Cancer Institute Research Articles

Prostate cancer incidence rates, trends, and treatment related to prostate-specific antigen screening recommendations in the United States

BackgroundChanges in US prostate-specific antigen (PSA) screening guidelines have impacted prostate cancer (PCa) incidence rates and trends. This study shows corresponding changes in PCa incidence rates and describes treatment patterns by tumor stage, age, and race/ethnicity. MethodsAnalyses were based on 777,152 cases diagnosed in 17 population-based tumor registries in the SEER Program of the US National Cancer Institute, 2007–2021. Rates were age adjusted and trends assessed using annual percent change and joinpoint regression. ResultsPCa age-adjusted incidence rates (per 100,000) fell from 165.8 in 2007 to 101 in 2014 (APC=-6.51, p<0.05) and then rose to 121.2 in 2021 (APC=1.87, p< 0.05). The significant fall and rise in rates appeared in ages 55–69 and ≥70, all racial/ethnic groups (except in Hispanics during 2014–2021), and in local/regional stage. PCa incidence rates by tumor stage, age, and race/ethnicity were presented and discussed. A few PCa cases were identified through autopsy or death certificate among the racial/ethnic groups (0.68 %-1.37 %). Unstaged cases identified through sources other than autopsy or death certificate significantly varied by race/ethnicity, ranging from 4.13 % for non-Hispanic (NH) Whites to 9.5 % for Hispanic (Chi-square p <.0001). In 2017–2021, surgery occurred in 33 % of cases (primarily in local/regional cases, inversely associated with age), radiation in 30 % of cases (increasing with age in local/regional stage cases and decreasing with age in distant stage cases), and chemotherapy in 2 % of cases (<1 % in local/regional stage cases and 9 %-38 % for age groups in distant stage cases). Several racial/ethnic differences in treatment exist, such as NH Blacks (vs. NH Whites) with local/regional disease were significantly less likely to receive surgery and more likely to receive radiation. ConclusionsUnderstanding trends and patterns of PCa rates and treatment among patients by tumor stage, age, and race/ethnicity can guide public health planning in relation to screening and treatment.

Discovery of the Aminated Quinoxalines as Potential Active Molecules

Background: In recent years, as the biological activity of the quinoxaline skeleton has been revealed in numerous studies, interest in synthesizing new prototype molecules for the treatment of many chronic diseases, especially cancer, has increased. Methods: The desired alkoxy substituted aminoquinoxalines (AQNX1-9) were synthesized by the reaction of QNX and alkoxy substituted aryl amines such as 2-methoxyaniline, 4-methoxyaniline, 2- ethoxyaniline, 3-ethoxyaniline, 4-ethoxyaniline, 4-butoxyaniline, 2,4-dimethoxyaniline, 3,4- dimethoxyaniline, and 3,5-dimethoxyaniline according to the previously published procedure. QNX was aminated in DMSO at 130°C. We synthesized various alkoxy-substituted aminoquinoxaline compounds (AQNX1-9) and evaluated their anticancer and antimicrobial activities in order to expand the search to related structures. In particular, two aminoquinoxaline (AQNX5 and AQNX6) compounds, coded as NSC D-835971/1 and NSC D-835972/1 by the National Cancer Institute in the USA, were screened for anticancer screening at a dose of 10-5 M on a full panel of 60 human cell lines obtained from nine human cancer cell types (leukemia, melanoma, non-small cell lung, colon, central (nervous system, ovarian, kidney, prostate, and breast cancer). Results: Further in silico studies were also conducted for the compound AQNX5 (NSC D- 835971/1), which was found to be the most active antiproliferative agent, especially against leukemia cell lines. Molecular docking studies showed that AQNX5 interacted with Glu286 and Lys271 through hydrogen bonding and π-stacking interaction in the ATP binding region of Abl kinase, which is indicated as a potential target of leukemia. Besides, AQNX5 occupied the minor groove of the double helix of DNA via π-stacking interaction with DG-6. Conclusion: According to in silico pharmacokinetic determination, AQNX5 was endowed with drug-like properties as a potential anticancer drug candidate for future experiments. In the light of these findings, more research will focus on aminated quinoxalines' ability to precisely target leukemia cancer cell lines.

