Total Cancer Research Articles

Upregulation of GREB1 in colorectal cancer ovarian metastases may be a potential therapeutic target.

e15596 Background: Classification of ovarian metastases (OM) in colorectal cancer (CRC) as peritoneal metastasis (PM) remains controversial. Moreover, OM demonstrate resistance to systemic therapy, suggesting distinct molecular tumorigenesis. Gene expression profiling and transcriptomic analysis was performed to distinguish OM, PM, and primary CRC (pCRC) and identify potential therapeutic targets. Methods: RNA sequencing was performed on tissue from the Total Cancer Care database. Raw counts were scaled in reads per million to filter out low-expressed genes. Afterward, raw counts of retained genes were normalized in trimmed mean of M-values and then log2-transformed using the Limma R package. Genes with a |Log2FC| > 0.58 and an adjusted p-value < 0.05 were considered dysregulated. In silico motif enrichment analysis of estrogen receptor 1 (ESR1) on growth regulating estrogen receptor binding 1 (GREB1) was conducted via the FIMO program. Results: There were 115 patients with tissue from OM (n = 6), PM (n = 4), and pCRC (n = 105). The average age was 58 years and most patients were male (57.4%), Caucasian (89.5%), and had microsatellite stable disease (69.6%). Most patients underwent cytotoxic chemotherapy (67%), while fewer underwent targeted therapy (38.3%) or radiation therapy (27.8%). The median overall survival for the pCRC, OM, and PM populations was 7.1, 3.4, and 4.0 months, respectively. Among upregulated genes, LAMC3, SCUBE1, and GREB1 had the highest differential expression in OM compared to PM and PEG3, C7, and GREB1 had the highest differential expression in OM compared to pCRC (all p < 0.001). Among downregulated genes, IGLC1, IGHG2, and IGHG1 had the greatest differential expression in OM compared to PM and IGHG1, IGKV4-1, and MMP12 had the greatest differential expression in OM compared to pCRC (all p < 0.001, Figure 1). GREB1 was upregulated in OM compared to both PM and pCRC. There are two estrogen response element (ERE) sites within the promoter region of GREB1. ESR1 transcription factor was shown to bind to these ERE (p < 0.001). Conclusions: Transcriptomic analysis demonstrated clear molecular distinction between OM, PM and pCRC. Differences in gene expression profiling suggest distinct underlying mechanisms of metastasis. We identified a significant upregulation of GREB1 in OM compared to PM and pCRC. GREB1 contains both ERE and ESR1 in the upstream promoter regions implying potential upstream transcription regulation mediated by ESR1. GREB1 is a potential novel, hormonal target in treatment of OM in CRC. Continued analysis is ongoing to identify other potential targets.

Temporal trends of cancer incidence rates for the most frequent cancer sites in Cyprus (2004-2017).

Cancer is one of the leading causes of morbidity and mortality, worldwide. Little information is available for the temporal trends of cancer in the Mediterranean region, including Cyprus. We aimed to analyze cancer incidence trends overall and by sex for the period 2004-2017 regarding the five most common cancer sites for the population of Cyprus. Data were obtained from the nationwide cancer registry dataset that included 27 017 total cancer cases in Cyprus (2004-2017). We estimated the crude, sex-, and age-specific, as well as age-standardized (ASR) cancer incidence rates and we analyzed the time trends of ASR using the joinpoint regression program. For the general population (0-85+ years of age), the most common cancer sites in descending order, were breast, prostate, lung, colorectal, and thyroid cancer. During the study period, breast and thyroid cancer ASR presented a significant (p < .05) increasing temporal trend. Lung cancer ASRs seemed to stabilize (no increase or decrease) during the more recent years (2009 onwards) for both sexes; a similar pattern was observed for colorectal cancer in males. The ASRs of prostate cancer in men were in steady decline from 2012 onwards and the same was observed for the female ASRs of colorectal cancer from 2007 onwards. The colorectal cancer ASR temporal patterns overall, during the whole study period appeared unchanged. This temporal analysis would feed into cancer surveillance and control programs that focus on prevention, early detection, and treatment, particularly for cancer sites of higher mortality rates or those with temporally increasing trends.

An emulated target trial assessing the impact of physical activity on 14-year cancer risk: Insights from the Cancer Prevention Study-II.

