Cancer Cases Research Articles

Global disparities in cancer care: Bridging the gap in affordability and access to medications between high and low‐income countries

AbstractBackgroundCancer remains a significant challenge for health care systems, despite notable progress in the field. These advancements have significant financial implications that disproportionately affect low‐income countries. This review article aims to explore the present state of drug development, assessing the availability of drugs in different income countries, and proposing potential solutions to address the inequality in access to new cancer treatments.MethodsA search was conducted on MEDLINE and PubMed on October 2, 2023 and updated on December 14, 2023, limited to English language articles.ResultsThere is a projected rise in cancer cases worldwide, particularly in low‐income countries where most cancer‐related deaths are expected. Although the approval rate of cancer treatments has risen, their excessive cost and lack of affordability pose significant barriers to widespread access. Disparities in the costs of crucial cancer medications are influenced by geographic location and procurement connections. Potential solutions to address the inequity in drug distribution include sharing production secrets, implementing price discrimination, international funding, improved primary health care measures, and the implementation of cost‐effective screening methods.ConclusionPreventing, screening for, and treating cancer should be a global priority with minimal differences in access to therapy among various countries.

Abstract B022: Investigating how monocytes impair NK cell cytotoxicity in lung metastasis of triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer (BC) cases worldwide, yet due to its aggressive phenotype and lack of targeted therapies it has the worst prognosis amongst BC subtypes. Up to 40% of TNBC patients will relapse after treatment and develop distant metastasis. Metastasis is the complex process by which disseminated tumor cells (DTCs) leave the primary tumor and grow at distal sites. Since most metastases occur within 3 years of diagnosis, the rapid onset and lack of effective treatments in metastatic TNBC (mTNBC) means less than 20% of patients survive after 4 years. Even though it is the most “immune-activated” BC subtype, and immune checkpoint blockade (ICB) has shown clinical benefits in early TNBC, there is a clear need for novel immunotherapeutic approaches for patients with mTNBC. Natural killer (NK) cells are innate lymphocytes that function as the body’s first line defense against metastatic cancer cells. NK cells eliminate DTCs in the blood or at distal sites via NK cell cytotoxicity (NKCC) and this process is known to be impaired in successful metastasis. We hypothesized that other cells within the tumor microenvironment (TME) can inhibit NKCC at the earliest stages of metastatic outgrowth. We have used Cherry-niche, an in vivo labelling tool, to characterize how TME cells change in early and established lung micro-metastases by single-cell RNA sequencing (scRNA-seq) and flow cytometry. Our initial analyses showed that monocytes are highly enriched, not only in the entire metastatic lung, but specifically in the established niche surrounding DTCs. Although we detected a slight increase in total NK cells, there was a shift in maturation status with fewer mature NK cells (CD27-CD11b+) and more immature NK cells (CD27+/-CD11b-) in the metastatic lung. Furthermore, NK cells were largely absent from the metastatic niche and those that were present displayed a dysfunctional phenotype. CellChat and NicheNet analyses of our scRNA-seq data predicted that several receptor-ligand interactions, including the cytokine macrophage migration inhibitory factor (MIF), can mediate the crosstalk between NK cells and monocytes. Next, we developed an in vitro 3D co-culture system to study the effect of blood-derived monocytes on human NKCC against mTNBC cells. We found that monocytes can suppress NKCC against MDA-MB-231 cells and decrease the viability of mature NK cells. Furthermore, recombinant MIF was able to directly inhibit NKCC, whilst a selective MIF antagonist was able to rescue monocyte-induced impairment of NKCC. These data implicate MIF as a critical monocyte-derived factor in the suppression of NK cell function against mTNBC cells. Future work will aim to identify the exact mechanism by which MIF inhibits NKCC, whilst also evaluate the effect of monocyte depletion and MIF inhibition on metastatic outgrowth and NK cell activation/maturation in vivo. This study will reveal novel inter-cellular dynamics occurring in the metastatic lung, as well as immunotherapeutic targets that may restore NKCC in mTNBC. Citation Format: Christos Ermogenous, Luigi Ombrato, Gordon Beattie. Investigating how monocytes impair NK cell cytotoxicity in lung metastasis of triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B022.

