Cancer Research Fund Research Articles

Incorporating costs and benefits to the evaluation of uncertain research results: applications to cancer research funding

Abstract Correctness is a key aspiration of the scientific process, yet recent studies suggest that many high-profile findings may be difficult to replicate or require considerable evidence for verification. Proposals to fix these issues typically ask for tighter statistical controls—e.g., stricter p-value thresholds or higher statistical power. However, these approaches often overlook the importance of contemplating research outcomes’ potential costs and benefits. Here, we develop a framework grounded in Bayesian decision theory that seamlessly integrates cost-benefit analysis into evaluating research programs with potentially uncertain results. We derive minimally acceptable pre-study odds and positive predictive values for cost and benefit levels. We show that tolerance to inaccurate results changes dramatically due to uncertainties posed by research. We also show that reducing uncertainties (e.g., by recruiting more subjects) may have limited effects on the expected benefit of continuing specific research programs. We apply our framework to several types of cancer research and their funding. Our analysis shows that highly exploratory research designs are easily justifiable due to their potential benefits, even when probabilistic models suggest otherwise. We discuss how the cost and benefit of research could and should always be part of the toolkit used by scientists, institutions, or funding agencies. Peer Review https://www.webofscience.com/api/gateway/wos/peer-review/10.1162/qss_a_00332

Abstract A028: Revisiting cancer care inequities in Sub-Saharan Africa: standpoint and recommendations

Abstract Introduction: Cancer is a major global public health concern that claims around 2000 lives per day in Africa alone. Mortality rates are expected to rise in the absence of appropriate interventions. Equity and prioritizing are the main obstacles to cancer care in Africa, as policymakers and other stakeholders in the healthcare system do not give cancer enough attention. All aspects of the cancer care continuum especially these three main levels of cancer care—prevention, diagnosis, and treatment/management—are negatively impacted by this neglect. Addressing concerns of equity and prioritizing is essential to promoting equality in cancer care, as it guarantees that all individuals have an equal opportunity at cancer prevention, early detection, appropriate therapy, and follow-up treatment. Methods: We present an overview of the current status of cancer care in Africa and offer recommendations to bridge the gap using the material currently accessible from recognized databases. Results: Insufficient funding for cancer research, inadequate screening or diagnostic facilities, a lack of a well-organized and efficient cancer registry system and access to care, a shortage of specialized medical staff, high costs for screening, vaccination, and treatment, a lack of technical capacity, poor vaccination response, and late patient presentation for cancer screening are some of the factors that we highlighted as contributing to the disparity in cancer care in Africa. We also offer suggestions on overcoming some of these barriers to achieving fairness in cancer care. Our recommendations are broken down into capacity-based and national-level initiatives. These include improving healthcare budgeting for personnel, supplies, and facilities; encouraging screening and vaccine uptake; raising awareness of cancer health among medical professionals during every hospital visit, gaining knowledge through specialized training, financing cancer research, offering cancer insurance, and putting mobile health technologies to use for telemedicine diagnosis.Conclusion: A comprehensive approach to addressing issues related to cancer equity would increase the chances of cancer patients surviving longer, reduce risk factors for at-risk groups, and guarantee fair access to cancer care across the continent. This report describes the present barriers to achieving equity in cancer care, identifies the African countries' current positions on the matter, and offers recommendations that could have the greatest impact on achieving equity in cancer care. Citation Format: John Oluwafemi Teibo, Olabode Omotoso, Festus Adebayo Atiba, Tolulope Oladimeji, Tomiwa Kehinde Paimo, Farid S. Ataya, Gaber El-Saber Batiha, Athanasios Alexiou. Revisiting cancer care inequities in Sub-Saharan Africa: standpoint and recommendations [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A028.

Circulating inflammatory and immune response proteins and endometrial cancer risk: a nested case-control study and Mendelian randomization analyses

Inflammation and immune dysregulation are hypothesized contributors to endometrial carcinogenesis; however, the precise underlying mechanisms remain unclear. We measured pre-diagnostically 152 plasma protein biomarkers in 624 endometrial cancer case-control pairs nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Odds ratios (ORs) were estimated using conditional logistic regression, accounting for confounding and multiple comparisons. Proteins considered as associated with endometrial cancer risk were further tested in a two-sample Mendelian randomization (MR) analysis using summary data from the UK Biobank (n=52,363) and the Endometrial Cancer Association Consortium (12,270 cases and 46,126 controls). In the EPIC nested case-control study, IL-6 [OR per NPX (doubling of concentration)=1.28 (95% confidence interval (CI) 1.03-1.57)], HGF [1.48 (1.06-2.07)], PIK3AP1 [1.22 (1.00-1.50)] and CLEC4G [1.52 (1.00-2.32)] were positively associated; HSD11B1 [0.67 (0.49-0.91)], SCF [0.68 (0.49-0.94)], and CCL25 [0.80 (0.65-0.99)] were inversely associated with endometrial cancer risk; all estimates had multiple comparisons adjusted P-value > 0.05. In complementary MR analysis, IL-6 [OR per inverse-rank normalized NPX=1.19 (95% CI 1.04-1.36)] and HSD11B1 [0.91 (0.84-0.99)] were associated with endometrial cancer risk. Altered IL-6 signalling and reduced glucocorticoid activity via HSD11B1 might play important roles in endometrial carcinogenesis. Funding for IIG_FULL_2021_008 was obtained from Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund International grant programme; Funding for INCA_15849 was obtained from Institut National du Cancer (INCa).

