.

RESULTS.

HPC2 1‐B3 was negative in all 31 cases of chronic pancreatitis that were tested. In contrast, HPC2 1‐B3 immunostained the cytoplasm and luminal surface of all 16 well‐ to moderately differentiated pancreatic ductal adenocarcinomas. It demonstrated only weak focal staining of poorly differentiated carcinomas. All high‐grade IPMNs were found to be positive for HPC2 1‐B3. The majority of low‐grade to intermediate‐grade IPMNs were positive (66% of cases). Immunostaining a separate series of pancreatic FNA cell blocks for HPC2 1‐B3 demonstrated that the relative risk for detecting at least low‐grade dysplasia (2.0 [95% confidence interval, 1.23‐3.26]) was statistically significant (P = .002 by the Fisher exact test).

CONCLUSIONS.

To reduce the mortality of pancreatic cancer, more effective early screening methods are necessary. The data from the current study indicate that a novel monoclonal antibody, HPC2 1‐B3, may facilitate the diagnosis of early pancreatic dysplasia. Cancer (Cancer Cytopathol) 2013;121:37–46 © 2012 American Cancer Society.     

KRAS mutation status in primary nonsmall cell lung cancer and matched metastases

BACKGROUND:

The objective of this study was to determine whether the mutation status of the v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) differed between primary tumors and matched distant metastases in nonsmall cell lung cancer (NSCLC).

METHODS:

Patients who underwent resection for both primary NSCLC and matched distant metastases were included in the study. KRAS and EGFR mutation status were assessed by polymerase chain reaction (PCR) amplification and direct sequencing on both primary tumors and metastases. For KRAS analysis, mutant‐enriched PCR (ME‐PCR) was performed in case of discordance between a primary tumor and its matched metastasis.

RESULTS:

Twenty‐one patients were included. No EGFR mutations were detected. KRAS mutations were detected in 6 patients (28%). In all patients, the mutations identified by direct sequencing were discordant between the primary tumor and the matched metastasis. The use of ME‐PCR allowed a resolution of the discordance in 3 of the 6 cases by demonstrating the presence of low levels of mutant KRAS in lesions that were negative by direct sequencing.

CONCLUSIONS:

Highly sensitive tools are required to identify biomarkers. The KRAS mutation status mostly was concordant between primary tumors and matched distant metastases. In a few patients, KRAS mutation status differed between different tumor sites. Cancer 2010. © 2010 American Cancer Society.     

CK19 and CD10 expression in pancreatic neuroendocrine tumors diagnosed by endoscopic ultrasound‐guided fine‐needle aspiration cytology

BACKGROUND:

CK19 and CD10 are useful markers in the differential diagnosis of pancreatic tumors. The authors evaluated CK19 and CD10 expression in pancreatic neuroendocrine tumors (NETs) obtained by endoscopic ultrasound (EUS)‐guided fine‐needle aspiration (FNA).

METHODS:

Twenty‐eight patients diagnosed with pancreatic NETs based on EUS‐FNA cytology were studied retrospectively (2004‐2007) for immunohistochemical expression of CK19 and CD10. Immunohistochemistry was performed on cell blocks for each case. The pattern of expression for CD10 (cytoplasmic or membranous) and its intensity (0‐2) were noted. The staining of the stromal elements for CD10 was recorded as negative. Cytoplasmic staining in tumor cells and percentage distribution (1+ to 4+) for CK19 were regarded as positive.

RESULTS:

Twenty‐three of 28 (82.14%) NETs showed positive cytoplasmic and/or membranous staining for CD10, and 25 of 28 (89.29%) cases were positive for CK19.

CONCLUSIONS:

The findings demonstrate the high expression of CD10 and CK19 in pancreatic NETs. This indicates that CD10 and CK19 cannot reliably differentiate NETs from other tumors with similar cytomorphologic features (solid pseudopapillary tumors, which frequently stain with CD10, and pancreatic adenocarcinoma, which stains with CK19). Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Suicide in patients with pancreatic cancer

BACKGROUND:

Depression is highly prevalent in patients with pancreatic cancer and can result in fatal outcomes from suicides. The authors report suicide rates among patients with pancreatic cancer in the United States and identify factors associated with greater suicide rates.