Abstract C045: The extracellular matrix glycoprotein periostin supports chemotherapy resistance by modulating macrophage recruitment and phagocytosis in triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancer cases and is notoriously aggressive, often developing resistance to standard chemotherapy thus leading to a high rate of metastatic relapse. Evidence suggests that this resistance is linked to changes in the extracellular matrix (ECM) composition, particularly an increase in periostin (POSTN) expression, which is also associated with poor prognosis in breast cancer. Our recent publication showed that the ECM alone can influence macrophage phenotypes. Furthermore, another study from our lab has demonstrated that POSTN mediates resistance to anti-angiogenic therapy by recruiting macrophages in pancreatic neuroendocrine tumors. Notably, POSTN deletion reduced monocyte/macrophage recruitment and enhanced cytotoxic CD8+ T-cell infiltration. Based on these findings, we hypothesized that paclitaxel (PTX), a widely used chemotherapeutic drug for the management of TNBC, may stimulate POSTN production by fibroblasts leading to the recruitment of pro-tumoral macrophages that facilitate tumor growth resulting into therapy resistance. In this study, we showed that PTX induces increased POSTN expression in mouse models of TNBC through immunohistochemistry, and in both 2D and 3D in vitro models via interactions between TNBC cell lines and mammary fibroblasts, as demonstrated by immunofluorescence. An in vitro migration assay confirmed that PTX-induced POSTN enhances the recruitment of human monocytes and macrophages, which display a mixed immunosuppressive and inflammatory phenotype, as revealed by flow cytometry. Not only did these recruited macrophages exhibit a reduced phagocytic capacity against labelled TNBC cells in an in vitro phagocytosis assay, but we also found that POSTN plays a crucial role in inducing SIRPα expression, that may diminish macrophage phagocytic potential. Increased sialylation and Siglec-1 expression are known to be linked to poor prognosis and polarization towards a more immunosuppressive macrophage phenotype in TNBC. Interestingly in our model, we observed that higher concentrations of recombinant human POSTN induce increased Siglec-1 expression on macrophages, a receptor that interacts with sialic acids in the tumor ECM. Further work using a decellularized tissue model that preserves only the ECM from patient-derived tumor biopsies pre- and post-chemo, aims to further explore the correlation between PTX-induced POSTN, ECM sialylation, and Siglec-1 expression on macrophages. Additionally, we have developed POSTN-knockout murine cancer cells and fibroblasts using CRISPR/Cas9, allowing us to investigate how POSTN influences macrophage phenotypes and chemotherapy responses in vivo. Understanding the mechanisms behind chemotherapy resistance in TNBC is crucial for developing effective treatments for this aggressive cancer subtype. By elucidating the intricate interplay between POSTN, macrophages, and chemotherapy response, we aim to identify new therapeutic strategies to improve outcomes for TNBC patients. Citation Format: Ludovica Tarantola, Ioanna Keklikoglou, Oliver M. Pearce. The extracellular matrix glycoprotein periostin supports chemotherapy resistance by modulating macrophage recruitment and phagocytosis in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C045.

Abstract C011: The impact of reproductive factors on breast tumor and normal-adjacent tissue immune profile from menarche to menopause

Abstract Background: Reproductive factors and sex hormones are tightly linked to systemic immunity. However, no studies have examined whether reproductive factors and exogenous hormone use modulate the immune microenvironment of breast tissue. Methods: We prospectively evaluated the associations of reproductive factors (age at menarche, parity, age at first birth, age at menopause, and menopausal status) and exogenous hormone use (oral contraceptives, and menopausal hormone therapy (MHT)) with breast tumor and normal-adjacent tissue immune cell markers among 935 breast cancer cases in the Nurses’ Health Studies. We deconvoluted immune cell abundance using CIBERSORTx and derived gene expression signatures of markers for immune checkpoint (PD1, PDL1, and CTLA4), co-regulatory signal and antigen presentation (MHC class I/ II and T cell receptor) and mammary cytokine signaling (IFN gamma, IL2, IL4, IL12, IL13, TGF beta). Linear regression was used with adjustment for potential confounders. Results: Majority of participants had estrogen receptor (ER)-positive breast cancer (81%) and were post-menopausal at diagnosis (72%). Compared to tumors from pre-menopausal women, tumors from post-menopausal women had higher signature scores for tumor pro-inflammatory cytokine signaling (IFN gamma, IL2, IL4, IL12, IL13, TGF beta) and antigen presentation (FDR≤0.05). Several of the inflammatory cytokine signatures showed modest inverse relations with signatures of immune checkpoint markers (ρ=-0.3 to -0.4). Women who reported current use of estrogen only MHT had higher expression of CTLA4 in ER-positive breast tumors. For normal-adjacent tissues of ER-positive tumors, parity was associated with higher CD8+ T cell abundance, higher PDL1 expression and lower cytokine signaling in normal-adjacent tissues at p≤0.05; while breastfeeding was associated with lower abundance of CD8+ T cell and higher expression of cytokine signaling in normal-adjacent tissues of ER-negative tumors (p≤0.05). None of the associations in normal-adjacent tissues met FDR significance. The associations between other reproductive factors and immune cell profiles were in general weak. Conclusions: Our study suggests pre-diagnostic reproductive factors may influence breast tumor immune profiles. Future studies are needed to validate these results. Citation Format: Cheng Peng, Yuxi Liu, Yujing Heng, Clara Bodelon, Daniel Stover, Wendy Y. Chen, Michelle D. Holmes, A. Heather Eliassen, Peter Kraft, Rulla M. Tamimi. The impact of reproductive factors on breast tumor and normal-adjacent tissue immune profile from menarche to menopause [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C011.

