Adjustment For Tumor Stage Research Articles

Associations of diabetes and mortality among colorectal cancer patients from the Southern Community Cohort Study.

We investigated associations between diabetes and mortality among participants with incident colorectal cancer (CRC) from the Southern Community Cohort Study. Participants (73% non-Hispanic Black; 60% income < $15,000) were recruited between 2002-2009. Diabetes was self-reported at enrollment and follow-up surveys at approximately 5-year intervals. Incident CRC and mortality were identified via state registries and the National Death Index. Proportional hazards models calculated associations between diabetes with overall, CRC-specific mortality among 1059 participants with incident CRC. Diabetes prior to diagnosis is associated with elevated overall (hazard ratio [95% confidence interval]: (1.46[1.22-1.75]), and CRC-specific mortality (1.36[1.06-1.74])) after adjustment for tumor stage. For non-Hispanic Black and non-Hispanic White participants, consistent associations were observed for overall (1.35[1.10-1.66] vs. 1.89[1.31-2.72], respectively, p-interaction = 0.11) and CRC-specific mortality (1.30[0.99-1.71] vs. 1.77[1.06-2.95], respectively, p-interaction = 0.28). For individuals with incomes <$15,000/year, associations with overall (1.44[1.15-1.79]) and CRC-specific mortality (1.28[0.94-1.73]) were similar to the full sample. Associations with overall (1.71[1.37-2.13]) and CRC-specific mortality (1.65[1.22-2.22]) were highest for diabetes ≥ 10 years at diagnosis. Pre-diagnosis diabetes is associated with higher mortality among participants with incident CRC from a predominantly non-Hispanic Black cohort with lower socioeconomic status. The higher prevalence of diabetes in this population may contribute to racial disparities in CRC mortality.

Abstract 6491: Temporal changes in circulating sex hormones and aromatase activity and associations with lung cancer survival in postmenopausal women

Abstract Background: Exogenous sex hormone supplements had been associated with increased lung cancer mortality in a large clinical trial. No study to date has evaluated temporal trajectories of circulating sex hormones and aromatase activity and their associations with lung cancer survival. Objective: To characterize temporal changes in prediagnostic levels of circulating sex hormones and aromatase activity and to evaluate their associations with overall survival in lung cancer patients. Methods: Included in the analysis were 385 incident lung cancer patients identified in a large prospective cohort among postmenopausal women who had never used cigarette products nor exogenous sex hormone supplements. Concentrations of sex hormones were quantitated using LC-MS/MS assays in prediagnostic plasma samples. The product-substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). A multivariable Cox model with restricted cubic spline functions was used to calculate hazard ratio (HR) for overall survival. Results: Of 385 patients with lung cancer, 308 died during a median follow-up of 18.1 years. Initial analyses in all patients showed that higher levels of circulating estrone and IAA and lower levels of androstenedione and testosterone were associated with poorer overall survival after adjusting for nonclinical covariates. In analyses restricted to those with clinical data (n=281), stronger associations were found after further adjustment for tumor stage and treatment regimens. Compared with patients at the median level of IAA, adjusted HRs (95% CI) for total mortality in those at the 30th, 70th, 90th and 95th percentiles were 0.98 (0.84-1.13), 1.05 (0.94-1.16), 1.28 (1.06-1.54), and 1.64 (1.27-2.12), respectively, with P-overall &amp;lt; 0.001. A similar positive association was observed for estrone. In contrast, inverse associations were seen for androgens. For example, compared with the median level of testosterone, HRs (95% CI) for those at the 5th, 10th, 30th, 70th percentiles were 2.10 (1.43-3.09), 1.69 (1.29-2.23), 1.45 (1.19-1.76), and 0.86 (0.78-0.94), respectively, with P-overall = 0.001. Further, we found that circulating levels of sex hormones changed during disease progression. The closer the hormone measurement to cancer diagnosis the higher the IAA and estrone levels (P-overall &amp;lt; 0.001 for both), and the temporal change plateaued 10 years before cancer diagnosis (P-nonlinearity &amp;lt; 0.001 for both). An opposite temporal pattern was found for testosterone. Moreover, the significant association between sex hormones and lung cancer survival was only observed when sex hormones were measured within 10 years before diagnosis. Conclusions: Findings from our study, for the first time, demonstrate temporal changes in circulating sex hormones and their associations with lung cancer survival in postmenopausal women. Citation Format: Yingya Zhao, Xiao-Ou Shu, Yu-Tang Gao, Mark M. Kushnir, Qiuyin Cai, Hui Cai, Qing Lan, Nathaniel Rothman, Wei Zheng, Gong Yang. Temporal changes in circulating sex hormones and aromatase activity and associations with lung cancer survival in postmenopausal women. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6491.