Beyond clinical trials: CDK4/6 inhibitor efficacy predictors and nomogram model from real-world evidence in metastatic breast cancer.

CDK4/6 inhibitors (CDK4/6i) have shown promising results in the treatment of hormone receptor-positive (HR+) metastatic breast cancer (MBC) when combined with endocrine therapy (ET). It is crucial to evaluate the actual effectiveness and safety of CDK4/6i in clinical practice, as well as to analyze the factors that can predict their outcomes. Patients with HR+ MBC who received CDK4/6i-based therapy between May 2016 and May 2023 at Hunan Cancer Hospital were evaluated for progression-free survival (PFS). Adverse reactions were assessed based on the National Cancer Institute Common Toxicity Criteria (version 5.0). This study included 344 patients, with a median PFS (mPFS) of 12.8 months (range: 10.4-15.2 months). After adjustment, Cox multivariate regression analysis revealed that visceral metastasis (specifically liver and brain metastases), Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 1, estrogen receptor ≤ 80%, progesterone receptor ≤ 10%, Ki-67 > 30%, and treatment in later stages were significant factors associated with reduced PFS. Based on this, we created a prognostic nomogram and validated its performance, obtaining a C-index of 0.714 (95% confidence interval: 0.640-0.787) as well as reliable calibration and clinical impact. The mPFS of CDK4/6i rechallenge was 7.7 months; for patients who initially discontinued CDK4/6i for reasons other than disease progression, CDK4/6i rechallenge still provided a mPFS of 11.4 months. The tolerability and safety of combining CDK4/6is with ET were manageable. Adverse events led to treatment discontinuation in 3.8% of patients. Neutropenia (29.1%), leukopenia (13.7%), and anemia (4.1%) were the primary grade 3/4 adverse reactions. This real-world study highlights the ample efficacy and reasonable safety of combined CDK4/6i and ET in patients with HR+ MBC. Individualized treatment decisions and ongoing safety monitoring are important to optimize the therapeutic benefit of CDK4/6i treatment.

Trends in Hepatocellular Carcinoma Mortality Rates in the US and Projections Through 2040

ImportanceThe burden of liver cancer varies worldwide. An upward trend in both hepatocellular carcinoma (HCC) incidence and mortality in the past 2 decades has been observed.ObjectiveTo assess observed HCC-related age-standardized mortality rates (ASMRs) in the US for 2006 to 2022 and provide ASMR projections through 2040.Design, Setting, and ParticipantsThis cross-sectional study used data from the National Vital Statistics System, which is accessible through the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research website. Data on deaths attributed to HCC (from January 1, 2006, to December 31, 2022) were obtained for adults 25 years or older and were stratified by liver disease etiology, age, sex, and race and ethnicity. Etiologies included alcohol-associated liver disease (ALD), hepatitis B virus (HBV), hepatitis C virus (HCV), and metabolic dysfunction–associated steatotic liver disease (MASLD).Main Outcomes and MeasuresThe main outcomes were (1) observed ASMRs of HCC per 100 000 persons using Joinpoint regression (National Cancer Institute) to assess trends during 2006 to 2022 and (2) ASMRs projected for 2023 to 2040 using Prophet and AutoARIMA modeling.ResultsThis study included 188 280 HCC-related deaths from 2006 to 2022. Most deaths occurred among males (77.4%). The annual percentage change was 4.1% (95% CI, 2.2% to 7.7%) for 2006 to 2009 and decreased to 1.8% (95% CI, 0.7% to 2.0%) for 2009 to 2022, with an overall observed ASMR of 5.03 per 100 000 persons in 2022 and a projected ASMR of 6.39 per 100 000 persons by 2040, with consistent trends for both sexes. By etiology, ASMRs decreased for HCV- and HBV-related mortality but increased for ALD- and MASLD-related mortality. In 2022, MASLD surpassed HBV as the third-leading cause of HCC-related death and was projected to overtake HCV in 2032 as the second-leading cause; ALD was projected to be the leading cause of HCC-related death in 2026. In 2022, the ASMR was higher among individuals aged 65 years or older compared with those aged 25 to 64 years (18.37 vs 1.79 per 100 000 persons). The American Indian or Alaska Native population had the largest increase in projected ASMR by 2040 (14.71 per 100 000 persons) compared with the Asian population (3.03 per 100 000 persons).Conclusions and RelevanceIn this cross-sectional study, ASMRs for ALD- and MASLD-related HCC death increased rapidly from 2006 to 2022; ALD-related HCC was projected to be the leading cause by 2026, with MASLD as the second-leading cause by 2032. These findings may serve as a reference for public health decision-making and timely identification of groups at high risk of HCC death.