METHODS:

The current study reviewed data in the SEER database for patients diagnosed with pancreatic adenocarcinoma from 1995‐2005. Logistic regression models were used to perform multivariate modeling for factors associated with suicide, while Kaplan‐Meier analysis was used to assess factors affecting survival.

RESULTS:

Among 36,221 patients followed for 22,145 person‐years, the suicide rate was 135.4 per 100,000 person‐years. The corresponding rate in the US population aged 65‐74 years was 12.5 per 100,000 person‐years, with a Standardized Mortality Ratio (SMR) of 10.8 (95% CI, 9.2‐12.7). Greater suicide rates were noted in males (Odds Ratio (OR) 13.5 [95% CI, 3.2‐56.9, P < .001]) and, among males, in patients undergoing an operative intervention (OR 2.5 [95% CI, 1.0‐6.5, P = .05]). Married men had a lesser risk of committing suicide (OR 0.3 [95% CI, 0.1‐0.6, P = .002]). Median survival among patients undergoing operative intervention was 2 months for those who committed suicide compared with 10 months for those who did not commit suicide.

CONCLUSIONS:

Male patients with pancreatic adenocarcinoma have a risk of suicide nearly 11 times that of the general population. Patients who undergo an operative intervention are more likely to commit suicide, generally in the early postoperative period. Cancer 2011. © 2010 American Cancer Society.     

Tumor suppressor XIAP‐Associated factor 1 (XAF1) cooperates with tumor necrosis factor‐related apoptosis‐inducing ligand to suppress colon cancer growth and trigger tumor regression

BACKGROUND:

XIAP‐associated factor 1 (XAF1) antagonizes the anticaspase activity of XIAP (X‐linked inhibitor of apoptosis) and functions as a tumor suppressor in colon cancer. The tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is known as a potential anticancer agent. In this study, the synergistic effect of XAF1 and TRAIL on colon cancer growth was investigated.

METHODS:

Adeno‐XAF1 virus was generated and purified. Cell apoptosis was detected by flow‐cytometry and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling assay. Protein expression of the different genes was determined by Western blot analysis. Tumorigenesis and tumor growth were assessed in subcutaneous nude mouse xenograft experiments.

RESULTS:

Stable overexpression of XAF1‐sensitized colon cancer cells to TRAIL‐induced apoptosis significantly increased the activity of caspase 3, 7, 8, and 9; released cytochrome c; and down‐regulated XIAP, survivin, and c‐IAP‐2. The restoration of XAF1 expression mediated by adenovirus (adeno‐XAF1) directly induced apoptosis, and synergized TRAIL‐induced apoptosis in colon cancer cells. Ex vivo transduction of adeno‐XAF1 suppressed colon cancer formation in vivo. Furthermore, adeno‐XAF1 treatment of mice significantly inhibited tumor growth, strongly enhanced TRAIL‐induced apoptosis and antitumor activity in colon cancer xenograft models in vivo, and markedly prolonged the survival. Notably, the combined treatment with adeno‐XAF1 and TRAIL completely eradicated the established tumors without detectable toxicity in normal tissue.

CONCLUSIONS:

The combined restoration of XAF1 expression and TRAIL treatment may be a potent strategy for colon cancer therapy. Cancer 2010. © 2010 American Cancer Society.     

Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma

BACKGROUND:

Neoadjuvant therapy has been used to improve survival in operable pancreatic cancer. The authors' objective was to compare long‐term outcomes in patients receiving neoadjuvant versus adjuvant therapy for resectable pancreatic adenocarcinoma.

METHODS:

The California Cancer Surveillance Program for Los Angeles County retrospectively identified 458 patients with nonmetastatic pancreatic adenocarcinoma who underwent definitive pancreatic resection and received systemic chemotherapy between 1987 and 2006. The cohort was grouped by timing of systemic therapy—neoadjuvant or adjuvant. Clinicopathologic characteristics and overall survival were compared. Multivariate Cox regression analysis was used to determine the benefit of neoadjuvant therapy, independent of other significant factors.