Abstract 759: Genome-wide cell-free DNA fragmentation in early detection and disease monitoring of hepatocellular carcinoma

Abstract Background: Genome-wide cell-free DNA fragmentation profiling was suggested to be useful for early cancer detection. However, it still needed to be evaluated using sample before cancer diagnosis. Methods: A prospective cohort with hepatitis B virus (HBV)-seropositive participants were enrolled in 2012 and followed-up biannually with blood sample collections till 31 December 2019. A case-control study with hospital hepatocellular carcinoma (HCC) cases were conducted to identify potential biomarkers for HCC detection (Discovery). We adapted the DELFI method (Cristiano et al, Nature, 2019) and evaluated cfDNA fragmentation profile (AdaptDelfi) for detecting HCC at the Discovery phase and validated AdaptDelfi in an independent prospective population cohort (Validation). Results: Of 18,373 participants, 2,893 were HBV-seropositive and developed 81 incident HCC cases. In Discovery, the AdaptDelfi model distinguished HCC cases from controls excellently (AUC [95% confidence interval] = 0.999 [0.997 - 1.0]), while the serum alpha-fetoprotein (AFP) had an AUC of 0.851 (95% CI = 0.796 - 0.906). High AdaptDelfi was associated with advanced tumor stage (P = 0.038). The hazard of death increased in high AdaptDelfi (hazard ratio 2.43, 95% CI = 1.13 - 5.2) after adjustment for tumor stage. In Validation, AdaptDelfi showed slightly increasing performance using pre-HCC samples collected ≥4 years (AUC = 0.530), 3-4 years (0.615), 2-3 years (0.781), 1-2 years (0.711), and 0-1 year (0.770) before diagnosis. These were comparable with the traditional biomarker - AFP that showed corresponding AUCs of 0.521, 0.525, 0.517, 0.575 and 0.727, respectively. Using a fixed cutoff value from Discovery, AdaptDelfi had a specificity of 88.0% and a sensitivity of 32.5% within one year before diagnosis in detecting early HCC, yielding an estimated positive predict value (PPV) of 1.4% (95% CI = 0.8% - 2.4%) among HBV-seropositive male population. Conclusions: The genome-wide cell-free DNA fragmentation is correlated with HCC stage and may be a useful biomarker for diagnosing clinical HCC and predict patient survival. However, the low PPV suggests its utility in HCC screening in high-risk populations so far may be limited. Citation Format: Shifeng Lian, Fang Fang, Zhiwei Liu, Mingfang Ji, Zongli Zheng. Genome-wide cell-free DNA fragmentation in early detection and disease monitoring of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 759.

Pathologist Validation of a Machine Learning–Derived Feature for Colon Cancer Risk Stratification

Identifying new prognostic features in colon cancer has the potential to refine histopathologic review and inform patient care. Although prognostic artificial intelligence systems have recently demonstrated significant risk stratification for several cancer types, studies have not yet shown that the machine learning-derived features associated with these prognostic artificial intelligence systems are both interpretable and usable by pathologists. To evaluate whether pathologist scoring of a histopathologic feature previously identified by machine learning is associated with survival among patients with colon cancer. This prognostic study used deidentified, archived colorectal cancer cases from January 2013 to December 2015 from the University of Milano-Bicocca. All available histologic slides from 258 consecutive colon adenocarcinoma cases were reviewed from December 2021 to February 2022 by 2 pathologists, who conducted semiquantitative scoring for tumor adipose feature (TAF), which was previously identified via a prognostic deep learning model developed with an independent colorectal cancer cohort. Prognostic value of TAF for overall survival and disease-specific survival as measured by univariable and multivariable regression analyses. Interpathologist agreement in TAF scoring was also evaluated. A total of 258 colon adenocarcinoma histopathologic cases from 258 patients (138 men [53%]; median age, 67 years [IQR, 65-81 years]) with stage II (n = 119) or stage III (n = 139) cancer were included. Tumor adipose feature was identified in 120 cases (widespread in 63 cases, multifocal in 31, and unifocal in 26). For overall survival analysis after adjustment for tumor stage, TAF was independently prognostic in 2 ways: TAF as a binary feature (presence vs absence: hazard ratio [HR] for presence of TAF, 1.55 [95% CI, 1.07-2.25]; P = .02) and TAF as a semiquantitative categorical feature (HR for widespread TAF, 1.87 [95% CI, 1.23-2.85]; P = .004). Interpathologist agreement for widespread TAF vs lower categories (absent, unifocal, or multifocal) was 90%, corresponding to a κ metric at this threshold of 0.69 (95% CI, 0.58-0.80). In this prognostic study, pathologists were able to learn and reproducibly score for TAF, providing significant risk stratification on this independent data set. Although additional work is warranted to understand the biological significance of this feature and to establish broadly reproducible TAF scoring, this work represents the first validation to date of human expert learning from machine learning in pathology. Specifically, this validation demonstrates that a computationally identified histologic feature can represent a human-identifiable, prognostic feature with the potential for integration into pathology practice.

