Showing papers in "Cancer Epidemiology, Biomarkers & Prevention in 2019"
TL;DR: In the United States, lung cancer is the second most common diagnosed cancer and the leading cause of cancer-related death and the major risk factor is tobacco smoking.
Abstract: In the United States, lung cancer is the second most common diagnosed cancer and the leading cause of cancer-related death. Although tobacco smoking is the major risk factor accounting for 80% to 90% of all lung cancer diagnoses, there are numerous other risk factors that have been identified as
308 citations
TL;DR: A large population-based epidemiologic assessment of the U.S. population defines the incidence and demographic burden of HPV-positive OPSCC and finds the favorable prognosis associated with HPV appears to be limited to the oropharynx.
Abstract: Background: Human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (OPSCC) is increasing in the United States. Current epidemiologic assessments of the national burden of HPV-positive OPSCC are needed. Methods: The Surveillance Epidemiology and End Results HPV Status Database included 12,017 patients with head and neck squamous cell carcinoma of pharyngeal subsites, including OPSCC and non-OPSCC head and neck cancer subsites (hypopharynx, nasopharynx, and “other pharynx”), diagnosed from 2013 to 2014. Age-adjusted incidence rates per 100,000 persons by HPV status were calculated. An exploratory Fine-Gray competing-risks regression determined the associations between HPV status and cancer-specific mortality. Results: From 2013 to 2014, the U.S. incidence of HPV-positive OPSCC was 4.62 [95% confidence interval (CI), 4.51–4.73] versus 1.82 (95% CI, 1.75–1.89) per 100,000 persons for HPV-negative OPSCC. The incidence of HPV-positive versus negative non-OPSCC of the head and neck was 0.62 (95% CI, 0.58–0.66) versus 1.38 (95% CI, 1.32–1.44). White race (5.47) and male sex (8.00) had the highest incidences of HPV-positive OPSCC, with a unimodal age incidence distribution peaking at ages 60 to 64 years (27.23). HPV positivity was associated with lower cancer-specific mortality than HPV-negative disease for OPSCC [adjusted HR (aHR), 0.40; P Conclusions: The U.S. incidence of HPV-positive OPSCC was 4.62 per 100,000 persons. Most cases were found in white male patients younger than 65 years, where it represents the sixth most common incident nonskin cancer. The favorable prognosis associated with HPV appears to be limited to the oropharynx. Impact: This large population-based epidemiologic assessment of the U.S. population defines the incidence and demographic burden of HPV-positive OPSCC.
115 citations
TL;DR: The performance of the GALAD score was superior to ultrasound for HCC detection, and the combination of GALad and ultrasound (GALADUS score) further enhanced the performance ofThe GAL AD score.
Abstract: Background/Aim: The GALAD score is a serum biomarker-based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison to liver ultrasound for detection of HCC.
Methods: A single center cohort of 111 HCC and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) Phase 2 HCC Study were analyzed.
Results: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI): 0.93-97], which was higher than the AUC of ultrasound (0.82, P<0.01). At a cut off of -0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early stage HCC detection remained high at 0.92 [95%CI: 0.88-0.96] (cut off -1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85-0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single center cohort, achieving an AUC of 0.98 [95%CI: 0.96-0.99] (cut off -0.18, sensitivity 95%, specificity 91%).
Conclusions: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score.
Impact: The GALAD score was validated in the US.
113 citations
TL;DR: Enhanced, multilevel efforts are needed to further reduce the prevalence of modifiable risk factors and improve screening and vaccination, particularly among those with lower socioeconomic status and racial/ethnic minorities.
Abstract: Overall cancer death rates in the United States have declined since 1990. The decline could be accelerated by eliminating socioeconomic and racial disparities in major risk factors and screening utilization. We provide an updated review of the prevalence of modifiable cancer risk factors, screening, and vaccination for U.S. adults, focusing on differences by educational attainment and race/ethnicity. Individuals with lower educational attainment have higher prevalence of modifiable cancer risk factors and lower prevalence of screening versus their more educated counterparts. Smoking prevalence is 6-fold higher among males without a high school (HS) education than female college graduates. Nearly half of women without a college degree are obese versus about one third of college graduates. Over 50% of black and Hispanic women are obese compared with 38% of whites and 15% of Asians. Breast, cervical, and colorectal cancer screening utilization is 20% to 30% lower among those with
105 citations
TL;DR: Bacterial DNA profiles in the pancreas were similar to those in the duodenum tissue of the same subjects, regardless of disease state, suggesting that bacteria may be migrating from the gut into the Pancreas.
Abstract: Background: In mice, bacteria from the mouth can translocate to the pancreas and impact pancreatic cancer progression. In humans, oral bacteria associated with periodontal disease have been linked to pancreatic cancer risk. It is not known if DNA bacterial profiles in the pancreas and duodenum are similar within individuals. Methods: Tissue samples were obtained from 50 subjects with pancreatic cancer or other conditions requiring foregut surgery at the Rhode Island Hospital (RIH), and from 34 organs obtained from the National Disease Research Interchange. 16S rRNA gene sequencing was performed on 189 tissue samples (pancreatic duct, duodenum, pancreas), 57 swabs (bile duct, jejunum, stomach), and 12 stool samples. Results: Pancreatic tissue samples from both sources (RIH and National Disease Research Interchange) had diverse bacterial DNA, including taxa typically identified in the oral cavity. Bacterial DNA across different sites in the pancreas and duodenum were highly subject specific in both cancer and noncancer subjects. Presence of genus Lactobacillus was significantly higher in noncancer subjects compared with cancer subjects and the relative abundance of Fusobacterium spp., previously associated with colorectal cancer, was higher in cancer subjects compared with noncancer subjects. Conclusions: Bacterial DNA profiles in the pancreas were similar to those in the duodenum tissue of the same subjects, regardless of disease state, suggesting that bacteria may be migrating from the gut into the pancreas. Whether bacteria play a causal role in human pancreatic cancer needs to be further examined. Impact: Identifying bacterial taxa that differ in cancer patients can provide new leads on etiologically relevant bacteria.