Healthy Eating and Active Lifestyle after Bowel Cancer (HEAL ABC)-feasibility randomised controlled trial.

Evidence from cohort studies indicates that a healthy lifestyle can improve cancer survival but evidence from randomised controlled trials (RCT) is lacking. Thus, this study tested the feasibility of conducting a lifestyle intervention in patients after colorectal cancer (CRC) treatment. An intervention was developed based on World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) recommendations, the Health Action Process Approach, Motivational Interviewing and tested a feasibility, mixed-methods RCT. Participants were allocated to a three-month telephone-based intervention versus standard care control group. The follow up period was six months. Data on feasibility and secondary outcomes were collected and analysed using Stata (V15, StataCorp LLC) and NVivo 12 (QSR International Pty Ltd., Doncaster, VIC). Recruitment was challenging (31 ineligible, 37 declined; recruitment rate = 48.6%.). In total, 34/35 participants completed the intervention, and 31 (89%) completed follow up; all 31 completers participated in six telephone calls during intervention and six months follow up. Study retention was 97% (34/35) and 89% (31/35) at three and six months, respectively. Data completion rates were high (>90%). Intervention was acceptable to participants, met their needs and kept them accountable towards their goals. Participants in the intervention group showed significant improvement in WCRF/AICR, Diet Quality Index-International score and a 10% reduction in ultra-processed food consumption. The HEAL ABC intervention was feasible for 87% of intervention participants, supporting them in healthy lifestyle changes. However, alternative recruitment strategies are needed for a fully powered RCT to determine the effectiveness of the intervention.

Psychological distress and health behaviours in people living with and beyond cancer: a cross-sectional study

This study aimed to examine whether psychological distress was cross-sectionally associated with meeting World Cancer Research Fund (WCRF) recommendations in people living with and beyond cancer. Participants were adults living with and beyond breast, prostate and colorectal cancer, participating in the baseline wave of the Advancing Survivorship after Cancer Outcomes Trial (ASCOT). Anxiety/depression was assessed using the EQ-5D-5L and dichotomised into any/no problems. WCRF recommendations were assessed via pedometers, 24-h dietary recalls, self-reported alcohol intake (AUDIT-C), and self-reported smoking status. Participants were categorised as meeting WCRF recommendations using the following cut-offs: average daily steps (≥ 10,000/day), average weekly aerobic steps (≥ 15,000/day), fruit and vegetables (≥ 400 g/day), fibre (≥ 30 g/day), red meat (< 500 g/week), processed meat (0 g/day), high calorie food (fat ≤ 33% of total daily energy intake and free sugar ≤ 5% of total daily energy intake), alcohol (≤ 14 units/week) and smoking (non-smoking). A composite health behaviour risk index (CHBRI) was calculated by summing the number of WCRF recommendations met (range: 0–9). Among 1348 participants (mean age = 64 years (SD = 11.4)), 41.5% reported anxiety/depression problems. The mean CHBRI score was 4.4 (SD = 1.4). Anxiety/depression problems were associated with lower odds of meeting WCRF recommendations for average daily steps (odds ratio (OR) = 0.73; 95% CI 0.55, 0.97), but not for any other health behaviour. Psychological distress is associated with lower adherence to WCRF recommendations for physical activity in people living with and beyond cancer. Physical activity may be a mechanism linking psychological distress and poorer outcomes among people living with and beyond cancer, and this should be explored in longitudinal studies.