Characteristics of homologous recombination repair pathway genes mutation in ovarian cancers.

Few studies have investigated the characteristics of non-BRCA homologous recombination repair (HRR) pathway somatic mutations, and the impact of these mutations on efficacy of treatment in ovarian cancer patients is not clear. Therefore, we conducted this study to analyze the frequency and spectrum of somatic mutations in HRR pathway genes in patients with ovarian cancer and to examine the relationships between somatic mutations in HRR pathway genes and their effects on the efficacy of platinum-based chemotherapy. We performed targeted sequencing of 688 genes related to the occurrence, development, treatment, and prognosis of solid tumors. Somatic mutations were identified by paired analysis of tumor tissue and germline DNA in blood cells. A total of 38 patients with ovarian cancer were included in the study, and 35 (92.1%) patients were diagnosed with high-grade serous carcinoma. All patients exhibited somatic mutations in the tumor tissue samples. The commonly mutated genes were TP53 (73.7%), BRCA2 (55.3%), NF1 (52.6%), BRCA1 (47.4%), and CDH1 (47.4%). Overall, 71.1% of the patients exhibited mutation in at least one HRR pathway gene. The most frequently altered HRR genes were BRCA2 (55.3%), followed by BRCA1 (47.4%), ATM (44.7%), BARD1 (42.1%), and CHEK1 (36.8%). The median progression-free survival (PFS) in patients with HRR pathway mutation was 36.0 months compared with 13.6 months in patients with no HRR pathway mutation (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.08-0.77; p = 0.016). Patients harboring BRCA1/2 and/or CDK12 mutations displayed a longer PFS (median, 36.0 months) compared with patients with no BRCA1/2 or CDK12 mutation (median, 13.6 months; HR, 0.21; 95% CI, 0.07-0.61; p = 0.004). In multivariate analysis Cox proportional hazards models, after adjustment for tumor stage at diagnosis and histology of initial diagnosis, patients with HRR pathway mutation had a longer PFS than patients with HRR wild-type genes (p = 0.006). HRR pathway somatic mutations are common in Chinese patients with ovarian cancer. HRR pathway somatic mutations were associated with improved sensitivity to platinum-based chemotherapy. Large-scale prospective studies are needed to verify our findings.

Soluble Neuropilin-1 is an independent marker of poor prognosis in early breast cancer

BackgroundNeuropilin-1 (NRP-1) is a transmembrane protein that acts as a multifunctional non-tyrosine kinase receptor with an established role in development and immunity. NRP-1 also regulates tumor biology, and high expression levels of tissue NRP-1 have been associated with a poor prognosis. Recently, ELISA-based quantification of soluble NRP-1 (sNRP-1) has become available, but little is known about the prognostic value of sNRP-1 in malignancies.Materials and methodsWe measured sNRP-1 in the serum of 509 patients with primary early breast cancer (BC) at the time of diagnosis using ELISA.ResultsMean serum values of sNRP-1 were 1.88 ± 0.52 nmol/l (= 130.83 ± 36.24 ng/ml). SNRP-1 levels weakly correlated with age, and were higher in peri- and postmenopausal patients compared to premenopausal patients, respectively (p < 0.0001). Low levels of sNRP-1 were associated with a significant survival benefit compared to high sNRP-1 levels at baseline (p = 0.005; HR 1.94; 95%CI 1.23–3.06). These findings remained significant after adjustment for tumor stage including lymph node involvement, grading, hormone receptor, HER2 status, and age (p = 0.022; HR 1.78; 95%CI 1.09–2.91).ConclusionOur findings warrant further investigations into the prognostic and therapeutic potential of sNRP-1 in BC.