103 citations
TL;DR: A potential relationship between the normal lung microbiota and lung cancer prognosis is demonstrated, for the first time, which requires confirmation in a larger study.
Abstract: Background: Human microbiota have many functions that could contribute to cancer initiation and/or progression at local sites, yet the relation of the lung microbiota to lung cancer prognosis has not been studied. Methods: In a pilot study, 16S rRNA gene sequencing was performed on paired lung tumor and remote normal samples from the same lobe/segment in 19 patients with non–small cell lung cancer (NSCLC). We explored associations of tumor or normal tissue microbiome diversity and composition with recurrence-free (RFS) and disease-free survival (DFS), and compared microbiome diversity and composition between paired tumor and normal samples. Results: Higher richness and diversity in normal tissue were associated with reduced RFS (richness P = 0.08, Shannon index P = 0.03) and DFS (richness P = 0.03, Shannon index P = 0.02), as was normal tissue overall microbiome composition (Bray–Curtis P = 0.09 for RFS and P = 0.02 for DFS). In normal tissue, greater abundance of family Koribacteraceae was associated with increased RFS and DFS, whereas greater abundance of families Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae were associated with reduced RFS or DFS (P Conclusions: We demonstrate, for the first time, a potential relationship between the normal lung microbiota and lung cancer prognosis, which requires confirmation in a larger study. Impact: Definition of bacterial biomarkers of prognosis may lead to improved survival outcomes for patients with lung cancer.
95 citations
TL;DR: Intriguingly, melatonin rhythms were dependent on both chronotype and rotating- shift work type, and better alignment of rotating-shift work and chronotype appeared to produce less disrupted melatonin rhythmic patterns.
Abstract: Background: Previous studies associated night-shift work with melatonin disruption, with mixed evidence regarding the modulating effects of chronotype (i.e., diurnal preference). Methods: One hundred and thirty active nurses (84 rotating-shift and 46 day-shift workers) in the Nurses' Health Study II wore a head-mounted light meter and collected spontaneous urine voids over 3 days. 6-Sulfatoxymelatonin (aMT6s), the major urinary metabolite of melatonin, was assessed. Results: Rotating-shift workers on night shifts had more light exposure and lower urinary melatonin levels during the night, and urinary melatonin rhythms with smaller peaks [11.81 ng/mg-creatinine/h, 95% confidence interval (CI), 9.49�14.71 vs. 14.83 ng/mg-creatinine/h, 95% CI, 11.72�18.75] and later peak onset (5.71 hours, 95% CI, 4.76�6.85 vs. 4.10 hours, 95% CI, 3.37�4.99), compared with day-shift workers. Furthermore, evening chronotypes' melatonin rhythms had later peak onset compared with morning types (4.90 hours, 95% CI, 3.94�6.09 vs. 3.64 hours, 95% CI, 2.99�4.43). However, among day-shift workers, morning chronotypes had melatonin rhythms with greater mean levels, larger peaks, and earlier peak onset compared with evening chronotypes; patterns were similar comparing evening versus morning chronotypes among rotating-shift workers on night shifts. The interaction of rotating-shift work and chronotype was significant across all parameters (P < 0.05). Conclusions: As expected, rotating-shift workers on night shifts had greater light exposure and lower urinary melatonin levels during the night compared with day-shift workers. Intriguingly, melatonin rhythms were dependent on both chronotype and rotating-shift work type, and better alignment of rotating-shift work and chronotype appeared to produce less disrupted melatonin rhythms. Impact: The joint effects of shift-work type and chronotype require attention in future studies. © 2019 American Association for Cancer Research.
81 citations
TL;DR: Colorectal cancer incidence has increased in people aged <50 years in Australia over the last two decades, however, colon and rectal cancer rates decreased inPeople aged 50+, likely due to de facto and organized bowel cancer screening.
Abstract: Background: Colorectal cancer is the third most commonly diagnosed cancer in Australia. Emerging evidence from several countries suggests increasing incidence in people aged Methods: We assessed colon and rectal cancer incidence trends in people aged 20+ in Australia from 1982 to 2014. We used data on 375,008 incident cases (248,162 colon and 126,846 rectal). We quantified the annual percentage change (APC) in rates by age group using Joinpoint regression. Results: For people aged 70 years) was estimated at 1.9% to 4.9% per annum for colon cancer from 2010 onward and 1.1% to 1.8% per annum in rectal cancer from the early 2000s onward. Conclusions: Colon and rectal cancer incidence has increased in people aged Impact: Further research is needed to examine the cause of the increase and to quantify the impact of future trends on the cost-effectiveness of population-based screening for those
81 citations
TL;DR: The APC for those ages <50 years was noted to be increasing at a faster rate as compared with those ages ≥50 years in many regions, including Australia, Canada, Japan, and the United States.
Abstract: Background: Colorectal cancer (CRC) incidence among young adults in the United States (US) is on the rise, but whether this phenomenon is present in other parts of the world is not well documented. This study aims to explore the temporal change of incidence rates for CRC in various countries across the globe.