Nicholas Avrion Mitchison. 5 May 1928 — 28 December 2022

Avrion Mitchison, universally known as Av, made enormous contributions to the field of cellular immunity. Working under Peter Medawar FRS during his PhD in Oxford, Av made the crucial discovery that viable lymphocytes were responsible for rejection of grafts of foreign tissue, initiating the field of cellular immunology, which was to preoccupy him throughout his career. In 1962 he was appointed head of the Division of Experimental Biology at the National Institute for Medical Research and began using proteins decorated with small synthetic molecules termed haptens, enabling him to make his second major discovery. He showed that optimal antibody responses to a hapten required the cooperation of two cell populations: bone-marrow-derived ‘B’ lymphocytes, which synthesized the antibody, and thymus-derived ‘T’ lymphocytes, which recognized moieties in the carrier protein molecule and provided help to the B cells. In 1971 Av became the Jodrell Professor of Zoology at University College London and head of the Imperial Cancer Research Fund Tumour Immunology Unit (TIU), where he continued to investigate how antibody and cytotoxic T cell responses are regulated and the role of major histocompatibility genes in this process. The TIU was a mecca for immunologists from around the world, and Av inspired those who passed through to make major contributions to cellular immunity, neuroimmunology, leukaemogenesis, tumour immunology and autoimmune disease. In 1991 he became the first director of the Rheumatism Research Centre in Berlin, and in a few short years after the fall of the Berlin wall established a flourishing institute. The annual award of the Mitchison Prize for Young Researchers honours his legacy.

Modifications of the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Score and Cancer Risk in the UK Biobank Prospective Cohort Study

Modifications of the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Score and Cancer Risk in the UK Biobank Prospective Cohort Study

Modifiable risk factors for cancer among people with lynch syndrome: an international, cross-sectional survey

BackgroundLynch syndrome is the most common cause of hereditary colorectal and endometrial cancer. Lifestyle modification may provide an opportunity for adjunctive cancer prevention. In this study, we aimed to characterise modifiable risk factors in people with Lynch syndrome and compare this with international guidelines for cancer prevention.MethodsA cross-sectional study was carried out utilizing survey methodology. Following public and patient involvement, the survey was disseminated through patient advocacy groups and by social media. Self-reported demographic and health behaviours were collected in April 2023. Guidelines from the World Cancer Research Fund (WCRF) were used to compare percentage adherence to 9 lifestyle recommendations, including diet, physical activity, weight, and alcohol intake. Median adherence scores, as a surrogate for lifestyle risk, were calculated and compared between groups.Results156 individuals with Lynch syndrome participated from 13 countries. The median age was 51, and 54% were cancer survivors. The mean BMI was 26.7 and the mean weekly duration of moderate to vigorous physical activity was 90 min. Median weekly consumption of ethanol was 60 g, and 3% reported current smoking. Adherence to WCRF recommendations for cancer prevention ranged from 9 to 73%, with all but one recommendation having < 50% adherence. The median adherence score was 2.5 out of 7. There was no significant association between median adherence scores and age (p = 0.27), sex (p = 0.31), or cancer history (p = 0.75).ConclusionsWe have characterised the modifiable risk profile of people living with Lynch syndrome, outlining targets for intervention based on lifestyle guidelines for the general population. As evidence supporting the relevance of modifiable factors in Lynch syndrome emerges, behavioural modification may prove an impactful means of cancer prevention.

Implications of food ultra-processing on cardiovascular risk considering plant origin foods: an analysis of the UK Biobank cohort

Comprehensive research evidence is lacking on the role of ultra-processed foods (UPF) in the relationship between the consumption of plant-sourced foods and their impact on cardiovascular disease (CVD) outcomes. This study aims to assess CVD risk associated with the dietary contribution of food groups that consider both plant or animal origin and food processing categories, within a large cohort of British adults. Data from the UK Biobank participants (40-69y) who completed at least two 24-h dietary recalls between 2009 and 2012 (n=126,842; median follow-up: 9y), with subsequent data linkage to hospital and mortality records, were used. Food groups were classified as either plant-sourced or non-plant/animal-sourced foods. These groups were further divided into non-UPF and UPF, and expressed as a percentage of total energy intake. Every 10 percentage points increase in plant-sourced non-UPF consumption was associated with a 7% lower risk of CVD (95% CI 0.91-0.95) and a 13% lower risk of CVD mortality (0.80-0.94). Conversely, plant-sourced UPF consumption was associated with a 5% increased risk (1.03-1.07) and a 12% higher mortality (1.05-1.20). The contribution of all UPF was linked to higher CVD risk and mortality, and no evidence for an association between contribution of all plant-sourced foods and CVD incidence and mortality was observed. The dietary contribution of plant-sourced non-UPF inversely linked to CVD risk, while plant-sourced UPF contribution showed a positive association. Recognizing the role of food processing is crucial for favourable CVD outcomes, even in plant-sourced diets. World Cancer Research Fund.