10541 Background: The American Cancer Society, along with the World Cancer Research Fund/American Institute of Cancer Research, recommends a weekly regimen of physical activity (at least 75 minutes of vigorous or 150 minutes of moderate-intensity aerobic physical activity) for cancer prevention. The positive impact of physical activity on reducing cancer risk is well-known; however, the causal link between physical activity and cancer risk reduction is not established, primarily due to the observational nature of the current evidence. Given the ethical considerations involved in assigning physical activity levels below the recommended minimum, coupled with the impracticality of conducting decades-long trials due to the latency period of cancer development, there is a need for an innovative approach beyond traditional observational and randomized trial methodologies. This highlights the importance of applying alternative strategies like emulated target trials to produce evidence of the causal effect of physical activity on cancer risk that would otherwise be difficult to obtain. This study aims to estimate the causal effect of adherence to recommended physical activity levels on the 14-year total cancer and obesity-related cancer risk using an emulated target trial framework. Methods: Data from 79,668 participants who were non-current smokers and without prevalent cancer diagnosis at pre-baseline in the Cancer Prevention Study-II were analyzed. This study estimated the effect of different physical activity levels (&lt;7.5, 7.5-&lt;15, and ≥15 MET-hrs/wk) on 14-year cancer risks using a parametric g-formula. Models adjusted for confounders include age, sex, education, years since quitting smoking, family history of cancer, physical activity, body mass index, alcohol consumption, diet quality (measured by the ACS diet score), history of cardiovascular disease, and diabetes. Results: Under no intervention, the estimated 14-year risk for any cancer was 27.9% (95% CI: 27.6%, 28.4%), and for obesity-related cancers, it was 11.2% (95% CI: 11.0%, 11.5%). Compared with no intervention, engaging in 7.5-&lt;15 MET-hrs/wk of physical activity (minimum recommended) was linked with a 0.31% reduction in the risk of any cancer (95% CI: -0.41%, -0.06%) and a 0.19% reduction in the risk of obesity-related cancers (95% CI: -0.37%, -0.04%). Engaging in ≥15 MET-hrs/wk of physical activity (twice the minimum recommended level) was linked with a 1.31% risk reduction for any cancer (95% CI: -1.67%, -1.20%) and a 0.91% risk reduction for obesity-related cancers (95% CI: -1.09%, -0.80%), compared with no intervention. Conclusions: Incremental adherence to physical activity recommendations for cancer prevention could significantly lower the risk of developing cancers, including those related to obesity.

Global, regional, and national burdens of cancer in children aged zero to nine years from 1990 to 2019.

The description of long-term trends in the cancer burden among children aged zero to nine years from 1990 to 2019 reveals significant changes in children's health. It helps in resource allocation and health policy planning. We analysed data on the incidence, mortality, and disability-adjusted life years (DALYs) by sex and age group in children aged zero to nine. Estimates of DALYs for children aged zero to nine years, appeared as part of the Global Burden of Diseases, Injuries, and Risk Factor Study 2019, by age, sex, and location for 1990-2019. We also provided estimations by the sociodemographic index (SDI) quintile, a systematic measure to indicate educational attainment, income per capita, and total fertility rate for those younger than 25 years. We used age-period-cohort models to investigate paediatric cancers prevalence, incidence, mortality, and DALYs rates and auto-regressive integrated moving average models to predict cancer in children of different age groups in males and females. A total of 6 224 010 DALY numbers for cancer cases occurred globally in 2019 among children aged zero to nine years. Additionally, the incidence of paediatric cancers in 2019 in the middle SDI countries was the highest, including 60 662 cases, and the highest mortality and DALYs cases of paediatric cancers were in the low SDI countries (25 502 and 2 199 790). The joinpoint regression analysis revealed that the trend of total cancer burden in age-standardised mortality rates and age-standardised DALYs rates showed a significant decrease with an average annual percentage change of -2.10 and -2.03 from 1990 to 2019. Furthermore, the paediatric cancer spectrum was changing. Other malignant neoplasms and other leukaemia were the major components of cancer in all age groups of children. The disease burden in children aged zero to nine years decreased significantly globally from 1990 to 2019. However, the overall prediction of childhood cancer increased slightly from 2020 to 2040. Our findings may help guide investments and inform policies. This highlights the necessity to improve current treatment measures and establish effective prevention strategies to reduce the cancer burden among children aged zero to nine years.

Dietary Flavonoids Consumption and Health: An Umbrella Review.