Methods: We extracted CRC incidence and population data from 1988-2007 based on data from the International Agency for Research on Cancer and compared incidence between age groups. Twelve representative jurisdictions from five continents were selected. Young-onset CRC cases were defined as those aged < 50 years. Joinpoint regression was used to measure the trends of CRC incidence, and to estimate the annual percent change (APC).
Results: The APC for those aged 50 in many regions including: Australia (+1.10% vs -0.35%), Brazil (+9.20% vs +5.72%), Canada (+2.60% vs -0.91%), China - Hong Kong (+1.82% vs -0.10%), China - Shanghai (+1.13% vs -2.68%), Japan (+2.63% vs +0.90%), the United Kingdom (+3.33% vs +0.77%) and the United States (+1.98% vs -2.88%). These trends were largely driven by rectal cancer, except in Brazil and the United Kingdom.
Conclusions: Increasing incidence of young-onset CRC was noted in many regions across the globe. Further studies focusing on young-onset colorectal cancer, particular with regard to risk factors and establishing the optimal age of screening is warranted.
77 citations
TL;DR: This study provides the first evidence that miR-425-3p in NSCLC patient–derived exosomes can be a marker for predicating the clinical response to platinum-based chemotherapy, as a potent predictive biomarker for low responsiveness and poor progression-free survival (PFS).
Abstract: Background: Platinum-based doublets with a third-generation agent are the recommended option for many patients with non–small cell lung cancer (NSCLC) with no contraindications to platinum compounds Unfortunately, the clinical effectiveness of such chemotherapy is limited by intrinsic or acquired resistance Methods: Circulating exosomal miRNAs were isolated and used to perform HiSeq deep-sequencing analyses on serum pool samples from platinum-resistant or platinum-sensitive patients, and six exosomal miRNAs were further validated for their predictive utility by qRT-PCR in 170 serum samples of patients with advanced NSCLC Gain- and loss-of-function experiments clarified the responsiveness regulating role of the clinically relevant miRNA IHC analyses were performed to evaluate the association between basal autophagy in lung cancer tissues and responsiveness in 203 patients with NSCLC receiving platinum-based chemotherapy Results: Six circulating exosomal miRNAs (miR-425-3p, miR-1273h, miR-4755-5p, miR-9-5p, miR-146a-5p, and miR-215-5p) were found to be differentially expressed with the largest fold change in platinum-resistant patients compared with platinum-sensitive patients High miR-425-3p proved to be a potent predictive biomarker for low responsiveness and poor progression-free survival (PFS) Mechanistically, miR-425-3p upregulated the autophagic levels via targeting AKT1, leading to the decrease in therapeutic response Concordantly, high levels of basal autophagy in lung cancer tissues correlate with low responsiveness in patients with NSCLC within the early and advanced disease stages Conclusions: Our study highlights circulating exosomal miR-425-3p as a potential biomarker for improved predictions of the clinical response to platinum-based chemotherapy in patients with NSCLC Impact: This study provides the first evidence that miR-425-3p in NSCLC patient–derived exosomes can be a marker for predicating the clinical response to platinum-based chemotherapy
67 citations
TL;DR: Improvements in 5 of 8 biomarkers of effect are supportive of the research hypothesis, suggestive of disease risk reduction potential for smokers switching to THS instead of continuing to smoke cigarettes.
Abstract: Background: Cigarette smoking increases the risk of chronic diseases; heating instead of burning tobacco can lower these risks, contributing to tobacco harm reduction. This study (with 984 adult American smokers) examined whether favorable changes occur in 8 co-primary endpoints (HDL-C, WBC, FEV1%pred, COHb, Total NNAL, sICAM-1, 11-DTX-B2, 8-epi-PGF2α) indicative of biological and functional effects when cigarette smokers switch to the heat-not-burn Tobacco Heating System 2.2 (THS). Additionally, these biomarkers of exposure (BoExp) were quantified: MHBMA, 3-HPMA, Total NNN, CEMA, 3-OH-B[a]P, HMPMA, Total 1-OHP, NEQ, and CO exhaled. Methods: Participants were randomized to continued smoking of their preferred cigarette brand (n = 496) or to using THS (IQOS brand; n = 488) for 6 months. THS has a maximum heating temperature of 350°C, delivering 1.21 mg nicotine/stick and 3.94 mg glycerin/stick under the Health Canada Intense smoking regimen. Results: The main outcome was a favorable change 6 months after baseline, with statistically significant improvements in 5 of 8 biomarkers of effect (HDL-C, WBC, FEV1%pred, COHb, Total NNAL) when smokers switched to THS compared with those who continued to smoke cigarettes. Likewise, BoExp were markedly reduced. Conclusions: All endpoints showed favorable changes in the same direction as with smoking cessation and improved biological effects were observed in smokers who predominantly used THS compared with continued cigarette smoking, with similar nicotine levels in both groups. Impact: Improvements in 5 of 8 biomarkers of effect are supportive of the research hypothesis, suggestive of disease risk reduction potential for smokers switching to THS instead of continuing to smoke cigarettes.
TL;DR: From 2008–2014, the proportion of HPV16/18-positive CIN2+ declined, with the greatest declines in vaccinated women; declines in unvaccinated women suggest herd protection.