Cancer research funding in South Asia

BackgroundThe rising burden of cancer significantly influences the global economy and healthcare systems. While local and contextual cancer research is crucial, it is often limited by the availability of funds. In South Asia, with 1.7 million new cancer cases and 1.1 million deaths due to cancer in 2020, understanding cancer research funding trends is pivotal. MethodsWe reviewed funded cancer studies conducted between January 1, 2003, and Dec 31, 2022, using ClinicalTrials.gov, International Cancer Research Partnership (ICRP) Database, NIH World RePORT, and WHO International Clinical Trials Registry Platform (ICTRP). We included funded studies related to all cancer types, conducted in South Asian countries, namely Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka. ResultsWe identified 6561 funded cancer studies from South Asia between 2003 and 2022, increasing from 400 studies in 2003‐2007 to 3909 studies in 2018–2022. India had the highest number of funded cancer studies, while Afghanistan, Bhutan, and the Maldives had minimal or no funded cancer research output. Interventional studies (67.3%) were the most common study type funded. The most common cancer sites funded were breast (17.8%), lung (9.9%), oropharyngeal (6.2%), and cervical (5.0%) cancers. On the WHO ICTRP, international funding agencies contributed to a majority of studies (57.5%), except in India where local funding agencies (58.2%) funded more studies. ConclusionThis study identified gaps in research funding distribution across cancer types and geographic areas in South Asia. This data can be used to optimize the distribution of cancer research funding in South Asia, fostering equitable advancement in cancer research.

The association of cancer-preventive lifestyle with colonoscopy screening use in border Hispanic adults along the Texas-Mexico border.

The relationship between engaging in two domains of cancer-preventive behaviors, lifestyle behaviors and colonoscopy screening, is unknown in Hispanic adults. Accordingly, the study examined the association between lifestyle and colonoscopy screening in Hispanic adults along the Texas-Mexico border, where there is suboptimal colorectal cancer prevention. Lifestyle behavior adherence and compliance with colonoscopy screening schedules were assessed using 2013-2023 data from the Cameron County Hispanic Cohorta population-based sample of Hispanic adults living along the Texas-Mexico border. The 2018 World Cancer Research Fund scoring system characterized healthy lifestyle engagement. Multivariable logistic regression quantified the association between lifestyle behaviors and colonoscopy screening. Among 914 Hispanic adults, there was a mean adherence score of 2.5 out of 7 for recommended behaviors. Only 33.0% (95% CI 25.64-41.39%) were up-to-date with colonoscopy. Complete adherence to fruit and vegetable (AOR [adjusted odds ratio] 5.2, 95% CI 1.68-16.30; p = 0.004), fiber (AOR 2.2, 95% CI 1.06-4.37; p = 0.04), and ultra-processed foods (AOR 2.8, 95% CI 1.30-6.21; p = 0.01) consumption recommendations were associated with up-to-date colonoscopy screening. Having insurance versus being uninsured (AOR 10.8, 95% CI 3.83-30.62; p < 0.001) and having local medical care versus in Mexico (AOR 7.0, 95% CI 2.26-21.43; p < 0.001) were associated with up-to-date colonoscopy. Adherence to dietary lifestyle recommendations was associated with being up-to-date with colonoscopy screenings. Those with poor dietary behavior are at risk for low-colonoscopy use. Improving lifestyle behaviors may complement colonoscopy promotion interventions. Healthcare accessibility influences up-to-date colonoscopy prevalence. Our findings can inform cancer prevention strategies for the Hispanic population.

Abstract PO3-10-09: The allocation of US $2.6 billion in global funding for breast cancer research between 2016 – 2020: are we investing wisely for breast cancer patients?