The current evidence between dietary flavonoids consumption and multiple health outcomes is inadequate and inconclusive. To summarize and evaluate the evidence for dietary flavonoids consumption and multiple health outcomes, an umbrella review of meta-analyses and systematic reviews is conducted. PubMed, Ovid-EMBASE, and the Cochrane Database of Systematic Reviews are searched up to January 2024. The study includes a total of 32 articles containing 24 unique health outcomes in this umbrella review. Meta-analyses are recalculated by using a random effects model. Separate analyses are performed based on the kind of different flavonoid subclasses. The study finds some unique associations such as flavonol and gastric cancer, isoflavone and uterine fibroids and endometrial cancer, total flavonoids consumption and lung cancer, ovarian cancer, and prostate cancer. Overall, the study confirms the negative associations between dietary flavonoids consumption and type 2 diabetes mellitus, cardiovascular diseases, breast cancer, colorectal cancer, lung cancer, and mortality, while positive associations are observed for prostate cancer and uterine fibroids. Although dietary flavonoids are significantly associated with many outcomes, firm generalizable conclusions about their beneficial or harmful effects cannot be drawn because of the low certainty of evidence for most of outcomes. More well-designed primary studies are needed.

Plasma albumin, bilirubin, and uric acid and the subsequent risk of cancer: a case-cohort study in the Japan Public Health Center-based Prospective Study.

Several epidemiologic studies have investigated the circulating levels of albumin, bilirubin, and uric acid (UA) in relation to cancer risk; however, they have provided equivocal evidence. In this prospective case-cohort study, we measured the plasma levels of albumin, bilirubin, and UA and investigated their association with cancer incidence in 3584 case patients and 4270 randomly selected participants with a median follow-up of 15.8years. The adjusted hazard ratios (HRs) and 95% CIs of total cancer for the highest quartile (Q4) versus lowest quartile (Q1) was 0.77 (95% CI, 0.67-0.90; P <.001 for trend) for albumin. This association was attenuated after excluding liver cancer cases with lower plasma albumin levels. Plasma bilirubin levels were positively related to liver cancer but inversely to total cancer after excluding liver cancer with, for Q4 versus Q1, an adjusted HR of 0.86 (95% CI, 0.74-0.99; P=.015 for trend). Plasma UA levels were not dose-responsively associated with total cancer risk. Higher plasma bilirubin levels were associated with a decreased risk of total cancer after excluding liver cancer, which is likely attributed to the antioxidant properties of bilirubin.

Diabetes and further risk of cancer: a nationwide population-based study

BackgroundIndividuals with diabetes have a significantly higher risk of developing various forms of cancer, and the potential biological links between these two diseases are not completely understood.MethodsThis was a longitudinal retrospective nationwide cohort study, a study design that allows us to examine the natural course of cancer development over an extended period of time with a large sample size. Initially, 3,111,975 and 22,208,395 eligible patients aged ≥ 20 years with and without diabetes, respectively, were matched by age, sex, and the Charlson comorbidity index. Ultimately, 1,751,457 patients were selected from each group. Stratified populations for diabetic retinopathy (DR) (n = 380,822) and without DR (n = 380,822) as well as proliferative DR (PDR) (n = 141,150) and non-proliferative DR (NPDR) (n = 141,150) were analyzed in this study. The main outcome measure was the first-time diagnosis of cancer during the follow-up period.ResultsWe observed a 20% higher risk of total cancer incidence [hazard ratios (HR), 1.20; p < 0.001] in the diabetes cohort compared to the non-diabetes cohort. The highest HR was observed for liver and pancreas cancers. Moderately increased risks were observed for oral, colon, gallbladder, reproductive (female), kidney, and brain cancer. Furthermore, there was a borderline significantly increased risk of stomach, skin, soft tissue, female breast, and urinary tract (except kidney) cancers and lymphatic and hematopoietic malignancies. The stratified analysis revealed that the total cancer incidence was significantly higher in the DR cohort compared to the non-DR cohort (HR, 1.31; p < 0.001), and there was a borderline increased risk in the PDR cohort compared to the NPDR cohort (HR, 1.13; p = 0.001).ConclusionsThis study provides large-scale, nationwide, population-based evidence that diabetes is independently associated with an increased risk of subsequent development of total cancer and cancer at specific sites. Notably, this risk may further increase when DR develops.