Comprehensive characterization of invasive mammary carcinoma with lobular features: integrating morphology and E-cadherin immunohistochemistry patterns.

Breast cancer treatment prioritizes molecular subtypes over histologic types. However, considering the unique biological behavior of invasive lobular carcinoma (ILC), its diagnosis is crucial for patient management. Therefore, this study aimed to review breast cancer cases, focusing on the E-cadherin patterns and lobular morphology of cases misclassified in the original reports. A comprehensive review was conducted on 481 breast cancer biopsy cases diagnosed as invasive breast carcinoma of no special type (IBC-NST) or ILC with E-cadherin staining. These cases were categorized into six groups based on tumor morphology (ductal/lobular) and E-cadherin expression pattern (membranous/loss/aberrant): (1) ductal/membranous, (2) lobular/loss, (3) lobular/aberrant, (4) mixed, (5) ductal/loss or aberrant, and (6) lobular/membranous. In 211 cases (43.8%), an E-cadherin pattern indicating ILC (loss and aberrant) was observed alongside lobular morphology, representing 5.52% of all breast cancer biopsies during the relevant period. Moreover, 181 cases (37.6%) showed a membranous pattern with ductal morphology, 4 (0.8%) were mixed IBC-NST and ILC, and 85 (17.7%) exhibited discordance between morphology and E-cadherin expression. Notably, only 25.9% (15/58) of cases in group 3, characterized by aberrant E-cadherin patterns, were initially diagnosed as ILC, highlighting a significant diagnostic discrepancy. In group 6, where membranous E-cadherin pattern was present with lobular morphology, only 3.4% (2/58) were diagnosed as ILC in the original reports, indicating diagnostic challenges in morphology and immunohistochemistry discordance. Similarly, in group 5, which had ductal morphology with loss or aberrant E-cadherin expression, the initial diagnosis rate of IBC-NST was 33.3% (9/27), reflecting the complexities in interpreting discordant cases. In real-world practice, diagnosing ILC often heavily depends on E-cadherin results. This study emphasizes the need for diagnostic clarification in cases with discordance between morphology and E-cadherin patterns.

Three-year survival follow-up of patients with gastrointestinal cancer treated during the COVID-19 pandemic in Spain: data from the PANDORA-TTD20 study.

The initial SARS-CoV-2 pandemic wave in Spain in 2020 precipitated significant paradigm shifts in gastrointestinal oncology patient management. This study captures the "Zeitgeist" of this period by analyzing adaptive strategies, treatment modifications, and survival outcomes, leveraging a 3-year follow-up perspective to extract insights from this unprecedented experience. We conducted a multicenter, retrospective cohort study utilizing the RETUD-TTD registry, encompassing 703 patients across 19 Spanish centers in April 2020. We evaluated alterations in clinical practice, therapeutic approaches, coronavirus disease 2019 (COVID-19)-related impacts, and patient survival. A Bayesian hierarchical model was employed to identify potential regional-specific frailties. The peak of the pandemic in April 2020 catalyzed substantial shifts in oncological care delivery. Outpatient consultations decreased by 13%, with a notable selection bias toward cases with more favorable prognostic indicators. Multidisciplinary tumor board discussions were significantly curtailed (eg, mean monthly colorectal cancer cases discussed was reduced from 40 to 23), compromising qualitative care measures. This occurred concurrently with an average of over 3 oncologists per center on medical leave. Contrary to initial concerns, the healthcare system demonstrated remarkable resilience. The majority of patients received standard-of-care therapies with regulatory approval, albeit with regimen modifications in 15% of cases. These adaptations included extended dosing intervals, dose intensity modulations, and transitions to oral formulations while maintaining unexpectedly stable long-term survival outcomes. The Bayesian frailty model detected minimal unmeasured prognostic factors related to geographic location, and the type of pandemic-induced adaptation did not significantly impact survival. The model revealed that coronavirus disease 2019's impact was less pronounced than other core prognostic variables. The decentralized Spanish healthcare system exhibited substantial robustness in managing pre-pandemic diagnosed gastrointestinal malignancies, despite asymmetrical, and occasionally severe organizational disruptions. The insights gleaned from this experience could inform future crisis preparedness strategies and optimize care provision during subsequent public health emergencies.