Abstract Background: Breast cancer is a global health challenge and the highest incident cancer globally, with over 2 million new cases and 685,000 deaths in 2020, making it the highest incident cancer globally. Furthermore, it is the most prevalent cancer, resulting in the loss of more disability-adjusted life years than any other malignancy. Research is thus crucial to improving outcomes and reducing suffering for breast cancer patients worldwide. This study aimed to analyse global patterns of funding for breast cancer research. Methods: We have previously created a comprehensive database of awards for human cancer research in this period using publicly available data on research funding awards. From this database we extracted all awards relating to breast cancer research, and categorised these by cancer type, cross-cutting research theme and phase of research. Findings: We identified 7051 awards with a total investment of $2.6 billion in 2016-2020, representing 11.2% of all global public and philanthropic cancer research funding during this period. Breast cancer research funding fell year on year, from $773.4 million in 2016 to $243.8 million in 2020. The majority of the investment was in pre-clinical research ($1.9 billion, 73.9%), with clinical trials ($276 million, 10.7%) and public health ($269.2 million, 10.5%) receiving roughly equivalent amounts of funding. The USA accounted for 66.9% of all global breast cancer research investment, with China ($110.4 million, 4.3%) and the UK ($96.6 million, 3.8%) the next largest funders. By research theme, cancer biology research received most funding ($926.2 million, 37.5% of investment), with drug treatment the next best funded research area ($600.5 million, 23.4%), and diagnosis, screening and monitoring third ($396 million, 15.4%). Surgery ($65.2 million, 2.5%) and radiotherapy ($35.3 million, 1.4%) accounted for only a small proportion of research investment. There was minimal investment into breast cancer as a global health issue ($8.1 million, 0.3%). Research into metastatic disease received a greater proportion of investment in breast cancer than in the overall cancer portfolio (23.2% in breast cancer, $597.4 million, compared with 11.7% across all cancers). Conclusions: Breast cancer public and philanthropic research funding is largely invested in pre-clinical research in high-income countries, with the main areas of investment being cancer biology research and drug treatment. The direct benefit to patients from such research is likely to be low and only apparent after a substantial time lag (if at all). Despite their pivotal role in the treatment of the majority of breast cancer patients, surgery and radiotherapy research received a tiny proportion of the overall research investment. Furthermore, relatively little investment is directed towards cancer prevention and early detection, despite their acknowledged key role in cancer control globally. Finally, more equitable research funding is required to align with the global burden of breast cancer, with increased funding for low- and middle-income countries, which account for an increasing proportion of this burden. These data should be considered by funders and policymakers in the allocation of finite resources, which must be invested wisely. Citation Format: Stuart McIntosh, Ellen Copson, Ramsey Cutress, Michael Head. The allocation of US $2.6 billion in global funding for breast cancer research between 2016 – 2020: are we investing wisely for breast cancer patients? [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 PO3-10-09.

Abstract PO5-12-02: Landscape analysis of oncology nutrition research among patients being treated for breast cancer

Abstract The American Institute for Cancer Research/World Cancer Research Fund and the American Cancer Society regularly conduct systematic reviews on the evidence supporting nutrition interventions during cancer treatment. These reviews have found that the evidence to support clinical oncology nutrition practice guidelines is limited. It is unclear how many oncology nutrition studies are currently being conducted, especially among patients being treated for breast cancer. The goal of this project was to conduct a landscape analysis of nutrition research being conducted among breast cancer patients over the past 10 years. Methods: This analysis was part of a larger effort to describe the oncology nutrition research landscape for all cancer sites. Searches of ClinicalTrials.gov were performed on 1/8/2023 using the following search terms/combinations: “cancer AND nutrition”, “cancer nutrition”, “oncology AND nutrition”, “diet AND cancer”, “cancer, oncology, neoplasms, nutrition, diet”. Search results were downloaded as .csv files and uploaded to RStudio for merging and data cleaning (elimination of duplicates, and exclusion of studies registered in ClinicalTrials.gov before 1/1/2013 or after 12/31/2022). The resulting harmonized dataset was then uploaded to REDCap, and each entry was reviewed for eligibility by one of the authors. To be included in this landscape analysis, studies must have included data collection from patients who were actively receiving cancer treatment at the time of the study and the study had to be first posted to ClinicalTrials.gov between 1/1/2013 and 12/31/2022. Studies were excluded if they: 1) focused on the role of diet in primary cancer prevention, 2) focused on cancer survivors who had completed primary treatment for their cancers. Following eligibility review, the study datafile was returned to RStudio for further cleaning and analysis. Results: The initial ClinicalTrials.gov search identified 4,345 unique study listings. After review, 1,267 studies met the inclusion criteria, of which 132 (10.4%) studies were specific to breast cancer (117 intervention studies and 15 observational studies). Among breast cancer studies, reasons for exclusion were: study focused on diet/nutrition in the prevention of a primary cancer diagnosis (n=40), study participants had already completed their cancer treatment (n=128), study did not include a diet/nutrition intervention or assessment (n=31). The largest number of breast cancer specific studies were based in the United States (n=55, 41.6%), Italy (n=11, 8.3%), France (n=10, 7.6%) and Canada (n=9, 6.8%). Dietary supplement interventions were the most common type of intervention (n=50 studies, 42.7%), followed by behavior change interventions (n=22, 18.8%), diet in relation to a drug intervention (n=25, 21.4%), diet in relation to a device/procedure/radiation intervention (n=16, 14%), fasting/time-restricted feeding studies (n=13, 11.1%) and ketogenic diet interventions (n=3, 2.6%). Changes in weight or body composition (n=52, 39.4%), quality of life (n=45, 34.1%), adverse events (n=24, 18.2%), survival (n=20, 15,2%) and fatigue (n=17, 12.9%) were the most common outcome measures. Sixteen (12.1%) studies were supported by NIH funding and 9 (6.8%) studies were industry funded, although the majority (n=124, 93.9%) reported funding from “other” sources. Of the 41 studies that started between 2013-2017 (five years prior to the January 2023 ClinicalTrials.gov search), only 21 (51.2%) were listed as being “completed” and of those, only 7 were listed as “has results”. Conclusion: More research is needed to support evidence-based supportive care guidelines for oncology nutrition interventions during breast cancer treatment. Efforts should be made to support researchers in completing studies and disseminating research findings. Citation Format: Kim Robien, Heather Wopat. Landscape analysis of oncology nutrition research among patients being treated for 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 PO5-12-02.