A prognostic CpG score derived from epigenome-wide profiling of tumor tissue was independently associated with colorectal cancer survival

BackgroundResults of previous studies on the association of the CpG island methylator phenotype (CIMP) with colorectal cancer (CRC) prognosis were inconsistent and mostly based on different CIMP definitions. The current study aimed to comprehensively investigate the associations between DNA methylation on genes previously used to define CIMP status with CRC survival.ResultsPatients with CRC followed up for a median of 5.2 years were divided into a study cohort (n = 568) and a validation cohort (n = 308). DNA methylation was measured in tumor tissue using the Illumina Infinium HumanMethylation450 BeadChip and restricted to 43 genes used to define CIMP status in previous studies. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) of survival after CRC, including adjustment for tumor stage, microsatellite instability, and BRAF mutation status. In the study cohort, ten CpG sites were identified to be associated with CRC survival. Seven of these ten CpG sites were also associated with CRC survival in the validation cohort and were used to construct a prognostic score. CRC patients with a prognostic score of the lowest methylation level showed poorer disease-specific survival compared with patients with the highest methylation level in both the study cohort and the validation cohort (HR = 3.11 and 95% CI = 1.97–4.91, and HR = 3.06 and 95% CI = 1.71–5.45, respectively).ConclusionsA CpG panel consisting of seven CpG sites was found to be strongly associated with CRC survival, independent from important clinical factors and mutations associated with CIMP. Further studies are required to confirm these findings.

Blood glucose, glucose balance, and disease-specific survival after prostate cancer diagnosis in the Finnish Randomized Study of Screening for Prostate Cancer.

Diabetes mellitus has been linked with adverse prostate cancer (PCa) outcomes. However, role of hyperglycemia in PCa progression is unclear. We evaluated the link between hyperglycemia and PCa survival among Finnish PCa patients. The study cohort included 1770 men with data on fasting glucose and diagnosed with PCa within the Finnish Randomized Study of Screening for PCa in 1995-2009. Additionally, 1398 men had data on glycated hemoglobin (HbA1c). Information on fasting glucose and HbA1c measurements was obtained from the regional laboratory database. Antidiabetic medication use was obtained from the prescription database of the Social Insurance Institution (SII). Time-dependent Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals for PCa death among diabetic, impaired glucose tolerant, and normoglycemic men. During median follow-up of 9.9 years after the diagnosis, 182 men died from PCa. After adjustment for tumor stage, Gleason grade, and PSA level at diagnosis, diabetic fasting glucose level after PCa diagnosis was associated with elevated risk of PCa death compared to normoglycemic men (HR 1.67 95% CI 1.18-2.36). The risk association was strongest among participants with localized cancer at diagnosis; HR 2.39, 95% CI 1.45-3.93. The risk elevation was observed for glucose measurements taken up to 5 years earlier. Diabetic glucose levels measured before the diagnosis were not associated with PCa death. Our study cohort suggests an increased risk of PCa death in men with diabetic fasting blood glucose levels, supporting the role of hyperglycemia as a risk factor for PCa progression.

Exposure to alendronate is associated with a lower risk of bone metastases in osteoporotic women with early breast cancer

BackgroundBisphosphonate (BP) treatment to prevent bone loss in breast cancer patients is already well established. However, data on the association between oral BP exposure before cancer diagnosis and disease outcomes in patients with early breast cancer are still scarce. Limited information is available on alendronate, the most common oral agent for the treatment of post-menopausal osteoporosis, regarding the association with bone metastases. AimTo examine the association between oral bisphosphonate exposure before cancer diagnosis and the risk of bone metastases in osteoporotic women diagnosed with early breast cancer. Subjects and methodsThis historical cohort study was conducted at the oncology division at Tel Aviv Medical Center. The study population included post-menopausal women with early breast cancer, diagnosed between 2002 and 2012. Data on cancer characteristics, diagnosis of osteoporosis, prior bisphosphonate exposure and outcome were collected from medical files. ResultsAmong 297 osteoporotic women identified, 145 (49%) were treated with bisphosphonates (alendronate in 90% of the cases) before cancer diagnosis. BP-treated women were significantly older than the BP-naïve ones (67.9 years vs 64.6 years, p = 0.01), but comparable in risk factors and disease characteristics. Over a mean follow up of 5.6 years, nine cases of bone metastases were identified, eight of them among BP-naïve patient (cumulative incidence of 9.9%) and one among BP-treated patients (0.7%). In a multivariable Cox's proportional hazards survival model the use of BP prior to cancer diagnosis was associated with a hazard ratio of 0.04 (95%CI:0.004–0.403, p = 0.006) for bone metastasis. The HR remained similar after further adjustment for tumor stage and cancer therapy. ConclusionsHistory of alendronate use is associated with a lower likelihood of bone metastases in postmenopausal women with early breast cancer. Oral bisphosphonate treatment could be sufficient for reducing the risk of bone metastases.

Nationwide treatment patterns and survival of older patients with prostate cancer.