Abstract C027: The role of Liver Receptor Homolog 1 (LRH-1) in regulating cancer progression by modulating the immune response

Abstract Breast cancer is a significant global health concern, being the second most common type of cancer and the second leading cause of cancer-related deaths among women in the U.S. Metastatic breast cancer is responsible for most of these deaths, and current FDA-approved immunotherapies are effective only for a small subset of patients with PD-L1-positive tumors. Thus, there is a critical need for new therapeutic targets to enhance the immune response against breast cancer. Elevated plasma cholesterol concentrations are associated with poor breast cancer outcomes. Our previous studies indicated that myeloid immune cells are highly sensitive to changes in cholesterol levels and other proteins involved in regulating cholesterol homeostasis. However, the role of Liver Receptor Homolog 1 (LRH-1), a key regulator of cholesterol homeostasis, in myeloid cells is not well understood. Notably, higher expression of LRH-1 mRNA in breast tumors is associated with longer time to recurrence and improved overall survival. Therefore, we aimed to investigate the role of LRH-1 in myeloid immune cells and its impact on breast cancer progression. Initial analysis indicated that LRH-1 is expressed in myeloid cells, with particularly high levels observed in neutrophils. Therefore, we examined how LRH-1 regulates neutrophil functions important to cancer biology, including migration, NETosis, and phagocytosis, as well as its influence through neutrophils on T cells. We found that LRH-1 inhibited neutrophil migration toward cancer cells. Since tumor infiltrating neutrophils are generally associated with poor prognosis, LRH-1 reducing neutrophil migration could indicate a decreased ability of these immune-suppressive cells to infiltrate tumors. Importantly, neutrophils treated with an LRH-1 agonist showed reduced NETosis, while antagonist led to increased NETosis. LRH-1 agonist treatment also significantly reduced neutrophil phagocytosis, whereas an antagonist had no notable effect. Furthermore, T cells exhibited increased expansion when co-cultured with neutrophils treated with an LRH-1 agonist, and reduced proliferation with neutrophils pretreated with an LRH-1 antagonist or inverse agonist, particularly in CD4+ helper T cells and later divisions. Since neutrophils were previously implicated in invoking recurrence from dormant lesions, we evaluated LRH-1 in this context. The treatment of mice harboring dormant D2.0R lesions with an LRH-1 inverse agonist resulted in sooner recurrence and metastatic outgrowth compared to vehicle treated mice. In summary, our findings suggest that LRH-1 plays a crucial role in regulating various neutrophil functions, including migration, NETosis, phagocytosis, and T cell expansion. The ultimate consequence of these regulations are control of dormant mammary cancer lesions. These results highlight LRH-1 as a potential therapeutic target for cancer treatment or prevention of metastatic recurrence. Funding: National Cancer Institute (ERN: R01CA234025) Department of Defense (ERN: BCRP Era of Hope Award) Citation Format: Yu Wang, Bryan Duong, Natalia Krawczynska, Shruti V. Bendre, Claire P. Schane, Erin Weisser, Lara Kockaya, Yifan Fei, Anasuya Das Gupta, Hashni E. Vidana Gamage, Adam T. Nelczyk, Dhanya Pradeep, Erik R. Nelson. The role of Liver Receptor Homolog 1 (LRH-1) in regulating cancer progression by modulating the immune response [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 C027.

Associations of Physical Activity and Sedentary Behavior With Mental Distress According to Caregiver Status: Analysis of the Health Information National Trends Survey, 2022.