RESULTS:

Of the 458 patients, 39 (8.5%) received neoadjuvant therapy, and 419 (91.5%) received adjuvant therapy. There was a significantly lower rate of lymph node positivity in the neoadjuvant group (45% vs 65%; P = .011) despite a higher rate of extrapancreatic tumor extension. On Kaplan‐Meier analysis, the neoadjuvant group had significantly better overall survival compared with the adjuvant group (median survival, 34 vs 19 months; P = .003). Overall survival was also improved in the neoadjuvant therapy patients with extrapancreatic disease (median survival, 31 vs 19 months; P = .018). On multivariate Cox regression analysis, neoadjuvant therapy was an independent predictor of improved survival (hazard ratio, 0.57; 95% confidence interval, 0.37‐0.89; P = .013).

CONCLUSIONS:

This is the first population‐based study to compare neoadjuvant versus adjuvant treatment strategies in resectable pancreatic cancer. Neoadjuvant therapy is associated with a lower rate of lymph node positivity and improved overall survival and should be considered an acceptable alternative to the surgery‐first paradigm in operable pancreatic cancer. Cancer 2011. © 2010 American Cancer Society     

Analysis of incidence and clinical outcomes in patients with thromboembolic events and invasive exocrine pancreatic cancer

BACKGROUND:

Pancreatic adenocarcinoma is among the most common malignancies associated with thromboembolic events (TEs); however, reported incidence figures vary significantly and contain small patient cohorts. Pancreatic cancer‐specific thrombosis studies examining the correlation between clinical variables, including thrombosis timing and the impact of thrombosis on survival, have not been reported.

METHODS:

Survival analyses were performed relating to the development and timing of a TE in 1915 patients administered chemotherapy at Memorial Sloan‐Kettering Cancer Center with invasive exocrine pancreatic cancer from January 1, 2000 to December 31, 2009. TE timing, relative to clinical parameters including laboratory data, erythropoietin‐stimulating agent use, and body mass index (BMI), were also analyzed.

RESULTS:

A thrombosis was identified in 690 (36%) patients. After adjusting for patients with pancreatic surgery and thrombosis (n = 127), developing a TE significantly increased the risk of death (hazard ratio [HR], 2.6; 95% confidence interval [CI], 2.3‐2.8; P < .01). Patients with an early TE (within 1.5 months from pancreatic cancer diagnosis) had a significantly higher risk of death (HR, 2.1; 95% CI, 1.7‐2.5; P < .01) compared with patients with late TE or no TE. Erythropoietin‐stimulating agent use and an elevated international normalized ratio were associated with significantly shorter time to thrombosis. Low BMI was associated with significantly longer time to thrombosis.

CONCLUSIONS:

TEs are common in exocrine pancreatic cancer, with coagulopathy, erythropoietin‐stimulating agent use, and underweight BMI influencing thrombosis timing. TEs, particularly early ones, confer a significantly worse prognosis, suggesting a biological significance, underscoring the relevance of ongoing prophylaxis trials, and raising the question of whether early TEs should be considered a stratification factor for clinical trials. Cancer 2012;118: 3053–61. © 2011 American Cancer Society.     

Prognostic significance of carbonic anhydrase IX expression by cancer‐associated fibroblasts in lung adenocarcinoma

BACKGROUND:

Cancer tissue is comprised of cancer cells and several types of stromal cells, including cancer‐associated fibroblasts (CAFs). Carbonic anhydrase (CA) IX has been used as an endogenous hypoxia marker, and although its expression by cancer cells has been reported to be associated with a poor outcome in a board range of tumors, to the authors' knowledge, the biologic significance of its expression by CAFs remains unclear.

METHODS:

The authors investigated CA IX expression by CAFs and cancer cells immunohistochemically in 158 consecutive resected cases of lung adenocarcinoma.

RESULTS:

CA IX was expressed by CAFs in 39 (24.7%) of the 158 cases and by cancer cells in 40 (25.3%) cases. CA IX expression by CAFs was found to be significantly correlated with conventional prognostic factors, including pathologic tumor classification and lymph node involvement. A univariate analysis and the log‐rank test demonstrated a significant association between CA IX expression by CAFs (P = .006 and P = .0052, respectively) and by cancer cells (P = .020 and P = .0179, respectively) with lower survival rate. A multivariate analysis of these 2 factors indicated a statistically significant association between CA IX expression by CAFs and a lower survival rate (hazards ratio [HR], 1.797; P = .032), but not between expression by cancer cells and lower survival rate (HR, 1.561; P = .102).