To examine the clinical features, applied treatments, and survival of older patients with prostate cancer compared with younger patients. All patients diagnosed with prostate cancer between 2005 and 2015 in the Netherlands were identified from the nationwide population-based Netherlands Cancer Registry (NCR). Patient and tumour characteristics, as well as applied treatments, were described by age groups and prognostic risk groups. Relative survival rates were determined, including multivariable relative survival regression analyses. Additionally, to assess if age was associated with receiving curative treatment, a multivariable logistic regression analysis was performed. In total, 48% of all patients were 70 years of age or older. Older patients had a higher prostate specific antigen (PSA) level, a higher Gleason score, as well as a higher disease stage at diagnosis. The 10-year relative survival decreased with increasing age, and after adjustment for disease stage, Gleason score, PSA level, and comorbidities, older patients had a worse survival rate. Older patients with intermediate- or high-risk disease appeared to be treated less often with curative intent compared with younger patients after adjustment for tumour stage, Gleason score, PSA level, and comorbidities. Older patients with intermediate/high risk prostate cancer treated with curative intent showed a 10-year relative survival rate similar to younger patients. The survival of older patients was worse than younger patients. This might be due to suboptimal treatment, as older patients were less often treated with curative intent. Although the increased risk of treatment complications should be considered, age alone should not be a decisive factor when offering a treatment.

CD151 Gene and Protein Expression Provides Independent Prognostic Information for Patients with Adenocarcinoma of the Esophagus and Gastroesophageal Junction Treated by Esophagectomy

Esophageal and gastroesophageal junctional (GEJ) adenocarcinoma is one of the most fatal cancers and has the fastest rising incidence rate of all cancers. Identification of biomarkers is needed to tailor treatments to each patient's tumor biology and prognosis. Gene expression profiling was performed in a test cohort of 80 chemoradiotherapy (CRTx)-naïve patients with external validation in a separate cohort of 62 CRTx-naïve patients and 169 patients with advanced-stage disease treated with CRTx. As a novel prognostic biomarker after external validation, CD151 showed promise. Patients exhibiting high levels of CD151 (≥median) had a longer median overall survival than patients with low CD151 tumor levels (median not reached vs. 30.9months; p=0.01). This effect persisted in a multivariable Cox-regression model with adjustment for tumor stage [adjusted hazard ratio (aHR), 0.33; 95% confidence interval (CI), 0.14-0.78; p=0.01] and was further corroborated through immunohistochemical analysis (aHR, 0.22; 95% CI, 0.08-0.59; p=0.003). This effect was not found in the separate cohort of CRTx-exposed patients. Tumoral expression levels of CD151 may provide independent prognostic information not gained by conventional staging of patients with esophageal and GEJ adenocarcinoma treated by esophagectomy alone.

Regional variations in cancer survival: Impact of tumour stage, socioeconomic status, comorbidity and type of treatment in Norway.

Cancer survival varies by place of residence, but it remains uncertain whether this reflects differences in tumour, patient and treatment characteristics (including tumour stage, indicators of socioeconomic status (SES), comorbidity and information on received surgery and radiotherapy) or possibly regional differences in the quality of delivered health care. National population-based data from the Cancer Registry of Norway were used to identify cancer patients diagnosed in 2002-2011 (n = 258,675). We investigated survival from any type of cancer (all cancer sites combined), as well as for the six most common cancers. The effect of adjusting for prognostic factors on regional variations in cancer survival was examined by calculating the mean deviation, defined by the mean absolute deviation of the relative excess risks across health services regions. For prostate cancer, the mean deviation across regions was 1.78 when adjusting for age and sex only, but decreased to 1.27 after further adjustment for tumour stage. For breast cancer, the corresponding mean deviations were 1.34 and 1.27. Additional adjustment for other prognostic factors did not materially change the regional variation in any of the other sites. Adjustment for tumour stage explained most of the regional variations in prostate cancer survival, but had little impact for other sites. Unexplained regional variations after adjusting for tumour stage, SES indicators, comorbidity and type of treatment in Norway may be related to regional inequalities in the quality of cancer care.

Surgical outcomes and survival after gastrectomy in octogenarians with gastric cancer

BackgroundThe aim of this study was to evaluate the surgical outcomes and survival after gastrectomy in octogenarians and identify the optimal treatment for these patients. MethodsThe medical records of 1262 patients with gastric cancer who underwent gastrectomy from January 2003 to December 2012 were reviewed retrospectively. Patients were divided into two age groups: octogenarians (≥80 y, n = 75) and nonoctogenarians (<80 y, n = 1187). The patients' clinicopathologic data, surgical outcomes, and survival were evaluated. ResultsOctogenarians exhibited a higher proportion of female patients, poorer performance scale scores, higher comorbidities, and more advanced tumor–node–metastasis (TNM) stages than did nonoctogenarians. There was no difference in the surgical curability between the two groups, although octogenarians were more likely to have higher postoperative morbidity and mortality than those of nonoctogenarians. In an analysis of risk factors affecting survival after gastrectomy for octogenarians, only advanced TNM stage was an independent prognostic factor. Overall survival was significantly lower in octogenarians than in nonoctogenarians, whereas disease-specific survival was comparable between the two groups. There was no difference in the disease-specific survival for each stage of cancer after adjustment for tumor stage. ConclusionsOctogenarians had higher postoperative morbidity and mortality rates but comparable cancer-specific survival compared with nonoctogenarians. Only an advanced TNM stage influenced the prognosis of octogenarians. Early detection and thorough postoperative care would improve the overall survival for octogenarians with gastric cancer.