Soil Physico-chemical Responses to Integrated Nutrient Management in Lentil Intercropped with Bhimal (Grewia optiva) in Agroforestry vs. Open Systems

The growing concern over health risks associated with the heavy use of chemical fertilizers and pesticides in India, which have been linked to rising cancer cases, underscores the need for sustainable agricultural practices. Integrated Nutrient Management offers a promising solution to enhance soil fertility and support crop health, especially for lentil cultivation within agroforestry systems. This study, conducted at Dr. Y. S. Parmar University of Horticulture and Forestry in Nauni, Solan, Himachal Pradesh, examined the effects of INM on the soil’s physical and chemical properties when lentils were intercropped within a Grewia optiva (Bhimal) agroforestry system in the mid-hills region of Himachal Pradesh. The experiment evaluated various combinations of organic and inorganic fertilizers, including T1: Recommended Dose of Fertilizer, T2: Farmyard Manure, T3: Vermicompost, T4: Goat Manure, T5: 50% Recommended dose of fertilizer + 50% Farm yard manure, T6: 50% Recommended dose of fertilizer + 50% Vermicompost, T7: 50% Recommended dose of fertilizer + 50% Goat Manure, and T8: Control. These treatments were applied in plots both under the Bhimal-based agroforestry system (S1) and in open field conditions (S2), with three replications per treatment following a factorial randomized block design. Key physical parameters such as bulk density, particle density, porosity, and soil moisture were measured alongside chemical properties, including soil pH, electrical conductivity, organic carbon content, and the availability of nitrogen, phosphorus, and potassium. Data collected over two years was analyzed using R Statistical Software, revealing that INM significantly improved soil properties in the agroforestry system compared to the control. Notably, 100% FYM emerged as the most effective treatment, enhancing soil porosity, moisture, pH, and nutrient availability (N, P, and K). Improvements in soil structure and nutrient levels were particularly evident in the second year, positively impacting lentil growth and yield. The study highlights the potential of INM to promote sustainable, chemical-free agriculture in hilly areas, offering valuable recommendations for farmers and policymakers focused on sustainable agriculture. Specifically, 100% FYM is recommended for improving soil health and crop productivity in the mid-hill region of Himachal Pradesh, providing a model for similar agro-ecological zones aiming to reduce chemical inputs and support human health.

INCIDÊNCIA DE PAPILOMAVÍRUS HUMANO EM MULHERES EM SÃO PAULO NO ANO DE 2018 A 2021

HPV is the acronym for the Human Papillom Virus, which is a virus that can cause cervical cancer, in addition to other diseases. It is transmitted by sexual contact and is very common among young and sexually active adults. There are more than 100 types of HPV, most infections without manifestations of symptoms and resolve spontaneously, while others can cause warts on the skin and mucous membranes. Some strains account for about 70% of cervical cancer cases. In addition, HPV may also increase the risk of cancer, such as cancer of the anus, penis, vulva, vagina and oropharynx. HPV affects many people in society, especially young people. Women discovering the disease late can lead to serious health complications. Therefore, it is crucial to invest in studies for diagnosis and treatment prevention for better quality of life. The media is the main factor of awareness of this disease. Identifying the places of higher incidence can contribute to care programs for prevention and treatment, so that in the long term the rates of the disease can become reduced.

Biogenic synthesis of silver nanoparticles from Hylocereus undatus peel waste: exploring EGFR inhibition for targeted therapy of cervical and breast carcinomas

Abstract Background Cancer is one of the leading causes of death worldwide, with breast and cervical cancers being the most common among women. Over 100,000 new cases of breast cancer and 510,000 new cases of cervical cancer are diagnosed annually. This study aimed to develop and evaluate an eco-friendly, low-cost method to synthesize silver nanoparticles using Hylocereus undatus (dragon fruit) peel extract for their anticancer activity. Results Silver nanoparticles loaded with Hylocereus undatus fruit peel extract were successfully developed by a green synthesis technique and were optimized by UV–vis spectroscopy. The nanoparticles had an average size of 71.66 nm, a polydispersity index of 0.3754, and a zeta potential of − 38.52, with a spherical shape and 79.5% silver content. Their maximum absorbance was at 448 nm. Further, in vitro anticancer activity via MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay was evaluated and the synthesized nanoparticles displayed IC50 values at 23.51 µg/ml and 23.66 µg/ml against Hela and MDA MB 231 cell lines, respectively. Cytocompatibility studies showed high cell viability (≥ 95%) in L929 mouse fibroblast cells, indicating low toxicity. In silico analyses, including network pharmacology and molecular docking, identified kaempferol and quercetin as key anticancer compounds, with epidermal growth factor receptor (EGFR) (PDB ID: IM17) being the most significant protein target. Docking studies performed by using the Glide module of Schrodinger’s software displayed that kaempferol and quercetin had higher binding affinities for EGFR as compared to the standard drug erlotinib, with MET 769 being a crucial binding site. Conclusion Thus, the outcomes suggest that synthesized silver nanoparticles loaded with Hylocereus undatus fruit peel extract could be a potential and promising drug carrier aiding in cancer treatment.