Prevalence of sleep disorders in patients with advanced cancer: a cross-sectional study.

Patients with advanced cancer are more susceptible to develop sleep disorders like insomnia, restlessness, hypersomnolence, and sleep apnea due to a series of stressful events and side effects of chemotherapeutic agents. Poor sleep quality is associated with bad cancer outcomes and substandard quality of life. The authors assessed the prevalence of sleep disorders among advanced cancer patients in a tertiary center in Nepal. Patients with stage three and four solid malignancies were enrolled from February 2023 to July 2023 to assess their sleep status. The data were collected using the Pittsburgh Sleep Quality Index (PSQI) questionnaire, analyzed using the Statistical Package for the Social Sciences (SPSS) version 27, and subgroup exploration was done to assess the relationship of poor sleep quality with gender, marital status, malignancy type, and treatment received. An ethical clearance was obtained from the Institutional Review Committee (IRC). The authors evaluated data from 357 patients in the study. Of them, 58.3% were female and 41.7% were male. The mean age of the patients was 51.1 years. Among total cancer patients, 56% had significant sleep disorders. A significant association was observed between the quality of sleep and gender, type of malignancy, and treatment methods (p value <0.05). A majority of the patients demonstrated increased sleep latency, struggling to fall asleep swiftly. More than half of the patients had poor sleep, which has an adverse impact on the prognosis of the disease and quality of life of cancer patients. Therefore, this aspect of cancer management requires special consideration for better quality of life and appropriate end-of-life care.

Assessment of Organochlorine Pesticide Residue Levels in Fruits and Vegetables Sold in Federal Capital Territory (FCT), Nigeria

The study evaluated the organochlorine pesticide residue levels in fruits and vegetables sold in Federal Capital Territory, Abuja. Six samples were bought from eleven major markets across the six Area Councils of FCT, Abuja. The samples were mixed to form composite groups of the fruits and vegetables, and prepared using QuEChERS method. It was analysed using Agilent 7890 Gas Chromatography equipped with a micro-cell Electron Capture Detector (μECD). The analysis revealed that the hazard index (HI) for all the fruits and vegetables studied were well below the levels of adverse health effect for chronic exposure except for Onion in children which was 1.2287. The HI for the various fruits and vegetables in children were higher than those for the adult. For example, the HI for Tomato, Green Amaranth Leaves and Pepper all in children were 0.4485, 0.4411 and 0.3981 respectively while the HI for Tomato, Green Amaranth Leaves and Pepper all in adult were 0.1121, 0.1103 and 0.0995 respectively. The calculated cancer risk associated with the consumption of these fruits and vegetable showed values well below the upper bound of 1.0x10-6 except for Aldrin, Dieldrin, Heptachlor, Heptachlor Epoxide. a-BHC, b-BHC, and d-BHC especially in children. From the hazard index and cancer risk analysis, Aldrin and Dieldrin have been implicated as the pesticides of concern since they were present in reasonable concentrations for almost all the samples and age groups studied. The highest potential of cancer risk was found in Onions for children. Also, the total cancer risk implicated Onions (with a value of 1.2x10-4 for adult and 4.7x10-4 for children) and Pepper (with a value of 5.5x10-5 for adult and 2.2x10-4 for children) as the most contaminated foodstuffs with pesticide residues in the studied area. The order of the total cancer risk from the study was Onions &gt; Pepper &gt; Tomato &gt; Green Amaranth Leaves &gt; Fluted Pumpkin Leaves &gt; Okra for both adult and children. In conclusion it was observed that pesticide residues of Endrin, o,p'-DDE and Heptachlor in Onions, Green Amaranth Leaves and Pepper were above the Codex maximum residue level (MRL). Endrin in Onions had 858.0%, o, p'-DDE in Onions had 276.0%, o, p'-DDE in Green Amaranth Leaves had 100.8%, Heptachlor in Pepper had 168.4% and Heptachlor in Onions had 119.2%. Also, the hazard index of chronic exposure and cancer risk of children for Onions requires urgent attention as their values were well above the acceptable limit. Therefore, periodic monitoring of pesticides residues in these fruits and vegetables cannot be over emphasized, but will go a long way to prevent, control and reduce environmental pollution and health risks. Also, taking precautionary measures like proper cooking before consumption of these foodstuffs is advised.