To (1) examine how physical activity and sedentary behavior are related to mental distress and (2) identify and compare how various levels of sedentary behaviors may differentially predict mental distress after accounting for physical activity, among caregivers vs non-caregivers. Cross-sectional secondary data. National Cancer Institute's Health Information National Trends Survey Cycle 6 fielded online from March-November 2022. U.S. adults aged 18 and older. The Patient Health Questionnaire-4 was administered along with caregiving status, moderate weekly physical activity, sedentary behavior, and sociodemographic characteristics. After applying population weights, we conducted multiple adjusted logistic regression models and estimated predictive margins to understand whether a specific dose of sedentary behavior (hours/day) is associated with risk of mental distress, at different levels of physical activity. Caregivers (15.41% of sample) reporting 10-hour of daily sedentary behavior were significantly more likely to experience mental distress, than those reporting lower amounts of sedentary behavior (OR = 3.372, 95%CI = 1.968, 5.776, P < 0.001). Regardless of physical activity amount, 10 hours of sedentary behavior may be a risk factor for mental distress among non-caregivers. Just 6 hours of sedentary behavior may be related to mental distress among caregivers. Physical activity interventions tailored to caregivers' needs, responsibilities, and circumstances are required. Innovative methodologies are needed to understand caregivers' daily behaviors and the intensity of their caregiving activities.

Perspectives on Quality of Life in Women with Breast Cancer

Objectives: The objectives of the study are to assess changes in the quality of life amongst breast cancer patients undergoing treatment at a cancer institute in Colombia. Materials and Methods: Analytical observational prospective cohort study in patients over 18 years of age diagnosed with breast cancer. Health-related quality of life (HRQoL) was analysed using the EQ-5D-3L questionnaire and a Visual Analogue Scale measured at diagnosis and after a 6-month follow-up. Sociodemographic and clinical factors were analysed using a logistic regression model, with STATA 16 software. Results: A total of 103 patients met the included criteria and were included in the study, with a median age of 56 years. According to the Tumour, Node, Metastasis classification of cancer stage, the majority of participants (35.92%) were in stage 2 of cancer. Multivariate analysis revealed that changes in HRQoL were significantly associated with age (odds ratio [OR] = 1.06, P = 0.001), radiotherapy (OR = 3.56, P = 0.038) and moderate anxiety and depression (OR = 5.54, P = 0.007). Conclusion: While the overall quality of life in women with breast cancer showed a slight improvement over the 6 months, older patients and those receiving radiotherapy experienced a greater decline in health perception.

Local Recurrence and Survival in Patients With Melanoma >2 mm in Thickness at Difficult Sites Treated With 1-cm Versus 2-cm Margins.

Melanoma guidelines recommend surgical excision with 2-cm margins for melanomas >2 mm in thickness. However, this procedure may be problematic at critical anatomic sites. We aimed to compare the outcomes of wide (2 cm) versus narrow (1 cm) excision margins in patients with melanoma >2 mm in thickness near critical structures. We retrospectively examined 736 patients undergoing excision with wide versus narrow margins at the National Cancer Institute in Milan, Italy, between 2001 and 2015. A total of 265 (36.0%) patients received a wide local excision-82 (30.9%) with linear repair and 183 (69.1%) with flap or graft reconstruction. A total of 471 (64.0%) patients received a narrow excision-320 (67.9%) with linear repair and 151 (32.1%) with flap or graft reconstruction (P<.001). The 10-year overall survival rate was 69.5% (95% CI, 63.3%-76.2%) in the wide group and 68.7% (95% CI, 63.8%-74.0%) in the narrow group (P=.462); 10-year crude cumulative incidence (CCI) of local recurrence was 5.4% (95% CI, 3.2%-9.2%) in the wide and 8.8% (95% CI, 6.4%-12.1%) in the narrow group (P=.150). Multivariable Fine-Gray modeling of the CCI of local recurrence showed that Breslow thickness (P=.010) was the only statistically significant parameter. Multivariable Cox models for overall survival showed that age (P<.001), Breslow thickness (P<.001), and sentinel lymph node status (P=.019) were statistically significant covariates. Excision margin was not a significant parameter affecting patients' outcome. Wide local excision with 1-cm margins for melanoma >2 mm in thickness was not associated with an increased risk of local recurrence and did not affect overall survival.