Abstract: Background: The impact of human papillomavirus (HPV) vaccination has been observed in the United States through declining cervical precancer incidence in young women. To further evaluate vaccine impact, we described trends in HPV vaccine types 16/18 in cervical precancers, 2008–2014. Methods: We analyzed data from a 5-site, population-based surveillance system. Archived specimens from women age 18–39 years diagnosed with cervical intraepithelial neoplasia grades 2–3 or adenocarcinoma in situ (CIN2+) were tested for 37 HPV types. We described the proportion and estimated number of cases of CIN2+ by HPV-type groups over time. Trends in HPV16/18-positive CIN2+ were examined, overall and by vaccination status, age, histologic grade, and race/ethnicity, using Cochrane–Armitage tests. Results: In 10,206 cases, the proportion and estimated number of cases of HPV16/18-positive CIN2+ declined from 52.7% (1,235 cases) in 2008 to 44.1% (819 cases) in 2014 (P Conclusions: From 2008–2014, the proportion of HPV16/18-positive CIN2+ declined, with the greatest declines in vaccinated women; declines in unvaccinated women suggest herd protection. Impact: The declining proportion of HPV16/18-positive CIN2+ provides additional evidence of vaccine impact in the United States.
TL;DR: There is a critical need for additional epidemiologic studies focused on gender and regional incidence together with molecular investigations on common tumorigenic pathways in these endocrine cancers.
Abstract: Breast and thyroid cancers are two malignancies with highest incidence in women. These cancers often occur metachronously. Women with thyroid cancer are at increased risk for subsequent breast cancer; women with breast cancer have an increased incidence of later development of thyroid cancer, suggesting a common etiology. This bidirectional relationship is reported worldwide; however, the underlying reasons for this co-occurrence are unknown. In this review, we summarize the current epidemiologic evidence and putative mechanisms of these metachronous or synchronous cancers. Key potential causative factors are chemotherapy and radiotherapy of the primary tumor, genetic variants linking the two diseases, hormonal signaling both from the thyroid gland and from estrogens, and lifestyle and environmental factors. There is a critical need for additional epidemiologic studies focused on gender and regional incidence together with molecular investigations on common tumorigenic pathways in these endocrine cancers. Understanding the putative mechanisms will aid in the diagnosis and clinical management of both diseases.
TL;DR: Shifts in the Barrett's esophagus–associated microbiome were observed in patients with HGD and esophageal adenocarcinoma, with increases in certain potentially pathogenic bacteria.
Abstract: Background: The incidence of esophageal adenocarcinoma has risen dramatically over the past half century, and the underlying reasons are incompletely understood. Broad shifts to the upper gastrointestinal microbiome may be partly responsible. The goal of this study was to describe alterations in the esophageal microbiome that occur with progression from Barrett9s esophagus to esophageal adenocarcinoma. Methods: A case–control study was performed of patients with and without Barrett9s esophagus who were scheduled to undergo upper endoscopy. Demographic, clinical, and dietary intake data were collected, and esophageal brushings were collected during the endoscopy. 16S rRNA gene sequencing was performed to characterize the microbiome. Results: A total of 45 patients were enrolled and included in the analyses [16 controls; 14 Barrett9s esophagus without dysplasia (NDBE); 6 low-grade dysplasia (LGD); 5 high-grade dysplasia (HGD); and 4 esophageal adenocarcinoma]. There was no difference in alpha diversity between non–Barrett9s esophagus and Barrett9s esophagus, but there was evidence of decreased diversity in patients with esophageal adenocarcinoma as assessed by Simpson index. There was an apparent shift in composition at the transition from LGD to HGD, and patients with HGD and esophageal adenocarcinoma had decreased Firmicutes and increased Proteobacteria. In addition, patients with HGD or esophageal adenocarcinoma had increased Enterobacteriaceae and Akkermansia muciniphila and reduced Veillonella. In the study population, patients taking proton pump inhibitors had increased Streptococcus and decreased Gram-negative bacteria overall. Conclusions: Shifts in the Barrett9s esophagus–associated microbiome were observed in patients with HGD and esophageal adenocarcinoma, with increases in certain potentially pathogenic bacteria. Impact: The microbiome may play a role in esophageal carcinogenesis.
TL;DR: Findings demonstrate the importance of examining cancer disparities betweenAI/AN and white populations and highlight opportunities for targeted public health interventions to reduce AI/AN cancer incidence.
Abstract: Background: Cancer incidence rates for American Indian and Alaska Native (AI/AN) populations vary by geographic region in the United States. The purpose of this study is to examine cancer incidence rates and trends in the AI/AN population compared with the non-Hispanic white population in the United States for the years 2010 to 2015. Methods: Cases diagnosed during 2010 to 2015 were identified from population-based cancer registries and linked with the Indian Health Service (IHS) patient registration databases to describe cancer incidence rates in non-Hispanic AI/AN persons compared with non-Hispanic whites (whites) living in IHS purchased/referred care delivery area counties. Age-adjusted rates were calculated for the 15 most common cancer sites, expressed per 100,000 per year. Incidence rates are presented overall as well as by region. Trends were estimated using joinpoint regression analyses. Results: Lung and colorectal cancer incidence rates were nearly 20% to 2.5 times higher in AI/AN males and nearly 20% to nearly 3 times higher in AI/AN females compared with whites in the Northern Plains, Southern Plains, Pacific Coast, and Alaska. Cancers of the liver, kidney, and stomach were significantly higher in the AI/AN compared with the white population in all regions. We observed more significant decreases in cancer incidence rates in the white population compared with the AI/AN population. Conclusions: Findings demonstrate the importance of examining cancer disparities between AI/AN and white populations. Disparities have widened for lung, female breast, and liver cancers. Impact: These findings highlight opportunities for targeted public health interventions to reduce AI/AN cancer incidence.
TL;DR: The ability to identify women at higher risk of CIN2+ and CIN3+ based on both HPV genotype and viral load could be important for individualizing triage plans, particularly as HPV becomes the primary screening test.