CONCLUSIONS:

The findings of the current study indicate that CA IX expression by CAFs was a better predictor of outcome than CA IX expression by cancer cells and provides new insights into the biologic significance of CAFs in the hypoxic microenvironment of the lung adenocarcinoma. Cancer 2009. © 2009 American Cancer Society.     

Results and patterns of failure in patients treated with adjuvant combined chemoradiation therapy for resected pancreatic adenocarcinoma

BACKGROUND:

Although adjuvant chemoradiation is used commonly in the United States for the treatment of resected pancreatic cancer, there is no consensus on the benefit of this therapy, because the results from randomized trials are conflicting. The authors of this report reviewed their experience in a consecutive, unselected series of patients who received adjuvant 5‐fluorouracil (5‐FU) and radiation therapy (RT) for resected pancreatic adenocarcinoma.

METHODS:

Eighty‐six patients with resected pancreatic adenocarcinoma who received adjuvant therapy from 1998 to 2005 were identified, and their medical records were reviewed. Ninety‐three percent of patients were treated with external beam RT to ≥50.4 grays, and 91% of patients received concurrent 5‐FU by continuous infusion. Forty‐five percent of patients went on to receive adjuvant gemcitabine.

RESULTS:

The median follow‐up was 31 months (range, 21‐62 months) among the 20 patients who remained alive. Less than half of patients had positive (33%) or close (<1 mm; 15%) resection margins, 81% of tumors were classified as T3, and 66% of patients had involved lymph nodes. The median overall survival (OS) for all patients was 22 months. Negative lymph node status (P = .016) was a significant prognostic factor for improved OS, whereas treatment with gemcitabine trended toward improved OS (P = .080). The median disease‐free survival (DFS) for all patients was 10 months: Treatment with gemcitabine (P = .044) and the receipt of any chemotherapy (P = .047) were significant predictors of DFS. Seventy‐five patients (87%) had disease recurrence, and the majority recurred with peritoneal metastases (55%) or liver metastases (53%). Patients who had negative lymph nodes trended toward a lower rate of distant failure (P = .060).

CONCLUSIONS:

The median survival of the current cohort was greater than that of the chemoradiation arms of European Organization for Research and Treatment of Cancer trials and European Study Group for Pancreatic Cancer 1 trials and was comparable to the survival observed on the Gastrointestinal Tumor Study Group chemoradiation arm. Lymph node status and treatment with adjuvant chemotherapy were significant predictors of OS and DFS, respectively. Future survival improvements should be directed at reducing peritoneal and liver metastases. Further randomized trials will be required to define the role of adjuvant therapy for pancreatic adenocarcinoma. Cancer 2009. © 2009 American Cancer Society.     

Inhibition of farnesoid X receptor controls esophageal cancer cell growth in vitro and in nude mouse xenografts

BACKGROUND:

Gastroesophageal reflux is a risk factor for esophageal adenocarcinoma, and bile acid and its farnesoid X receptor (FXR) have been implicated in esophageal tumorigenesis. The authors investigated the role of FXR expression and activity in esophageal cancer initiation and growth.

METHODS:

FXR expression in esophageal adenocarcinoma tissues was assessed by immunohistochemistry. Knockdown of FXR expression in esophageal cancer cells in vitro and in nude mice xenografts was suppressed by FXR small hairpin RNA (shRNA) and guggulsterone (a natural FXR inhibitor). Esophageal cancer cells were treated with bile acids to demonstrate their effects on growth‐promoting genes.

RESULTS:

FXR was expressed in 48 of 59 esophageal adenocarcinoma tissues (81.3%), and this overexpression was associated with higher tumor grade, larger tumor size, and lymph node metastasis; however, was inversely associated with retinoic acid receptor‐β₂ (RAR‐β₂) expression. Knockdown of FXR expression suppressed tumor cell growth in vitro and in nude mouse xenografts. Guggulsterone reduced the viability of esophageal cancer cells in a time‐dependent and dose‐dependent manner, whereas this effect was diminished after knockdown of FXR expression. Guggulsterone induced apoptosis through activation of caspase‐8, caspase‐9, and caspase‐3 in tumor cells. FXR mediated bile acid‐induced alterations of gene expression, eg, RAR‐β₂ and cyclooxygenase‐2 (COX‐2).