Serum urea concentration and risk of 16 site-specific cancers, overall cancer, and cancer mortality in individuals with metabolic syndrome: a cohort study.

The relationship between serum urea concentration and cancer in patients with metabolic syndrome (MetS) remains unclear. This study aimed to investigate the association between serum urea concentration and 16 site-specific cancers, overall cancer incidence, and cancer mortality in individuals with MetS. We analysed the data of 108,284 individuals with MetS obtained from the UK Biobank. The Cox proportional hazards model was used to determine the association between serum urea concentration at recruitment and cancer. The Benjamini-Hochberg correction was used to account for multiple comparisons. Over the median follow-up period of 11.86years, 18,548 new incident cases of cancer were documented. There were inverse associations of urea concentration with overall cancer incidence, and the incidence of oesophageal and lung cancers, with respective hazard ratios (95% confidence intervals) [HR (95% CI)] for the highest (Q4) vs lowest (Q1) urea quartiles of 0.95 (0.91-0.99), 0.68 (0.50-0.92), and 0.76 (0.64-0.90). However, high serum urea concentrations increased the male prostate cancer risk (HR 1.15; 95% CI 1.02-1.30). Although the Cox model indicated a protective effect of higher urea levels against stomach (HR 0.67; 95% CI 0.45-0.98; p = 0.040; FDR 0.120) and colorectal cancer (HR 0.86; 95% CI 0.74-0.99; p = 0.048; FDR 0.123), no strong evidence of association was found after applying the Benjamin-Hochberg correction. Moreover, across the median follow-up period of 13.77years for cancer mortality outcome, 5034 cancer deaths were detected. An "L-shaped" nonlinear dose-response relationship between urea concentration and cancer mortality was discovered (p-nonlinear < 0.001), and the HR (95% CI) for urea concentration Q4 vs Q1 was 0.83 (0.77-0.91). Serum urea concentration can be considered as a valuable biomarker for evaluating cancer risk in individuals with MetS, potentially contributing to personalised cancer screening and management strategies.

Partial response to treatment with ALK inhibitor in a patient with SQSTM1-ALK fusion positive lung adenocarcinoma

Introduction: Lung cancer is the second most common cancer worldwide and the leading cause of cancer deaths; non-small cell lung cancer (NSCLC) constitutes about 85% of lung cancer cases, with ALK fusions representing 3–6% of them. The SQSTM1-ALK fusion is a rare finding in NSCLC, accounting for only 1.1% of ALK rearrangements. We present a case of lung adenocarcinoma with documentation of SQSTM1-ALK fusion that showed a partial response to alectinib. Case description: This case details the clinical course of a 71-year-old, non-smoking woman with no significant medical history who presented with confusion, aphasia and multiple cerebral lesions detected on imaging. Further investigations revealed a stage IV lung adenocarcinoma with metastases to the brain and adrenal gland. Molecular profiling identified a rare SQSTM1-ALK fusion mutation alongside other genetic abnormalities, including low programmed death-ligand 1 expression and ROS1 kinase protein presence. Treatment with alectinib, initiated based on the identified ALK fusion, resulted in significant tumour regression in the lungs and complete resolution of the adrenal mass, as evidenced by follow-up imaging and clinical assessments. Conclusion: This case highlights the efficacy of alectinib in treating rare ALK fusion variants in and underscores the importance of comprehensive molecular profiling in guiding targeted therapy decisions.

Exposure to air pollutants and breast cancer risk: mediating effects of metabolic health biomarkers in a nested case-control study within the E3N-Generations cohort.

Growing epidemiological evidence suggests an association between exposure to air pollutants and breast cancer. Yet, the underlying mechanisms remain poorly understood. This study explored the mediating role of thirteen metabolic health biomarkers in the relationship between exposure to three air pollutants, i.e. nitrogen dioxide (NO2), polychlorinated biphenyls 153 (PCB153), and benzo[a]pyrene (BaP), and breast cancer risk. We used data from a nested case-control study within the French national prospective E3N-Generations cohort, involving 523 breast cancer cases and 523 matched controls. The four-way decomposition mediation of total effects for thirteen biomarkers was applied to estimate interaction and mediation effects (controlled direct, reference interaction, mediated interaction, and pure indirect effects). The analyses indicated a significant increase in breast cancer risk associated with BaP exposure (odds ratio (OR)Q4 vs Q1 = 2.32, 95% confidence intervals (CI): 1.00-5.37). PCB153 exposure showed a positive association only in the third quartile (ORQ3 vs Q1 = 2.25, CI 1.13-4.57), but it appeared to be non-significant in the highest quartile (ORQ4 vs Q1 = 2.07, CI 0.93-4.61). No association was observed between NO2 exposure and breast cancer risk. Estradiol was associated with an increased risk of breast cancer (OR per one standard deviation (SD) increment = 1.22, CI 1.05-1.42), while thyroid-stimulating hormone was inversely related to breast cancer risk (OR per 1SD increase = 0.87, CI 0.75-1.00). We observed a suggestive mediated effect of the association between the three pollutants and breast cancer risk, through albumin, high-density lipoproteins cholesterol, low-density lipoprotein cholesterol, parathormone, and estradiol. Although limited by a lack of statistical power, this study provides relevant insights into the potential mediating role of certain biomarkers in the association between air pollutant exposure and breast cancer risk, highlighting the need for further in-depth studies in large populations.