Abstract: Background: Human papillomavirus (HPV) testing provides a much more sensitive method of detection for high-grade lesions than cytology, but specificity is low. Here, we explore the extent to which full HPV genotyping, viral load, and multiplicity of types can be used to improve specificity. Methods: A population-based sample of 47,120 women undergoing cervical screening was tested for 13 high-risk HPV genotypes. Positive predictive values (PPV) for cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+; N = 3,449) and CIN3 or worse (CIN3+; N = 1,475) over 3 years of follow-up were estimated for HPV genotype and viral load. Weighted multivariate logistic regression models were used to estimate the odds of CIN2+ or CIN3+ according to genotype, multiplicity of types, and viral load. Results: High-risk HPV was detected in 15.4% of women. A hierarchy of HPV genotypes based on sequentially maximizing PPVs for CIN3+ found HPV16>33>31 to be the most predictive, followed sequentially by HPV18>35>58>45>52>59>51>39>56>68. After adjusting for higher ranked genotypes, the inclusion of multiple HPV infections added little to risk prediction. High viral loads for HPV18, 35, 52, and 58 carried more risk than low viral loads for HPV16, 31, and 33. High viral load for HPV16 was significantly more associated with CIN3+ than low viral load. Conclusions: HPV genotype and viral load, but not multiplicity of HPV infections, are important predictors of CIN2+ and CIN3+. Impact: The ability to identify women at higher risk of CIN2+ and CIN3+ based on both HPV genotype and viral load could be important for individualizing triage plans, particularly as HPV becomes the primary screening test.
TL;DR: PD-L1 expression in more than 10% of tumor cells was associated with poorer survival, and established as a clinically relevant cut-off point, and emerges as an independent poor prognosis marker in patients with OSCC.
Abstract: Background: The immune checkpoint PD-1 and its ligand PD-L1 are involved in the induction of immunological tolerance of solid tumors including oral squamous cell carcinoma (OSCC). The aim of the study was to establish the clinical and prognostic significance of PD-L1 in OSCC.
Methods: Tissue microarrays of 125 resected OSCC were stained with two different commercially available PD-L1 antibodies (clones E1L3N and 22C3), alongside with PD-1 immunostaining.
Results: PD-L1 expression in more than 10% of tumor cells was associated with poorer survival, and established as a clinically relevant cut-off point. This relevant PD-L1 expression was detected in 10-15% OSCC specimens depending on the anti-PD-L1 antibody, and showed an inverse correlation with tobacco and alcohol consumption. We consistently found that PD-L1 expression was associated with tumor recurrence and lower disease-specific survival. Multivariate analysis further revealed that neck node metastasis (HR 2.304, p = 0.009) and tumor PD-L1 expression (HR 2.571, p = 0.01) were significant independent factors for poor prognosis.
Conclusions: PD-L1 expression in more than 10% of tumor cells was a significant and independent factor of poor prognosis in OSCC.
Impact: PD-L1 expression in more than 10% of tumor cells was consistently established as a clinically relevant cut-off point by using two different antibodies. Remarkably, PD-L1 expression emerges as an independent poor prognosis marker in OSCC patients.
TL;DR: It is suggested that folic acid and vitamin B12 supplementation may increase the risk of colorectal cancer and should be limited to patients with a known indication, such as a proven deficiency.
Abstract: Background: Folic acid and vitamin B12 play key roles in one-carbon metabolism. Disruption of one-carbon metabolism may be involved in the risk of cancer. Our aim was to assess the long-term effect of supplementation with both folic acid and vitamin B12 on the incidence of overall cancer and on colorectal cancer in the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) trial. Methods: Long-term follow-up of B-PROOF trial participants (N = 2,524), a multicenter, double-blind randomized placebo-controlled trial designed to assess the effect of 2 to 3 years daily supplementation with folic acid (400 μg) and vitamin B12 (500 μg) versus placebo on fracture incidence. Information on cancer incidence was obtained from the Netherlands cancer registry (Integraal Kankercentrum Nederland), using the International Statistical Classification of Disease (ICD-10) codes C00–C97 for all cancers (except C44 for skin cancer), and C18–C20 for colorectal cancer. Results: Allocation to B vitamins was associated with a higher risk of overall cancer [171 (13.6%) vs. 143 (11.3%); HR 1.25; 95% confidence interval (CI), 1.00–1.53, P = 0.05]. B vitamins were significantly associated with a higher risk of colorectal cancer [43(3.4%) vs. 25(2.0%); HR 1.77; 95% CI, 1.08–2.90, P = 0.02]. Conclusions: Folic acid and vitamin B12 supplementation was associated with an increased risk of colorectal cancer. Impact: Our findings suggest that folic acid and vitamin B12 supplementation may increase the risk of colorectal cancer. Further confirmation in larger studies and in meta-analyses combining both folic acid and vitamin B12 are needed to evaluate whether folic acid and vitamin B12 supplementation should be limited to patients with a known indication, such as a proven deficiency.
TL;DR: The combination of a comprehensive set of biospecimens collected at multiple time points, jointly with detailed assessments of health behaviors and other prognostic factors, results in a unique resource that facilitates wide-ranging, innovative, and impactful research on colorectal cancer.