Abstract PO5-05-10: Analysis of Trends in Funding of Metastatic Breast Cancer Research

Abstract Introduction To inform funding strategies for research in metastatic breast cancer (MBC), knowledge of the current research landscape and identification of potential gap areas requiring additional research are essential. In 2014, the Metastatic Breast Cancer Alliance (MBCA) published an analysis that showed that between 2000 and 2013, only 7% of all funds for breast cancer research were devoted to metastasis. As more people are living with MBC, addressing research priorities for those living with the disease is important, as is understanding gaps in the current funding landscape of MBC research to appropriately target investment. Methods A collaborative effort between funders and patients was undertaken to analyze breast cancer projects funded between 2014 and 2020 from the International Cancer Research Partnership database, the Health Resource Alliance database, and MBCA members, representing grants from 83 non-profit organizations worldwide. Project titles, abstracts, and classifications of these grants were extracted from these databases. Next, to identify research projects in the databases that are related to metastasis, a classification tool that uses a machine learning algorithm was built, trained on manually coded grants from the 2000-2013 analysis, and validated by expert coders. Projects were then coded according to a pre-established metastasis classification policy to categories such as type of research (e.g., treatment), genes or proteins studied, site of metastasis, breast cancer subtype, and patient priority questions. In terms of the latter, MBCA members living with MBC were surveyed about research priorities. Member advocates ranked survey questions according to highest patient priority, and these were converted to language that could be queried with the tool. Results Investment in MBC research nearly doubled from 2014 to 2020. Research into understanding and overcoming treatment resistance, which was the highest patient priority question, increased from 15% in 2014 to 26% of the MBC portfolio in 2020; this was a statistically significant increase above the rate of inflation. In terms of treatment resistance according to subtype, the highest number of projects focused on triple-negative MBC (&amp;gt;300). By contrast, &amp;lt; 20 projects were focused on overcoming treatment resistance in metastatic invasive lobular breast cancer. Of the six categories evaluated (e.g. biology and detection/diagnosis/prognosis), the largest increase in investment was for treatments. Discussion The coding tool allows for ongoing complex queries such as identification of funded research relevant to areas identified as important by MBC advocates (Table) and provides a funders’ ‘dashboard’ to identify gap areas in need of further research funding. This collaborative effort between funders and patient advocates, and the resulting current and future analyses, can be used to focus advocacy efforts to drive research funding of priorities and understudied areas of MBC. Despite the increase in funding, the investment in metastatic research–the primary cause of death from breast cancer–remains insufficient. Table. Research Priorities of MBC Patient Advocates Citation Format: Margaret Flowers, Teri Pollastro, Kari Wojtanik, Katherine McKenzie, Kimberly Badovinac, Medha Deoras-Sutliff, Lynne Davies. Analysis of Trends in Funding of Metastatic Breast Cancer Research [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 PO5-05-10.

Post-diagnosis adiposity, physical activity, sedentary behaviour, dietary factors, supplement use and colorectal cancer prognosis: Global Cancer Update Programme (CUP Global) summary of evidence grading.

Based on the World Cancer Research Fund Global Cancer Update Programme, we performed systematic reviews and meta-analyses to investigate the association of post-diagnosis adiposity, physical activity, sedentary behaviour, and dietary factors with colorectal cancer prognosis. We searched PubMed and Embase until 28th February, 2022. An independent expert committee and expert panel graded the quality of evidence. A total of 167 unique publications were reviewed, and all but five were observational studies. The quality of the evidence was graded conservatively due to the high risk of several biases. There was evidence of non-linearity in the associations between body mass index and colorectal cancer prognosis. The associations appeared reverse J-shaped, and the quality of this evidence was graded as limited (likelihood of causality: limited-no conclusion). The evidence on recreational physical activity and lower risk of all-cause mortality (relative risk [RR] highest vs. lowest: 0.69, 95% confidence interval [CI]: 0.62-0.77) and recurrence/disease-free survival (RR: 0.80, 95% CI: 0.70-0.92) was graded as limited-suggestive. There was limited-suggestive evidence for the associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), intake of whole grains and coffee with lower risk of all-cause mortality, and between unhealthy dietary patterns and intake of sugary drinks with higher risk of all-cause mortality. The evidence for other exposures on colorectal cancer outcomes was sparse and graded as limited-no conclusion. Analyses were conducted excluding cancer patients with metastases without substantial changes in the findings. Well-designed intervention and cohort studies are needed to support the development of lifestyle recommendations for colorectal cancer patients.