Ashwagandha (Withania somnifera) in Cancer Therapy: Anticancer Activities and Their Mechanisms

Cancers are characterized by rapid development of abnormal cells that multiply uncontrollably, leading to invasive tumors. By 2040, new cancer cases worldwide are expected to reach 30.2 million. In response, research focuses on the anti-cancer properties of ashwagandha (Withania somnifera), used in traditional Indian medicine. Ashwagandha exhibits anti-inflammatory effects by modulating pathways like NF-kB, Nrf2/HO-1, JAK-STAT, MAPK, and NLRP3, reducing cancer-related inflammation. It also has strong antioxidant properties due to compounds like withanolides, increasing antioxidant enzyme activity and reducing oxidative stress, potentially lowering cancer risk. Ashwagandha extract shows cytotoxic effects against cancer cells, inducing apoptosis and arresting cells in the resting phase, leading to DNA damage in cancer cells. It inhibits angiogenesis, the process of forming new blood vessels that supply tumors, through mechanisms such as VEGF inhibition and reduced macrophage infiltration. Additionally, ashwagandha modulates T lymphocytes and cytokine production, enhancing the immune response against cancer, and stimulates NK cell activity, crucial for controlling tumor growth and development. Supplementation with ashwagandha reduces cortisol levels and improves cognitive functions and quality of life in people experiencing stress, potentially lowering cancer risk. Research suggests ashwagandha may be a valuable addition to anti-cancer therapy, acting on various levels of cancer pathogenesis. However, further clinical studies are needed to fully understand its mechanisms of action and to evaluate its efficacy and safety in cancer treatment.

OCCURRENCE OF HUMAN PAPILLOMAVIRUS (HPV) IN WOMEN OF LGBTQIA+ COMMUNITY TREATED IN MANAUS, AMAZONAS

Human papillomavirus (HPV) is a significant etiological factor for several types of cancer, including cervical carcinoma, with 80% of cases of cervical cancer occurring in Latin America. In Brazil, cervical carcinoma is the third most prevalent cancer among women, and the northern region and the state of Amazonas have the highest incidence in the country. However, not all women benefit from cervical cancer screening measures. Most women in the LGBTQIA+ community do not seek gynecological health services since they often face barriers related to female homosexuality when accesing sexual health services. Using PCR, this study perfomed the molecular detection and genotyping of HPV in thirty-six patients (20 homosexual and 16 bisexual women) from Manaus, Amazonas, Brazil. Samples of the cervical epithelium were taken during the preventive examination and genotyping was perfomed to detect HPV 16, 18, 31 and 58. Of the thirty-six patients analyzed in this study, 88% of bisexual women (n=14) and 60% of homosexual women (n=12) tested positive for HPV. The HPV 18 genotype was the most frequent among the findings. The results indicate that homosexual and bisexual women are more vulnerable to HPV infections due to the lack of more specific gynecological care directed to this group, which includes the lack of training of professionals to deal with the particularities of this population group. Therefore, more HPV screening studies for LGBTQIA+ women and improved training for specialized health professionals are needed.

A genome-wide association study in Swedish colorectal cancer patients with gastric- and prostate cancer in relatives.

A complex inheritance has been suggested in families with colorectal-, gastric- and prostate cancer. Therefore, we conducted a genome-wide association study (GWAS) in colorectal cancer patients, who's relatives had prostate-, and/or gastric cancer. The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model.Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case-control study. Candidate loci/genes on ten chromosomal regions were suggested with odds ratios between1.71-3.62 and p-values < 5 × 10-8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of DNA from 122 colorectal cancer patients with gastric- and/or prostate cancer in their families was performed to search for candidate variants in the haplotype regions. The identified candidate variants were tested in a nested case-control study of similar colorectal cancer cases and controls. There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested. This study demonstrated a proof of principle strategy to identify risk variants found by GWAS, and identified ten candidate loci that could be associated with colorectal, gastric- and prostate cancer.