Clinical and Genomic Features of Patients with Renal Cell Carcinoma and Advanced Chronic Kidney Disease: Analysis of a Multi-Institutional Database

Background: Patients with advanced chronic kidney disease (ACKD) are at an increased risk of developing renal cell carcinoma (RCC), but molecular alterations in RCC specimens arising from ACKD and overall survival (OS) in affected patients are not well defined. Patients and Methods: Using the Oncology Research Information Exchange Network (ORIEN) Total Cancer Care® protocol, 296 consented adult patients with RCC and somatic tumor whole exome sequencing were included. Patients with ACKD were defined as those with serum creatinine ≥1.5 mg/dL prior to RCC diagnosis. Results: Of 296 patients with RCC, 61 met the criteria for ACKD. The most common somatic mutations in the overall cohort were in VHL (126, 42.6%), PBRM1 (102, 34.5%), and SETD2 (54, 18.2%). BAP1 had a decreased mutational frequency in RCC specimens from patients without ACKD as compared to those with ACKD (10.6% versus 1.6%), but this was not statistically significant in univariable (OR 0.14, p = 0.056) or multivariable (OR 0.15, p = 0.067) analysis. Median OS was not reached in either cohort. Conclusions: Using the clinicogenomic ORIEN database, our study found lower rates of BAP1 mutations in RCC specimens from patients with ACKD, which may reflect a BAP1-independent mutational driver of RCC in patients with ACKD.

Effect of fertilization on the accumulation and health risk for heavy metals in native Andean potatoes in the highlands of Perú

Soil infertility is a global problem, amendments such as organic fertilizers and mineral fertilizers are used to improve crop yields. However, these fertilizers contain heavy metals as well as essential mineral elements. The objective of the study was to determine the effect of organic and inorganic fertilizer on the accumulation and health risk of heavy metals in tubers. The plants were cultivated at an altitude of 3970 m using four treatments (poultry manure, alpaca manure, island guano and inorganic fertilizer) and a control group. Soil contamination levels and the degree of metal accumulation in the tubers were also determined. As a result, it was found that the use of inorganic fertilizer and poultry manure increased the values of Cu and Zn in soils, exceeding the recommended standards. The accumulation of heavy metals in potato tubers did not exceed the maximum recommended limits with the exception of Pb, which exceeded the limit allowed by the FAO/WHO (0.1 mg kg−1). Poultry manure contributed to the highest accumulation of Zn, Cu and Pb in tubers with 11.62±1.30, 3.48±0.20 and 0.12 ±0.02 mg kg-1 respectively. The transfer of metals from the soil to the tubers was less than 1. Individual and total non-carcinogenic risk values were less than 1, indicating a safe level of consumption for children and adults. The cancer risk was found to be within an acceptable range. However, poultry manure and inorganic fertilizer treatments had the highest total cancer risk values in both age groups, suggesting a long-term carcinogenic risk.

Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women's Health Initiative.

In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials. A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status. After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p=.03), 53% more deaths after breast cancer (p<.001), and 44% higher breast cancer mortality (p=.03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p<.001), more total breast cancers (p<.001), and more deaths after breast cancer (p<.001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m2; p<.001). MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.

Health impact assessment of the surface water pollution in China

China suffers from severe surface water pollution. Health impact assessment could provide a novel and quantifiable metric for the health burden attributed to surface water pollution. This study establishes a health impact assessment method for surface water pollution based on classic frameworks, integrating the multi-pollutant city water quality index (CWQI), informative epidemiological findings, and benchmark public health information. A relative risk level assignment approach is proposed based on the CWQI, innovatively addressing the challenge in surface water-human exposure risk assessment. A case study assesses the surface water pollution-related health impact in 336 Chinese cities. The results show (1) between 2015 and 2022, total health impact decreased from 3980.42 thousand disability-adjusted life years (DALYs) (95 % Confidence Interval: 3242.67–4339.29) to 3260.10 thousand DALYs (95 % CI: 2475.88–3641.35), measured by total cancer. (2) The annual average health impacts of oesophageal, stomach, colorectal, gallbladder, and pancreatic cancers added up to 2621.20 thousand DALYs (95 % CI: 2095.58–3091.10), revealing the significant health impact of surface water pollution on digestive cancer. (3) In 2022, health impacts in the Beijing-Tianjin-Hebei and surroundings, the Yangtze River Delta, and the middle reaches of the Yangtze River added up to 1893.06 thousand DALYs (95 % CI: 1471.82–2097.88), showing a regional aggregating trend. (4) Surface water pollution control has been the primary driving factor to health impact improvement, contributing −3.49 % to the health impact change from 2015 to 2022. It is the first city-level health impact map for China's surface water pollution. The methods and findings will support the water management policymaking in China and other countries suffering from water pollution.