Abstract: Background: Colorectal cancer is a leading cause of cancer death. Biomarkers to predict treatment outcomes are needed, as is evidence whether postdiagnosis diet and lifestyle can affect well-being and clinical outcomes. The international ColoCare Consortium aims to identify new biologic markers (e.g., metabolomic, transcriptomic, metagenomic, genetic, epigenetic, proteomic markers) that predict clinical outcomes, and to characterize associations between modifiable risk factors (e.g., diet, supplement use, physical activity) with short-term and long-term patient-reported and clinical outcomes among patients with colorectal cancer. Methods/Results: ColoCare is recruiting newly diagnosed patients with colorectal cancer across six sites in the United States and one site in Germany. As of April 2018, we have recruited >2,000 patients across all sites. Our projected enrollment is >4,000 multiethnic patients with colorectal cancer. The study includes uniformly collected, comprehensive sets of data and biospecimens at multiple time points up to 5 years after diagnosis. Treatment and clinical data are abstracted from medical records and centrally harmonized. Biospecimens are archived according to standardized procedures. Our initial studies demonstrated metabolic differences in adipose tissue types. We further reported on associations of biological factors (e.g., inflammation, DNA methylation, metabolomics) with lifestyle factors (e.g., adiposity, smoking, physical activity, dietary supplement use) or joint associations with clinical outcomes. Conclusions: ColoCare is a consortium for the investigation of multilevel factors relevant to colorectal cancer survivorship. Impact: The combination of a comprehensive set of biospecimens collected at multiple time points, jointly with detailed assessments of health behaviors and other prognostic factors, results in a unique resource that facilitates wide-ranging, innovative, and impactful research on colorectal cancer.
Johns Hopkins University1, University of California, San Francisco2, University of Toronto3, University of Texas MD Anderson Cancer Center4, QIMR Berghofer Medical Research Institute5, Memorial Sloan Kettering Cancer Center6, International Agency for Research on Cancer7, Mayo Clinic8, University of Hawaii9, Yale University10
TL;DR: Overall heritability of pancreatic cancer is estimated to be 21.2%, which is higher than previous studies but may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data.
Abstract: Background: Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. Methods: Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. Results: Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. Conclusions: Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. Impact: Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.
TL;DR: Evidence is provided of the role of immune cells in TNBC progression that may have clinical utility and suggest that plasma cells and CD4+ Tcm in the tumor microenvironment may play a role in the subsequent progression of TNBC.
Abstract: Background: The impact of the immune landscape of the microenvironment on cancer progression is not well understood for triple-negative breast cancer (TNBC). We, therefore, aimed to examine the association of immune cell enrichment scores as a proxy for immune profiles of tumor microenvironment with TNBC prognosis. Methods: We included 76 patients with TNBC diagnosed between 2008 to 2016 in West China Hospital and 158 patients with TNBC from The Cancer Genome Atlas. On the basis of transcriptome data, we calculated the overall ImmuneScore and type-specific enrichment scores for 34 types of immune cells, using xCell, a gene signature–based method. HRs of recurrence-free survival (RFS) and overall survival (OS) were calculated by Cox proportional hazards models. Results: During the median follow-up time of 2.8 (0.1–9.8) years, 42 patients had a recurrence, and 34 patients died. The overall ImmuneScore and most immune cell enrichment scores were relatively higher in tumors than normal tissues. A higher enrichment score of plasma cells was associated with favorable RFS [HR 0.45; 95% confidence interval (CI), 0.27–0.73] and OS (HR 0.32; 95% CI, 0.17–0.61). The score of CD4+ central memory T cell (Tcm) was negatively associated with RFS (HR 1.52; 95% CI, 1.17–1.97). Besides, CD4+ Tcm enrichment score was higher in invasive tumors that were not ductal/lobular carcinoma (OR 1.59; 95% CI, 1.06–2.37). Conclusions: Our findings suggest that plasma cells and CD4+ Tcm in the tumor microenvironment may play a role in the subsequent progression of TNBC. Impact: This study provides evidence of the role of immune cells in TNBC progression that may have clinical utility.
TL;DR: A systematic review with meta-analyses of current knowledge on prognostic factors for invasive disease after a diagnosis of ductal carcinoma in situ identified frequently occurring biases in studies on invasive recurrence after DCIS.
Abstract: We performed a systematic review with meta-analyses to summarize current knowledge on prognostic factors for invasive disease after a diagnosis of ductal carcinoma in situ (DCIS). Eligible studies assessed risk of invasive recurrence in women primarily diagnosed and treated for DCIS and included at least 10 ipsilateral-invasive breast cancer events and 1 year of follow-up. Quality in Prognosis Studies tool was used for risk of bias assessment. Meta-analyses were performed to estimate the average effect size of the prognostic factors. Of 1,781 articles reviewed, 40 articles met the inclusion criteria. Highest risk of bias was attributable to insufficient handling of confounders and poorly described study groups. Six prognostic factors were statistically significant in the meta-analyses: African-American race [pooled estimate (ES), 1.43; 95% confidence interval (CI), 1.15-1.79], premenopausal status (ES, 1.59; 95% CI, 1.20-2.11), detection by palpation (ES, 1.84; 95% CI, 1.47-2.29), involved margins (ES, 1.63; 95% CI, 1.14-2.32), high histologic grade (ES, 1.36; 95% CI, 1.04-1.77), and high p16 expression (ES, 1.51; 95% CI, 1.04-2.19). Six prognostic factors associated with invasive recurrence were identified, whereas many other factors need confirmation in well-designed studies on large patient numbers. Furthermore, we identified frequently occurring biases in studies on invasive recurrence after DCIS. Avoiding these common methodological pitfalls can improve future study designs.
TL;DR: This review updated the previous review by searching Medline and EMBASE to identify models incorporating at least one SNP and applicable to asymptomatic individuals in the general population and identified 23 new models, giving a total of 29.