Candidate genetic loci modifying the colorectal cancer risk caused by lifestyle risk factors

Objective: 65-70% of colorectal cancer (CRC) cases are considered sporadic; they arise under the influence of environmental factors in individuals lacking a family history of CRC. Low-risk genetic variants are believed to contribute to CRC risk, in tandem with lifestyle factors. Design: 616 non-familial Swedish CRC cases with at least 1 of the following five risk factors: smoking, excessive alcohol consumption, physical inactivity, adherence to an unhealthy diet, and excess body weight were included in this study. A control group consisting of 1642 healthy individuals was used. Cases and controls were genotyped from blood samples at the Centre for Inherited Disease Research at Johns Hopkins University within the Colorectal Transdisciplinary Study (CORECT) research collaboration, using the Illumina Infinium® OncoArray-500 K BeadChip. Five separate genome-wide haplotype association analyses were performed, one for each risk factor. Logistic regression models were employed to estimate associations between haplotypes (exposure) and CRC (outcome) in cases with lifestyle risk factors versus controls. Haplotypes with an odds ratio (OR) &gt;1 were considered candidate risk markers, denoting an area of interest in the genome. A significance threshold of p &lt; 5×10-8 was used. Results: We found 17 haplotype regions significantly associated with CRC in cases vs controls. Several regions included genes linked to inflammation and tumor promotion. Conclusion: We concluded that having certain genetic variants was associated with an increased risk of CRC compared to healthy controls among cases with known lifestyle risk factors. The interplay of lifestyle and genetic risk factors calls for further elucidation.

Assessing the correlation between Gamma passing rate and clinical dosimetric variations in breast cancer IMRT plans with multi-leaf collimator errors: perspectives from the ArcCHECK QA system.

This study aimed to comprehensively investigate the influence of multi-leaf collimator (MLC) position errors on both the clinical absolute dose distribution and Gamma passing rate (%GP) in intensity-modulated radiation therapy (IMRT) plans for breast cancer. Additionally, the correlation between %GP and the clinical absolute dose relative difference (%DE) caused by MLC position errors was analysed. Ten IMRT plans for breast cancer were randomly selected. Systematic and random MLC position errors were introduced into DICOM files representing the investigated treatment plans by modifying the plan files and adjusting the MLC positions. Systematic errors were categorized as MLC opening errors, closing errors, and shift errors. The %DE in the tumour planning target volume (PTV) and organs at risk (OARs) caused by MLC errors were statistically analyzed using dose-volume histogram (DVH) analysis. The ArcCHECK quality assurance (QA) system was used to detect the %GP differences between baseline plans and plans with MLC errors. The correlation between %GP and %DE was obtained using linear regression methods. The results of this study indicate that MLC opening and closing errors have a significant impact on %DE and %GP in IMRT plans for breast cancer. Opening and closing errors can be detected at a gamma level of 3%/2mm, if error values are greater than or equal to 0.5mm, and %GP can predict DVH dosimetric changes caused by MLC opening and closing errors. It is concluded that DVH-based verification of IMRT plans can serve as an adjunct method to Gamma analysis to improve QA accuracy for breast cancer cases. Additionally, it is concluded that greater attention should be given to MLC leaf opening and closing errors in clinical practice.

Timeliness of lung cancer care and area-level determinants in Victoria: A Bayesian spatio-temporal analysis.

It has been reported that the timeliness of lung cancer care varies significantly across different regions. According to the Victorian Lung Cancer Registry (VLCR) report, the timeliness of lung cancer care in Victoria has changed over time. Therefore, we aimed to quantify the extent of these spatial inequalities over time and to identify area-level determinants contributing to these changes. The study analysed lung cancer cases reported to the VLCR between 2011 and 2022. Bayesian spatio-temporal Conditional Autoregressive (CAR) models were fitted, incorporating spatial random effects, temporal random effects, as well as spatio-temporal interactions. The best-performing model was selected using the Deviance Information Criterion (DIC). For the final best-fit model, the adjusted Relative Risks (aRR) and their 95% Credible Interval (CrI) were reported. Over half (51.24%) of lung cancer patients experienced treatment delays, while approximately one-third (30.98%) encountered diagnostic delays. Moderate spatio-temporal variations were observed in both delayed diagnosis and treatment. In the final best-fit model for treatment delay, an increase in the percentage of smokers was significantly associated with a higher risk of treatment delay (RR = 2.13, 95% CrI: 1.13, 4.20). Identifying high-risk areas provides useful information for policymakers, helping in the reduction of delays in lung cancer diagnosis and treatment. This study has revealed spatio-temporal inequalities in diagnostic and treatment delays, providing valuable insights for identifying areas that should be prioritized to ensure timely care for lung cancer.