Spatial and single-cell colocalisation analysis reveals MDK-mediated immunosuppressive environment with regulatory T cells in colorectal carcinogenesis

Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.

Abstract 2170: Effects of folic acid supplementation on early stages of colitis-associated carcinogenesis

Abstract Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by persistent mucosal inflammation extending throughout the colon. Due to compromised intestinal surface integrity and the prolonged use of medication, individuals with UC often develop a folate deficiency, requiring folic acid (FA) supplementation. Prior findings from this group indicate that FA supplementation, at clinically relevant levels, promotes UC-associated dysplasia. Supplementation with FA resulted in an increased multiplicity of dysplasia and a significant elevation in the expression of several inflammatory genes (e.g. IL-6, Cox-2, Iκκ-β) within the colonic mucosa of mice with UC. Genome-wide expression profiling of normal and dysplastic colonic epithelial cells from mice treated with different doses of FA revealed differentially expressed genes were enriched for members of the ERK and NF-κB pathways. Subsequent in vitro analyses, utilizing isogenic RKO colon adenocarcinoma cells exposed to various doses of FA, demonstrated the downregulation of ERK and p-ERK in wild type (WT) p53+/+ cells, while an increase in expression was observed in p53−/− cells at the protein level. The goal of this study is to investigate the role of the MAPK/ERK pathway in the development of UC-associated neoplasms. An in vitro model that faithfully reproduces the inflamed microenvironment in the context of WT vs. mutant p53, the putative gatekeeper of UC-associated carcinogenesis, is needed to enhance our understanding of early changes in the colon that are induced by FA and drive tumor formation. Colon organoids are being generated by isolating crypts from WT p53+/+ and mutant p53+/515A mice. These organoids are then co-cultured with mouse macrophages (RAW264.7 cells) in inserts to stimulate crosstalk between the macrophages and colonic epithelial cells, as in the inflamed colon. Analyses demonstrate that the macrophages express pivotal inflammatory cytokines characteristic of UC, including IL-1β, IL-10, TNF-α, and IL-6, irrespective of the presence or absence of LPS stimulation. Co-cultured organoids and macrophages will be exposed to different concentrations of FA for various lengths of time, and the impact of treatment on the levels of ERK, p-ERK, and p65 will be assessed. The ability of p-ERK to mediate the transcriptional activation of NF-κB and its downstream effector IL-6 will also be evaluated. Subsequent investigations employing this innovative experimental model will reveal the mechanisms by which FA supplementation promotes the progression of UC-associated dysplasia. Given the potential risks associated with FA supplementation in individuals with UC, there is an urgent need to translate these results to a clinical setting. (Supported by CA262551 and the Timothy and Aurora Hughes Cancer Research Fund). Citation Format: Ariane Rocha Bartolomeu, Wen-Chi Chang, Lisa Vanderveer, Kristen N. Harvey, Mitchell Cheung, Harry S. Cooper, Margie Lee Clapper. Effects of folic acid supplementation on early stages of colitis-associated carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2170.