Abstract: Colorectal cancer screening reduces colorectal cancer incidence and mortality Risk models based on phenotypic variables have relatively good discrimination in external validation and may improve efficiency of screening Models incorporating genetic variables may perform better In this review, we updated our previous review by searching Medline and EMBASE from the end date of that review (January 2014) to February 2019 to identify models incorporating at least one SNP and applicable to asymptomatic individuals in the general population We identified 23 new models, giving a total of 29 Of those in which the SNP selection was on the basis of published genome-wide association studies, in external or split-sample validation the AUROC was 056 to 057 for models that included SNPs alone, 061 to 063 for SNPs in combination with other risk factors, and 056 to 070 when age was included Calibration was only reported for four The addition of SNPs to other risk factors increases discrimination by 001 to 006 Public health modeling studies suggest that, if determined by risk models, the range of starting ages for screening would be several years greater than using family history alone Further validation and calibration studies are needed alongside modeling studies to assess the population-level impact of introducing genetic risk-based screening programs
TL;DR: Elevated plasma B 12 levels were associated with a higher 1-year cancer risk than normal B12 levels among persons seen in UK primary care, suggesting that some cancers may affect B12 metabolism.
Abstract: Background: Elevated vitamin B12 levels (B12) are associated with increased short-term cancer risk. However, the implications for early cancer detection in primary care have not been assessed. Methods: Individuals with plasma B12 measurements were sampled from The Health Improvement Network primary care database, UK. Persons with low B12 levels were excluded together with persons with cancer or B12 treatment before date of B12 measurement. Incident cancer was the outcome of interest and was identified through Read codes. Individuals were disaggregated according to plasma B12 levels (unit: pmol/L): 150–600 (reference range values), 601–800, 801–1,000, and >1,000. Results: Among the 757,185 persons who met the inclusion criteria, we identified 33,367 incident cancers during 2,874,059 years of follow-up. We found a higher 1-year cancer risk among the 25,783 (3.4%) persons with elevated B12 levels compared with those with normal B12 levels. After multivariable adjustment for lifestyle factors and social deprivation, persons with B12 >1,000 pmol/L had a 1-year incidence rate ratio of 4.72 (95% confidence interval: 3.99–5.58). The association showed a nonlinear dose–response pattern, and it remained robust in stratified analyses, including when reducing the risk of confounding by indication in subanalyses. The risks were particularly elevated for liver cancer, pancreas cancer, and myeloid malignancies among persons with elevated B12 levels. Conclusions: Elevated plasma B12 levels were associated with a higher 1-year cancer risk than normal B12 levels among persons seen in UK primary care, suggesting that some cancers may affect B12 metabolism. Impact: Elevated B12 may mark occult cancer.
TL;DR: It is concluded that PF4V1, CXCL7, F13A1, and ApoA1 from SEs may be related to the metastasis of OS CC, which would be helpful in the diagnosis of OSCC-LNM.
Abstract: Background: Blood contains exosomes that are related to tumor cells. Those exosomes can regulate communication between cells and have a great influence on a variety of tumor-associated proceedings through their target cells. Therefore, serum exosomes (SE) were supposed to play a crucial role in cancer development. Methods: This study presented a quantitative proteomics analysis to identify the protein content in SEs including 30 subjects from oral squamous cell carcinoma (OSCC) patients with lymph node metastasis (LNM), OSCC patients with no LNM (NLNM), and healthy controls (HC). Differentially expressed proteins (DEP) were analyzed by bioinformatics, and then a total of 30 subjects were used for Western blot and 60 subjects for IHC, ELISA, and RT-PCR verifications. The correlations were assessed between DEP expression and clinicopathologic factors. Results: A total of 415 proteins were identified. Comparing with HC and OSCC-NLNM, we found 37 proteins and 28 proteins in the SEs of OSCC-LNM, respectively. There were significant correlations among the expression of PF4V1 with tumor differentiation level, PF4V1 and F13A1 with the number of positive nodes, and ApoA1 with smoking and drinking. ROC curve analysis indicated that the combinations of the different biomarkers or specimen were obviously superior to single biomarker or specimen for diagnosing OSCC-LNM. Conclusions: We conclude that PF4V1, CXCL7, F13A1, and ApoA1 from SEs may be related to the metastasis of OSCC, which would be helpful in the diagnosis of OSCC-LNM. Impact: Biomarkers from SEs could help with the diagnosis of metastasis in OSCC.
TL;DR: This study introduces a functional regulator of inflammatory chemokines that can determine an infiltrating tumor immune cell landscape that is distinct among patients of African ancestry and reports the clinical relevance of DARC/ACKR1 tumor expression in breast cancer.
Abstract: Background: Tumor-specific immune response is an important aspect of disease prognosis and ultimately impacts treatment decisions for innovative immunotherapies. The atypical chemokine receptor 1 (ACKR1 or DARC) gene plays a pivotal role in immune regulation and harbors several single-nucleotide variants (SNV) that are specific to sub-Saharan African ancestry. Methods: Using computational The Cancer Genome Atlas (TCGA) analysis, case–control clinical cohort Luminex assays, and CIBERSORT deconvolution, we identified distinct immune cell profile–associated DARC/ACKR1 tumor expression and race with increased macrophage subtypes and regulatory T cells in DARC/ACKR1-high tumors. Results: In this study, we report the clinical relevance of DARC/ACKR1 tumor expression in breast cancer, in the context of a tumor immune response that may be associated with sub-Saharan African ancestry. Briefly, we found that for infiltrating carcinomas, African Americans have a higher proportion of DARC/ACKR1-negative tumors compared with white Americans, and DARC/ACKR1 tumor expression is correlated with proinflammatory chemokines, CCL2/MCP-1 (P Conclusions: DARC/AKCR1 regulates immune responses in tumors, and its expression is associated with sub-Saharan African-specific alleles. DARC/ACKR1-positive tumors will have a distinct immune response compared with DARC/AKCR1-negative tumors. Impact: This study has high relevance in cancer management, as we introduce a functional regulator of inflammatory chemokines that can determine an infiltrating tumor immune cell landscape that is distinct among patients of African ancestry.