External validation of the RIETE and SOME scores for occult cancer in patients with venous thromboembolism: a multicentre cohort study.

Venous thromboembolism (VTE) may be the first sign of an undiagnosed cancer. The RIETE and SOME scores aim to identify patients with acute VTE at high risk of occult cancer. In the present study, we evaluated the performance of both scores. The scores were evaluated in a retrospective cohort from two centers. The area under the receiver-operating characteristics curve (AUC) evaluated the discriminatory performance. The RIETE score was applied to 815 patients with provoked and unprovoked VTE, of whom 56 (6.9%) were diagnosed with cancer. Of the 203 patients classified as high-risk, 18 were diagnosed with cancer, representing 32.1% (18/56) of the total cancer diagnoses. In the group of 612 low-risk patients, 67.9% of the cancer cases were diagnosed (38/56). Sensitivity, specificity, negative and positive predictive values, and AUC were 32%, 76%, 94%, 9%, and 0.430 (95% confidence interval [CI], 0.38‒0.47), respectively. The SOME score could be calculated in 418 patients with unprovoked VTE, of whom 33 (7.9%) were diagnosed with cancer. Of the 45 patients classified as high-risk, three were diagnosed with cancer, representing 9.1% (3/33) of the total cancer diagnoses. In the group of 373 low-risk patients, 90.9% of the cancer cases were diagnosed (30/33). Sensitivity, specificity, negative and positive predictive values, and AUC were 33%, 88%, 94%, 20%, and 0.351 (95% CI, 0.27‒0.43), respectively. The performance of both scores was poor. Our results highlight the need to develop new models to identify high-risk patients who may benefit from an extensive cancer screening strategy.

Bile Acid Diarrhea Is Associated With an Increased Incidence of Gastrointestinal Cancers.

Bile acid diarrhea (BAD) is an underrecognized and socially debilitating disease caused by high concentrations of bile acids in the colon. Bile acids directly and indirectly promote carcinogenesis. In this article, we investigated whether individuals with BAD have an increased risk of gastrointestinal (GI) cancers. By using the Danish health registries, adult individuals with BAD were identified by International Classification of Diseases 10th revision code K90.8 or referral to the diagnostic ⁷⁵selenium-homotaurocholic acid test followed by prescription of a bile acid sequestrant within 365 days (n = 5,245). Age- and sex-matched individuals without BAD were included for comparison (n = 52,450). We analyzed the cumulative incidence of GI cancers after BAD diagnosis and the odds ratios (ORs) of GI cancer 8 and 15 years before BAD diagnosis/matching. Cumulative incidence of GI cancer 6 years after BAD diagnosis/matching was 1.6% in the BAD group and 1.1% in controls ( P = 0.01). The ORs of total GI cancer 8 and 15 years before BAD diagnosis were 6.16 (5.08-7.48) and 5.19 (4.28-6.29), respectively. Furthermore, 47 individuals with BAD (0.9%) and 250 (0.5%) controls died of GI cancer. This nationwide cohort study indicates an association between BAD and GI cancers. We found both a higher incidence of GI cancer after BAD diagnosis compared with controls and increased OR of GI cancer before BAD diagnosis. Bearing in mind the underdiagnosis of BAD, the delay of BAD diagnosis, and the carcinogenic effect of bile acids, these findings warrant further investigations of the risk of GI cancer in individuals with BAD.