CONCLUSIONS:

Inhibition of FXR by FXR shRNA or guggulsterone suppressed tumor cell viability and induced apoptosis in vitro, and it reduced tumor formation and growth in nude mouse xenografts. FXR also mediated bile acid‐induced alterations of cell growth‐related genes in esophageal cancer cells. Cancer 2013. © 2012 American Cancer Society.     

Benefit of postoperative adjuvant therapy for pancreatic cancer

BACKGROUND:

Despite the recent completion of several trials of adjuvant therapy after resection for pancreatic adenocarcinoma, the absolute impact on survival and the identification of appropriate patients for treatment has remained controversial. In the current study, the authors sought to identify the impact of adjuvant therapy and factors associated with any improvement in survival after resection of pancreatic cancer.

METHODS:

Through the California Cancer Registry, all California residents diagnosed with pancreatic cancer between 1994 and 2002 were identified. Factors potentially impacting survival were analyzed, including patient demographics, tumor characteristics, and treatment provided. Univariate and multivariate survival analyses were performed by Kaplan‐Meier and Cox regression methods.

RESULTS:

A total of 26,518 patients were identified; 3196 (12.1%) underwent resection as their primary treatment. The median overall survival was 16 months for patients who underwent resection. Prognostic factors associated with better survival included negative lymph node status, well‐differentiated tumors, younger age, female sex, and the receipt of any adjuvant therapy. On multivariate analysis, adjuvant therapy demonstrated a statistically significant, although modest, impact on survival, with a hazards ratio of 0.79 (95% confidence interval, 0.72‐0.87; P < .001). The benefit of adjuvant therapy was only apparent in those patients with lymph node–positive or poorly differentiated tumors.

CONCLUSIONS:

Adjuvant therapy provided for a modest improvement in overall survival after surgical resection of pancreatic cancer. The absolute effect was most pronounced in those patients with poor prognostic indicators. To identify effective systemic therapy for this deadly cancer, future clinical trials of adjuvant therapy should focus on these groups of patients. Cancer 2009. © 2009 American Cancer Society.     

Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer

BACKGROUND:

Pancreatic cancer is 1 of the most common and poorly treated tumors. In search of new therapeutic approaches, the oxygen sensors prolyl hydroxylases (PHD) are potential targets. PHD2 is considered the key oxygen sensor‐regulating hypoxia‐inducible factor (HIF). Currently, there is conflicting evidence regarding the exact role of PHD2 in tumorigenesis. The objective of this study was to investigate the role of PHD2 in pancreatic cancer growth and progression.

METHODS:

PHD2 expression was analyzed by quantitative real‐time polymerase chain reaction analysis and immunohistochemistry in human tissue specimens and cell lines. Knockdown of PHD2 was done by using short‐interfering RNAs (siRNAs) specific against PHD2, and PHD2 overexpression was achieved by stable combinational DNA transfection. In vivo, an orthotopic murine model was used. Angiogenic cytokines were assessed with enzyme‐linked immunosorbent assays, and invasion was studied with Matrigel assays.

RESULTS:

PHD2 expression was not altered substantially in cancer tissues and their metastases. Lymph node‐negative tissues had higher levels of PHD2 than lymph node‐positive tissues. PHD2 was hypoxia‐inducible in pancreatic cancer cell lines and regulated cell growth through cyclin D1 down‐regulation samples with PHD2 suppression and through p21 up‐regulation in samples with of PHD2 overexpression. In vivo, PHD2 caused tumor growth retardation and reduced tumor invasion by inhibiting angiogenesis. This observation was caused by the suppression of angiogenic cytokines and tumor invasion.

CONCLUSIONS:

The current results indicated that PHD2 plays an important role in pancreatic tumorigenesis. In summary, the authors concluded that PHD2 may function as a tumor suppressor gene in pancreatic cancer and, thus, may define a potential target for the treatment of pancreatic cancer. Cancer 2012;. © 2011 American Cancer Society.