Abstract 1467: Contribution of estrogen metabolites to never-smoking lung cancer

Abstract There has been a consistent rise in the incidence of non-small cell lung cancer (NSCLC) among individuals who have never smoked. Remarkably, over 50% of diagnosed female cases and 15-20% of male cases are never-smokers. Notably, NSCLC in never-smokers exhibits distinctive clinical and pathological features, notably a higher incidence of tumors with EGFR mutations, setting it apart from its counterpart in smokers. Despite the improved disease-free survival observed with EGFR-tyrosine kinase inhibitors, eventual relapse and limited responsiveness to immunotherapy are common, underscoring the urgency to comprehend the molecular mechanisms driving the escalating prevalence of NSCLC in never-smokers and develop targeted preventive and interceptive therapeutic strategies. The preponderance of females among NSCLC patients who never smoked has prompted an exploration into the potential contribution of estrogen to lung tumorigenesis. In contrast to prevailing research focused on estrogen receptor-mediated signaling, our investigations have yielded compelling evidence supporting the involvement of estrogen metabolism in lung carcinogenesis among never-smokers. This group is the first to report that estrogen is metabolized extensively in both mouse and human lungs, resulting in the generation of various derivatives, including the potential carcinogen 4-hydroxyestrogen (4-OHE). Notably, recent findings from our laboratory indicate that prolonged exposure of nonneoplastic human bronchial epithelial cells to 17β estradiol or 4-OHE, at concentrations approximating physiological levels, induces the accumulation of double-strand DNA breaks and cellular transformation. A comprehensive analysis was performed to further elucidate the mechanisms underlying the transformation process. Isolated transformed clones obtained after 9, 18, and 22 wks of exposure to 4-OHE were subjected to karyotyping, F.I.S.H., and RNA and exome sequencing. A longitudinal progression of aberrant chromosomal rearrangements and copy number alterations was observed, that increased with time of 4-OHE exposure. In addition, RNA-Seq analyses revealed the epithelial-mesenchymal transition pathway was highly enriched at the early timepoint (9 wks), while replicative stress-related signaling pathways were induced at all timepoints. To determine if the differentially expressed genes were also dysregulated in clinical lung cancer cases, TCGA lung adenocarcinoma (LUAD) data were examined. Interestingly, many of the genes upregulated after estrogen exposure were similarly overexpressed in the LUAD samples and often associated with a worse prognosis. In conclusion, our data support the role of estrogen metabolites in promoting lung cancer among never-smokers. (Supported by CA217161 and generous contributions from the Hellendall Family Foundation, Gregory G. Lawton and the Timothy and Aurora Hughes Cancer Research Fund.) Citation Format: Mitchell Cheung, Lisa A. Vanderveer, Daniel Krzizike, J. Nicholas Bodor, Joseph Treat, Joseph R. Testa, Margie L. Clapper. Contribution of estrogen metabolites to never-smoking lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1467.

Demographic, clinical, and sociocognitive determinants related to physical activity and dietary intake in patients with ovarian cancer: A cross-sectional study

ObjectiveTo study physical activity and dietary intake among patients with ovarian cancer and to examine which demographic, clinical, and sociocognitive determinants are associated with these behaviours. MethodsThis cross-sectional study included 139 patients with ovarian cancer scheduled for (neo)adjuvant chemotherapy. Physical activity was measured with the Physical Activity Scale for the Elderly questionnaire (PASE). Dietary intake was measured with a questionnaire assessing energy and protein intake and a questionnaire assessing adherence to the World Cancer Research Fund (WCRF) lifestyle recommendations. Demographic, clinical, and sociocognitive (e.g., self-efficacy) determinants of physical activity and dietary intake were examined using backward linear regression analyses. ResultsPatients reported a median PASE score of 50 (IQR 24–94), a mean ± SD dietary intake of 1831 ± 604 kcal/day and 76 ± 27 g protein/day. Patients adhered to 3 out of 5 WCRF lifestyle recommendations. The absence of comorbidities, lower physical outcome expectations, and higher cancer specific outcome expectations were independently associated with higher physical activity levels. Higher age, lower cancer specific outcome expectations, and higher diet-related self-efficacy were significantly associated with adhering to more WCRF lifestyle recommendations, whilst no variables associated with total caloric or protein intake were identified. ConclusionsPatients with ovarian cancer have low physical activity levels and a suboptimal diet, particularly low fruit and vegetable consumption and dietary fibre intake. Interventions aiming to improve physical activity and dietary intake could focus on increasing self-efficacy and outcome expectations, and should consider age and comorbidity as factors that may impact behaviour.Trial registration: Netherlands Trial Registry NTR6300.

The Swedish initiative for the study of Primary sclerosing cholangitis (SUPRIM)

Despite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools for the associated hepatobiliary cancers. Importantly, the limited understanding of the underlying biological mechanisms in PSC and its natural history not only affects the identification of new drug targets but implies a lack of surrogate markers that hampers the design of clinical trials and the evaluation of drug efficacy. The lack of easy access to large representative well-characterised prospective resources is an important contributing factor to the current situation. We here present the SUPRIM cohort, a national multicentre prospective longitudinal study of unselected PSC patients capturing the representative diversity of PSC phenotypes. We describe the 10-year effort of inclusion and follow-up, an intermediate analysis report including original results, and the associated research resource. All included patients gave written informed consent (recruitment: November 2011-April 2016). Out of 512 included patients, 452 patients completed the five-year follow-up without endpoint outcomes. Liver transplantation was performed in 54 patients (10%) and hepatobiliary malignancy was diagnosed in 15 patients (3%). We draw a comprehensive landscape of the multidimensional clinical and biological heterogeneity of PSC illustrating the diversity of PSC phenotypes. Performances of available predictive scores are compared and perspectives on the continuation of the SUPRIM cohort are provided. We envision the SUPRIM cohort as an open-access collaborative resource to accelerate the generation of new knowledge and independent validations of promising ones with the aim to uncover reliable diagnostics, prognostic tools, surrogate markers, and new treatment targets by2040. This work was supported by the Swedish Cancer Society, Stockholm County Council, and the Cancer Research Funds of Radiumhemmet.