Hospital teaching status and volume related to mortality after pancreatic cancer surgery in a national cohort.

The association between hospital teaching status and mortality after pancreatic resection is not well explored. Although hospital volume is related to short-term mortality, the effect on long-term survival needs investigation, taking into account hospital teaching status and selective referral patterns. This was a nationwide retrospective register-based cohort study of patients undergoing pancreatic resection between 1990 and 2010. Follow-up for survival was carried out until 31 December 2011. The associations between hospital teaching status and annual hospital volume and short-, intermediate- and long-term mortality were determined by use of multivariable Cox regression models, which provided hazard ratios (HRs) with 95 per cent c.i. The analyses were mutually adjusted for hospital teaching status and volume, as well as for patients' sex, age, education, co-morbidity, type of resection, tumour site and histology, time interval, referral and hospital clustering. A total of 3298 patients were identified during the study interval. Hospital teaching status was associated with a decrease in overall mortality during the latest interval (years 2005-2010) (university versus non-university hospitals: HR 0·72, 95 per cent c.i. 0·56 to 0·91; P = 0·007). During all time periods, hospital teaching status was associated with decreased mortality more than 2 years after surgery (university versus non-university hospitals: HR 0·86, 0·75 to 0·98; P = 0·026). Lower annual hospital volume increased the risk of short-term mortality (HR for 3 or fewer compared with 4-6 pancreatic cancer resections annually: 1·60, 1·04 to 2·48; P = 0·034), but not long-term mortality. Sensitivity analyses with adjustment for tumour stage did not change the results. Hospital teaching status was strongly related to decreased mortality in both the short and long term. This may relate to processes of care rather than volume per se. Very low-volume hospitals had the highest short-term mortality risk.

Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma.

Risk of cancer progression is reduced for patients with human papillomavirus (HPV) -positive oropharynx cancer (OPC) relative to HPV-negative OPC, but it is unknown whether risk of death after progression is similarly reduced. Patients with stage III-IV OPC enrolled onto Radiation Therapy Oncology Group trials 0129 or RTOG 0522 who had known tumor p16 status plus local, regional, and/or distant progression after receiving platinum-based chemoradiotherapy were eligible for a retrospective analysis of the association between tumor p16 status and overall survival (OS) after disease progression. Rates were estimated by Kaplan-Meier method and compared by log-rank; hazard ratios (HRs) were estimated by Cox models. Tests and models were stratified by treatment protocol. A total of 181 patients with p16-positive (n = 105) or p16-negative (n = 76) OPC were included in the analysis. Patterns of failure and median time to progression (8.2 v 7.3 months; P = .67) were similar for patients with p16-positive and p16-negative tumors. After a median follow-up period of 4.0 years after disease progression, patients with p16-positive OPC had significantly improved survival rates compared with p16-negative patients (2-year OS, 54.6% v 27.6%; median, 2.6 v 0.8 years; P < .001). p16-positive tumor status (HR, 0.48; 95% CI, 0.31 to 0.74) and receipt of salvage surgery (HR, 0.48; 95% CI; 0.27 to 0.84) reduced risk of death after disease progression whereas distant versus locoregional progression (HR, 1.99; 95% CI, 1.28 to 3.09) increased risk, after adjustment for tumor stage and cigarette pack-years at enrollment. Tumor HPV status is a strong and independent predictor of OS after disease progression and should be a stratification factor for clinical trials for patients with recurrent or metastatic OPC.

Increased local failure risk with prolonged radiation treatment time in head and neck cancer treated with concurrent chemotherapy

Prolonged radiation treatment time (RTT) in head and neck squamous cell carcinoma (HNSCC) is associated with inferior tumor control in patients treated with radiation therapy (RT) alone. However, the significance of prolonged RTT with concurrent chemotherapy is less clear. We reviewed outcomes for 171 patients with primary HNSCC treated with curative intent RT and concurrent drug therapy from 2001 to 2009. The effects of RTT and other variables on local control and survival were analyzed. Patients with RTT >7 weeks had a significantly increased risk of local failure (hazard ratio [HR], 2.6; p = .018) and death (HR, 1.9 p = .035). These results retained significance even after adjustment for tumor stage (age was not significant). For patients treated with concurrent chemoradiotherapy (chemoRT), prolonged RTT may compromise tumor control as has been established in the setting of RT alone. Symptoms of patients with HNSCC undergoing definitive chemoRT should be managed aggressively to limit treatment interruptions.