Mineral composition and heavy metal risk assesment of selected geophagic soils from Tanzania

Geophagy or Pica is the unintentional traditional behavior of eating soil by indigenous people in different countries. practiced in many countries due to nausea among pregnant women and mineral deficiencies without knowing the associated health risks. In this study the mineral composition of geophagic soil and its associated health risk among consumers was determined. Dry soil sticks consumed by women were obtained from open markets in Morogoro, Njombe and Mwanza regions in Tanzania. The elemental concentration of geophagic soil was analyzed using Flame Atomic Absorption spectrophotometer. Health risk assessment methods were used to obtain health information after chronic exposure to geophagic soils. The tests used were Target Hazard Quotients (THQ), Total Target Hazard Quotients (TTHQ) and Cancer Risks (CR). The concentration range of metals in samples obtained from three different regions were 16,335.7–47,773.7 mg/kg for Fe, 46.2–1073.5 mg/kg for Ca, 155.3–514.9 mg/kg for K, 44.5–112.4 mg/kg for Zn, 40.7–95.1 mg/kg for Na, 2.4–66.7 mg/kg for Cu, 109.5–572.6 mg/kg for Mn, 3.8–6.85 mg/kg for Pb, 3.1–93 mg/kg for Ni, 62.7–638.6 mg/kg for Cr and 0.4 mg/kg for Cd. The Provisional Daily Intake (PDI), THQ, TTHQ and CR ranged between 3.0 × 10−3 –34.12 mg/kg/day bw, 0.043–48.75, 34.52–77.36 and 2.55×10−5- 0.23 respectively. The TTHQ>1 was evident for metals in all sampling sites which is indicative of non-carcinogenic health effects. Prolonged exposure to Pb at low concentrations in samples from all the sites can cause pathological effects. The cancer risk values for Pb, Ni, Cr and Cd were <1 in which the consumer is likely not to develop cancer in a life time. Essential minerals – Fe, Ca, Zn, Na, K and toxic metals Pb, Cr, Ni and Cu were detected in all the samples. Cd occurred only in samples from Mwanza region that was below the tolerable daily intake. According to WHO/FAO expert’s joint committee any amount of Pb consumption is not permitted. Given the presence of essential minerals in the geophagic soils which are however accompanied by toxic minerals in some cases which might have carcinogenic effects, prolonged consumption should be discouraged to avoid risks of serious adverse effects to the health of the general population.

Longitudinal tracking of circulating rare events in the liquid biopsy of stage III–IV non-small cell lung cancer patients

In the United States, lung cancer is the second most common type of cancer with non-small cell lung cancer (NSCLC) encompassing around 85% of total lung cancer cases. Late-stage patients with metastatic disease have worsening prognosis, highlighting the importance of longitudinal disease monitoring. Liquid biopsy (LBx) represents a way for physicians to non-invasively track tumor analytes, such as circulating tumor cells (CTCs), and understand tumor progression in real-time through analyzing longitudinal blood samples. CTCs have been shown to be effective predictive biomarkers in measuring treatment efficacy and survival outcomes. We used the third-generation High-Definition Single Cell Assay (HDSCA3.0) workflow to analyze circulating rare events longitudinally during treatment in a cohort of 10 late-stage NSCLC patients, identifying rare events including circulating cancer cells (i.e., CTCs), and oncosomes. Here, we show (1) that there is a cancer specific LBx profile, (2) there is considerable heterogeneity of rare cells and oncosomes, and (3) that LBx data elements correlated with patient survival outcomes. Additional studies are warranted to understand the biological significance of the rare events detected, and the clinical potential of the LBx to monitor and predict response to treatment in NSCLC patient care.

Abstract PO2-16-01: Molecular correlates of drug response to guide therapy in triple-negative breast cancer