TL;DR: Financial hardship and limiting care due to cost are both associated with lower HRQOL among diverse cancer survivors, and this association is partially explained by limiting careDue to cost.
Abstract: Background: Financial hardship is common among cancer survivors and is associated with both limiting care due to cost and with poor health-related quality of life (HRQOL). This study estimates the association between limiting care due to cost and HRQOL in a diverse population of cancer survivors and tests whether limiting care mediates the association between financial hardship and HRQOL. Methods: We used data from 988 participants (579 African American, 409 white) in the Detroit Research on Cancer Survivors (ROCS) pilot, a hospital-based cohort of breast, colorectal, lung, and prostate cancer survivors. We assessed associations between financial hardship, limiting care, and HRQOL [measured by the Functional Assessment of Cancer Therapy—General (FACT-G)] using linear regression and mediation analysis controlling for demographic, socioeconomic, and cancer-related variables. Results: FACT-G scores were 4.2 [95% confidence interval (CI), 2.0–6.4] points lower among survivors who reported financial hardship compared with those who did not in adjusted models. Limiting care due to cost was associated with a −7.8 (95% CI, −5.1 to −10.5) point difference in FACT-G scores. Limiting care due to cost explained 40.5% (95% CI, 25.5%–92.7%) of the association between financial hardship and HRQOL overall, and 50.5% (95% CI, 29.1%–188.1%) of the association for African American survivors. Conclusions: Financial hardship and limiting care due to cost are both associated with lower HRQOL among diverse cancer survivors, and this association is partially explained by limiting care due to cost. Impact: Actions to ensure patients with cancer can access appropriate care could lessen the impact of financial hardship on HRQOL.
TL;DR: The authors in this paper conducted a multilevel analysis to assess the role of neighborhood context, patient resources, facility characteristics, and mode of detection in determining the disparity in later stage at diagnosis.
Abstract: Background: There is a substantial racial/ethnic disparity in female breast cancer mortality in Chicago between non-Hispanic black (NHblack) and Hispanic patients compared with their non-Hispanic white (NHwhite) counterparts. This observation prompted a multilevel examination of factors that might account for the disparity, with the goal of identifying potential policy interventions that might meaningfully address it Methods: In the Breast Cancer Care in Chicago study, 411 NHblack, 397 NHwhite, and 181 Hispanic patients diagnosed between the ages of 30 and 79 were interviewed, and medical records were abstracted for information on screening and diagnostic follow-up. We conducted a multilevel analysis to assess the role of neighborhood context, patient resources, facility characteristics, and mode of detection in determining the disparity in later stage at diagnosis. Results: After adjustment for neighborhood context, mode of detection, and facility accreditation/resources, there was no significant disparity in later stage breast cancer diagnosis between NHblack or Hispanic patients compared with NHwhite patients. Conclusions: The results suggest that racial/ethnic differences in mode of detection and facility accreditation/resources account for most of the disparity in stage at diagnosis. Understanding the causes of differential screen detection and access to highly accredited facilities could inform interventions to meaningfully address this disparity. Impact: Multilevel approaches to studying health disparities are becoming the research standard for understanding and addressing health disparities. Optimal design of multilevel interventions addressing disparities in later stage diagnosis would benefit from enhanced understanding of pathways to detection and diagnosis available to patients in medically underserved communities.
TL;DR: Findings from genome-wide association studies and post-GWAS analyses of endometrial cancer are summarized and clinical implications of these findings are discussed, current knowledge gaps, and future directions for the study of endometricrial cancer genetics are discussed.
Abstract: Endometrial cancer, the most commonly diagnosed cancer of the female reproductive tract in developed countries, has a heritable component. To date, 16 genetic risk regions have been robustly discovered by genome-wide association studies (GWAS) of endometrial cancer. Post-GWAS analyses including expression quantitative trait loci analysis and laboratory-based functional studies have been successful in identifying genes and pathways involved in endometrial carcinogenesis. Mendelian randomization analysis studies have confirmed factors causal for endometrial cancer risk, including increased body mass index and early onset of menarche. In this review, we summarize findings from GWAS and post-GWAS analyses of endometrial cancer. We discuss clinical implications of these findings, current knowledge gaps, and future directions for the study of endometrial cancer genetics.
TL;DR: Monocyte-to-lymphocyte ratio independently predicts survival in gallbladder cancer patients undergoing chemotherapy and is an inexpensive and easily available biomarker for predicting prognosis in patients with gall Bladder cancer undergoing chemotherapy.
Abstract: Background: Monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have been reported to be prognostic markers in various cancers. However, the prognostic value of these inflammatory biomarkers, particularly MLR, in gallbladder cancer remains to be determined. Methods: From 2005 to 2016, 178 patients with histologically confirmed gallbladder adenocarcinoma who underwent palliative chemotherapy were queried in this study. The association between survival and various clinical and laboratory variables, including MLR, NLR, and PLR, was investigated. The optimal cutoff values for MLR, NLR, and PLR were determined using the maxstat package of R. Results: Patients with high MLR (>0.24) were expected to have shorter progression-free survival [PFS; hazard ratio (HR), 2.100; 95% confidence interval (CI), 1.397–3.157; P Conclusions: MLR independently predicts survival in gallbladder cancer patients undergoing chemotherapy. Future prospective studies are needed to validate its value as a prognostic biomarker. Impact: MLR is an inexpensive and easily available biomarker for predicting prognosis in patients with gallbladder cancer undergoing chemotherapy.