Comparison of genome-wide DNA methylation in urothelial carcinomas of patients with and without arsenic exposure

BackgroundArsenic is a well-documented carcinogen of human urothelial carcinoma (UC) with incompletely understood mechanisms. ObjectivesThis study aimed to compare the genome-wide DNA methylation profiles of arsenic-induced UC (AsUC) and non-arsenic-induced UC (Non-AsUC), and to assess associations between site-specific methylation levels and cumulative arsenic exposure. MethodsGenome-wide DNA methylation profiles in 14 AsUC and 14 non-AsUC were analyzed by Illumina Infinium methylation27 BeadChip and validated by bisulfite pyrosequencing. Mean methylation levels (β¯) in AsUC and non-AsUC were compared by their ratio (β¯ ratio) and difference (Δβ¯). Associations between site-specific methylation levels in UC and cumulative arsenic exposure were examined. ResultsAmong 27,578 methylation sites analyzed, 231 sites had β¯ ratio >2 or <0.5 and 45 sites had Δβ¯ >0.2 or <−0.2. There were 13 sites showing statistically significant (q<0.05) differences in β¯ between AsUC and non-AsUC including 12 hypermethylation sites in AsUC and only one hypermethylation site in non-AsUC. Significant associations between cumulative arsenic exposure and DNA methylation levels of 28 patients were observed in nine CpG sites of nine gens including PDGFD (Spearman rank correlation, 0.54), CTNNA2 (0.48), KCNK17 (0.52), PCDHB2 (0.57), ZNF132 (0.48), DCDC2 (0.48), KLK7 (0.48), FBXO39 (0.49), and NPY2R (0.45). These associations remained statistically significant for CpG sites in CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 in 20 non-smoking women after adjustment for tumor stage and age. ConclusionsSignificant associations between cumulative arsenic exposure and methylation level of CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 were found in smoking-unrelated urothelial carcinoma. Arsenic exposure may cause urothelial carcinomas through the hypermethylation of genes involved in cell adhesion, proteolysis, transcriptional regulation, neuronal pathway, and ion transport. The findings of this study, which are limited by its small sample size and moderate dose–response relation, remain to be validated by further studies with large sample sizes.

Abstract B33: Osteopontin expression is an independent poor prognostic marker in gastric cancer radically resected. Preliminary report of translational study of ITACA-S (Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach) study.

Abstract Osteopontin is overexpressed in gastric cancer. A correlation of OPN with clinicopathological features and prognosis has been previously shown. The ITACA-S is a randomized study that compares DFS and OS in radically resected gastric cancer patients, that received 5-FU/LV for 9 cycles(control arm) or FOLFIRI regimen for 4 cycles followed by cisplatin/docetaxel for 3 cycles (experimental arm). Inclusion criteria consisted of pN+ or pT3-4 (stage Ib-III). This study showed that the more intensive regimen failed to give any significant benefit versus monotherapy. An ancillary study was carried out for evaluating the prognostic role of different biological factors, prospectively determined on formalin-fixed, paraffin-embedded (FFPE) of primary gastric tumor tissue. The present study, focused on OPN immunohistochemical expression, correlates such biomarker with relapse free survival (RFS) and OS. OPN immunohistochemical expression was scored using a three grades system: negative if no tumor staining was found, positive-focal if &amp;lt; 50% of the tumor and positive-extensive if &amp;gt; 50% of tumor. RFS and OS curves were estimated using the Kaplan-Meier method and compared using the log-rank test. The multivariable analysis were performed using Cox models, in which the association between RFS or OS and OPN was estimated with adjustment for tumor stage, histotype, site and grading. Three-hundred and sixty tumor samples were analyzed, 49% in the control and 51% in the experimental arm. Median follow up was 61 months, 159 patients relapsed and died, 19 who relapsed were alive. The overall number of death was 190. Osteopontin resulted negative in 54 %, positive-focal in 24 % and positive-extended in 22 % of the cases. Six-year RFS was 49.7 %, in negative OPN group; 34% in positive OPN -focal and 22.9% in positive-extended OPN (p=0.0004). The corresponding figures for OS were 53%, 43.2% and 34.2% (p=0.0020). Osteopontin was confirmed as significant prognostic factor also at multivariable analysis (p=0.0011 for RFS and 0.0137 for OS). In patients with IIIb-IIIc stage, RFS was 30% in the negative OPN, 8.4% in the positive-focal and 4.4% in the positive-extended OPN (p=0.0004); OS was 32.4%, 12.8% and 11.4%, respectively (p=0.0013). The subgroup analyses according treatment arm showed that in positive-extended group the RFS was 12.4% in the control arm and 36.7% in the experimental arm (p=0.0751); OS was 28.8% in the control arm and 45.0% in the experimental arm (p=0.1210). No difference was observed between two treatment arms among OPN negative or OPN positive-focal groups. These data provides a definitive role of OPN as poor prognostic factor in patients radically resected. Studies evaluating the efficacy of combined adjuvant treatment in patients with OPN overexpression are warranted. We thank AIRC (Associazione Italiana Ricerca sul Cancro) for supporting this study. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B33. Citation Format: Maria Di Bartolomeo, Rosalba Miceli, Alessandro Pellegrinelli, Filippo Pietrantonio, Fiorella K. Dotti, Roberto Buzzoni, Claudia Maggi, Antonia Martinetti, Emilio Bajetta, Luigi Mariani, Filippo G. de Braud. Osteopontin expression is an independent poor prognostic marker in gastric cancer radically resected. Preliminary report of translational study of ITACA-S (Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach) study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B33.