Abstract TNBC accounts for 10-20% of total breast cancer cases in the US and is more aggressive, higher grade, and has a poorer prognosis than other forms of breast cancer. TNBC is more likely to metastasize within 3-5 years than other forms of breast cancer and has a median survival of 17.6-21.3 months after metastasis. Advances in immunotherapy are promising, but recent trial results of immunotherapy-chemo combination have resulted in a 3-year overall survival rate under 36% in a PD-L1 based selected cohort. Thus, there is an unmet need for innovations that lead to new treatment options and improve outcomes for patients with TNBC in a personalized manner beyond only one or a few markers. In our recently published study (PMID: 31655920), we tested the dose response for a panel of 78 investigational drugs and plotted this readout against molecular characterization to identify statistically significant DNA, RNA, and protein predictors of drug efficacy in TNBC. We have expanded on this published study by identifying correlates from 3D cell culture. According to the literature, 3D culture systems are more representative of in vivo activity. We have increased our sample number (now 27 cell lines and 8 ex vivo PDXs) and expanded our drug library to 387 compounds, selected for their diverse mechanisms and promise in other cancers. Following screening, we prioritized 35 compounds based on their elevated activity and variance of response. From these 35 prioritized compounds, we identified molecular correlates of drug response for 27 compounds (77% of prioritized compounds yielding molecular correlates compared to 50% in our previously published study). Focusing on a known active drug in TNBC that is approved for patients with metastatic TNBC, we identified multi-omic (protein expression/activity and RNA expression) molecular correlates of response to a chemotherapeutic- SN-38, the payload of Sacituzumab and the active metabolite of irinotecan. We utilized a sub-panel of RNA correlates to characterize treatment-naive PDXs and predict response to SN-38. We then tested SN-38 response ex vivo for 5 PDXs to show that we could accurately identify sensitive/resistant models to SN-38 therapy. From significant protein correlates, we identified that the autophagy and AKT pathways were elevated in models with poor response to SN-38. Co-targeting the autophagy or AKT pathway with SN-38 was an effective strategy to identify rational, synergistic therapeutic combinations at therapeutically relevant levels (effective dose (ED) 50 and ED75). We evaluated irinotecan in vivo using a cell line with sensitivity in our 3D assay, demonstrating strong activity in vivo to validate that our screening assay accurately predicts in vivo response. We have further applied this methodology to targeted inhibitors with potential activity in TNBC. We have identified an ATR inhibitor, berzosertib, that targets the DNA damage response (DDR) pathway and correlates with protein expression and activity of Aurora kinases (AKs). Furthermore, combining the pan-AK inhibitor danusertib with berzosertib results in synergistic killing of TNBC cells. As a future direction, we are evaluating this combination in vivo utilizing an ethnically diverse patient-derived xenograft library grown in mice to evaluate this novel combination in a mock clinical trial and to identify molecular correlates of response and resistance that could be used to guide future human trials. Citation Format: Nathan Merrill, Nathalie Vandecan, Athena Apfel, Habib Serhan, Peter Ulintz, Liwei Bao, Xu Cheng, Aki Morikawa, Sofia Merajver, Matthew Soellner. Molecular correlates of drug response to guide therapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-01.

Socioeconomic characteristics, cancer mortality, and universal health coverage: A global analysis

Achieving universal health coverage (UHC) involves all individuals attaining accessible health interventions at an affordable cost. We examined current patterns and temporal trends of cancer mortality and UHC across sociodemographic index (SDI) settings, and quantified these association. We used data from the Global Burden of Disease Study 2019 and Our World in Data. The UHC effective coverage index was obtained to assess the potential population health gains delivered by health systems. The estimated annual percentage change (EAPC) with a 95% confidence interval (CI) was calculated to quantify the trend of cancer age-standardized mortality rate (ASMR). A generalized linear model was applied to estimate the association between ASMR and UHC. The high (EAPC= -0.9% [95% CI, -1.0%, -0.9%]) and high-middle (-0.9% [-1.0%, -0.8%]) SDI regions had the fastest decline in ASMR (per 100,000) for total cancers from 1990 to 2019. The overall UHC effective coverage index increased by 27.9% in the high-SDI quintile to 62.2% in the low-SDI quintile. A negative association was observed between ASMR for all-cancer (adjusted odds ratio [OR]= 0.87 [0.76, 0.99]), stomach (0.73 [0.56, 0.95]), breast (0.64 [0.52, 0.79]), cervical (0.42 [0.30, 0.60]), lip and oral cavity (0.55 [0.40, 0.75]), and nasopharynx (0.42 [0.26, 0.68]) cancers and high UHC level (the lowest as the reference). Our findings strengthen the evidence base for achieving UHC to improve cancer outcomes. This work is funded by the China National Natural Science Foundation and Chinese Academy of Medical Sciences Innovation Fund for Medical Science.

Breast Cancer Screening: Guidelines and Opportunities for Gynecologists

Abstract Breast cancer is the most common cancer worldwide and is the leading cause of deaths from cancer among women. It accounts for 12% of all cancer cases worldwide and 39.4% of the total cancer cases in women in India. The number is expected to rise to more than 2.3 lakh cases by the year 2025. As a general instinct, females usually come to gynecologists with problems related to breasts apart from other gynecological problems. Hence, they play a vital role in early detection by identifying the high-risk patients, screening them and spreading awareness. Risk factors for each age group should be identified and guidelines for screening must be followed. Breast selfexamination should be promoted and awareness regarding it should be spread as it can detect almost 90% of breast cancers. Clinical breast assessment skills should be developed and mammography should be encouraged.