High-dose folic acid use and cancer risk in women who have given birth: A register-based cohort study.

This study was undertaken to study whether high-dose folic acid (>1 mg daily) use is associated with an increased risk of cancer in all women who have given birth and in women with epilepsy. High-dose folic acid supplementation during pregnancy has been linked to increased cancer risk in children born to mothers with epilepsy. We identified women with their first pregnancy in Denmark (1997-2017), Norway (2005-2017), and Sweden (2006-2017) using medical birth registers, linking individual data across nationwide health registers and statistical agencies. Exposure was defined as filled prescriptions for high-dose folic acid, considered time-varyingly. The primary outcome was the first malignant cancer diagnosis. Hazard ratios (HRs) of cancer after high-dose folic acid exposure were estimated using Cox proportional hazard models with 95% confidence intervals (CIs), adjusted for confounders including antiseizure medication (ASM) use, and stratified by maternal epilepsy diagnosis. A 6-month time lag was applied, as cancer is unlikely to develop immediately. With up to 21 years of follow-up, we identified 1 465 785 women who gave birth, including 64 485 (4.4%) exposed to high-dose folic acid. In the exposed group, 755 cancer cases were observed (208 per 100 000 person-years, 95% CI = 193.8-223.5), compared with 18 702 cases in the unexposed group (164 per 100 000 person-years, 95% CI = 161.5-166.2), yielding a 20% increased cancer risk overall (adjusted HR = 1.2, 95% CI = 1.1-1.2). This risk was attenuated after the 6-month lag analysis (adjusted HR = 1.1, 95% CI = 1.04-1.2). The risk for non-Hodgkin lymphoma was increased in all analyses (n = 28, adjusted HR = 2.0, 95% CI = 1.3-2.9). The association between high-dose folic acid use and overall cancer risk was similar in those with epilepsy regardless of ASM use (adjusted HR = 1.3, 95% CI = 1.0-1.8). High-dose folic acid use was associated with increased overall cancer risk in women who have given birth, with a consistent association with non-Hodgkin lymphoma, including those with epilepsy, regardless of ASM use.

Abstract A061: A cost-effective two-step approach for multi-cancer early detection in general population

Abstract In population-wide cancer screening, three key issues need to be focused on: number of cancer cases identified, the issue of false positives, and cost. A high false positive rate can result in a significant waste of healthcare resources. Large-scale screening inevitably leads to significant financial burdens on the healthcare system which is a key factor constraining nationwide screening. OncoSeek is a multi-cancer early detection (MCED) test using a panel of seven plasma protein tumor markers (PTMs) and artificial intelligence (AI). SeekInCare is a MCED test that integrates the seven PTMs and four cancer genomic features (aneuploidy, fragment size, end motifs, and oncogenic viruses) from cell-free DNA (cfDNA) by shallow whole-genome sequencing (sWGS). In a two-step approach, the initial screening is conducted using OncoSeek and SeekInCare is then used as the secondary test for those individuals who tested positive by OncoSeek. In a case-control study (n = 1197) including both OncoSeek and SeekInCare testing results, OncoSeek showed 49.9% sensitivity at 91.0% specificity, while SeekInCare demonstrated 60.0% sensitivity at 98.3% specificity. In the two-step process, specificity significantly increased from 91.0% to 99.3%, while sensitivity decreased from 49.9% to 39.9%. We modeled a screening in five million adults aged ≥ 50 years with a cancer incidence rate of 1.9%. The simulated real-world sensitivities of OncoSeek and two-step were adjusted downward proportionally to 28.0% and 22.4% based on the sensitivity differences observed between GRAIL’s CCGA study (case-control, 51.5%) and PATHFINDER study (prospective, 28.9%). While at 91.0% specificity OncoSeek had 441,450 cases of false positives, using the two-step approach significantly reduced false positives to 34,335 (0.7%). Although Galleri ($949 per test) identified more cancer cases than the two-step MCED, with 27,455 and 21,280 cases respectively, its total cost for the former reached $4,745 million. As the positive predictive value (PPV) of two-step (38.3%) was the same as Galleri (38.3%), it reduced cost 6.6-fold, amounting to a total cost of $713.6 million and a cost of $143 per individual screened. The cost of per cancer case detected using Galleri is $172,828 compared to $33,534 using the two-step MCED, which represents a 5.2-fold difference. In conclusion, the two-step approach not only significantly reduces false positives, but also cuts the screening cost down substantially, making it a cost-effective strategy for population-wide cancer screening. Citation Format: Mao Mao, Geng shuai peng, Li shi yong, Wu Wei, Chang Yin Yin. A cost-effective two-step approach for multi-cancer early detection in general population [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A061.