Recent childbirth is an adverse prognostic factor in breast cancer and melanoma, but not in Hodgkin lymphoma

BackgroundThe relationship between gestation, childbirth and cancer prognosis is unknown for most cancers (e.g. Hodgkin lymphoma), whereas a body of evidence exists for melanoma and breast cancer. MethodsThe national cancer registration and hospital discharge data for women in England (1998–2007) were linked, and the records for Hodgkin lymphoma, melanoma and breast cancer were indexed as to whether women had delivered a child in separate time periods prior to their cancer diagnosis. Survival analyses were conducted in order to characterise prognosis in relation to childbirth, with statistical adjustment for age and (where possible) stage. FindingsFor melanoma and breast cancer, survival was strongly reduced in women who gave birth in the year prior to cancer diagnosis. The age-adjusted hazard ratios (HR) with 95% confidence intervals (CI) were 2.06 (1.42–3.01) for melanoma and 1.84 (1.64–2.06) for breast cancer. The associations were only slightly attenuated by further adjustment for tumour stage. For breast cancer, the excess death rate in women with a recent childbirth peaked at 2years and remained elevated for 6 to 8years. Previous childbirth had no overall effect on the outcome of Hodgkin lymphoma. InterpretationMelanoma and breast cancer prognosis are adversely affected by recent gestation and childbirth in a way that is not due to stage of the cancer, but rather to inherent biological properties of the tumours. Possible biological mechanisms include immunosuppression (melanoma), the hormonal milieu in gestation and a tumour promoting microenvironment post-partum (breast cancer).

Estrogen receptor-β expression and pharmacological targeting in bladder cancer

A role for estrogen signaling in urothelial carcinoma of the bladder (UCB) is suggested to be associated with more advanced disease with worse outcomes in women. Estrogen receptor β (ERβ) is the predominant receptor in bladder tissues. We aimed to ascertain whether ERβ correlates with clinicopathological predictors of aggressive bladder cancer and worse survival outcomes. ERβ was measured by immunohistochemistry in malignant and adjacent benign bladder tissues in patients (N=72) with UCB who underwent radical cystectomy. ERβ expression was tested for statistical association with clinicopathological variables and patient survival. ERβ expression was determined in bladder cancer cell lines, and the effects of the selective estrogen modulator tamoxifen and the ERβ agonist diarylpropionitrile on cell growth were determined. The ERβ level was significantly higher in malignant vs. benign urothelium (P<0.001) and was strongly associated with aggressive tumor histology characterized by lymphovascular (P=0.008) and perineural (P=0.006) invasion, and clinical histories of pelvic irradiation (P=0.005), hydronephrosis (P=0.022) and no intravesical chemotherapy (P=0.038). All patients with a high (>70%) percentage of ERβ positivity in tissue with >3-month follow-up developed recurrent disease (P=0.009). Higher ERβ level was predictive of worse recurrence-free and overall survival following cystectomy, after adjustment for tumor stage, and remained significantly associated with recurrence-free survival in the multivariable analysis including tumor stage, nodal stage and lymphovascular invasion. Activation of ERβ in bladder cancer cell lines led to significant increases in proliferation, while pharmacological inhibition with tamoxifen blocked cell growth. Our study supports a role for ERβ in aggressive UCB. Pharmacological targeting of ERβ warrants further investigation as a therapeutic strategy in UCB.