Decoding β-catenin expression patterns in ovarian serous carcinoma with clinicopathological implications: insights from National Cancer Institute.

This study aimed to examine the immunohistochemical expression of β-catenin in serous ovarian carcinoma and to investigate its relationship with clinicopathological features and disease outcomes. A retrospective analysis was conducted on 67 cases of serous ovarian carcinoma diagnosed at the Pathology Department of the Egyptian National Cancer Institute, Cairo University, between January 1, 2015, and December 31, 2017. The age of the patients ranged from 26 to 76years. Aberrant β-catenin expression was defined by the presence of cytoplasmic staining with or without membranous staining in at least 10% of tumor cells. Of the cases analyzed, thirty exhibited cytoplasmic staining, 18 demonstrated preserved expression on the cell membrane, 15 showed combined cytoplasmic and membranous staining, while four cases were entirely negative. Significant correlations were observed between β-catenin positivity and both tumor grade and p53 expression, with p values of 0.004 for each correlation. Positive β-catenin expression significantly correlated with tumor grade in serous ovarian carcinoma. Most low-grade serous carcinoma cases exhibited membranous β-catenin expression, whereas high-grade serous carcinoma cases predominantly displayed cytoplasmic staining. Therapeutic strategies aimed at inhibiting β-catenin signaling could provide a novel approach to improving outcomes for patients with high-grade ovarian cancer.

Detection and molecular characterization of carbapenem-resistant gram-negative bacterial isolates.

Antimicrobial-resistant bacteria (ARB) are responsible for increased mortality and morbidity. Therefore, this study focuses on evaluating traditional and molecular diagnostic tools of carbapenem-resistant gram-negative bacteria (CRGNB). In order to achieve this, 94 samples, from different patients' specimens, and surrounding environment, were collected from intensive care units (ICUs) at Ain Shams University Specialized Hospital and the National Cancer Institute, Cairo, Egypt. The swabs were cultured on appropriate media, including Chromogenic medium (HiCrome KPC Agar Base "HIMEDI AM1831"), and MacConkey-10µg imipenem disc resulting in 136 isolates with different culture characteristics. Next, the selected isolates were subjected to VITEK 2 machine and 16SrRNA (16S ribosomal RNA) sequencing. The sensitivity of HiCROME KPC agar for CRGNB detection was 99.3% and 94.7%, in reference to the MacConkey-disc and VITEK-2 methods, respectively. The HiCrome KPC agar assumptions for bacterial identification were not as consistent as those of VITEK 2 (with only 47.4% agreement) and 16SrRNA gene sequencing analysis. The approaches discussed in this study facilitate providing rapid diagnosis and treatment of CRGNB, which helps increase survival rates. HiCrome KPC agar is considered a relatively accurate and easy method that can be used in any laboratory. In addition, the selected strains were deposited in the gene bank with the accession numbers OR553657, OR553658, and OR553659. It is noteworthy that Genus Acinetobacter is the major CRGNB isolated from the patients and environmental surfaces in the hospitals. This highlights the importance of proper environmental and terminal cleaning procedures in healthcare facilities and applying control measures to ensure infection prevention.

Implementation of a Screening Program for High-Grade Anal Dysplasia in High-Risk Patients in a Tertiary Cancer Center.

The incidence of anal squamous cell carcinoma (SCC) has been increasing over the last decades. Human papillomavirus (HPV) infection accounts for more than 90% of anal cancers, and HIV co-infection increases the risk of invasive cancer. Men who have sex with men (MSM) with HIV are the highest risk group for developing anal high-grade squamous intraepithelial lesions (aHSILs), which can be found in 45%-50% of these patients and are precursor lesions for invasive cancer. Anal cytology is an effective screening tool, but it lacks sensitivity. High-resolution anoscopy (HRA) is the gold standard procedure for diagnosis and treatment of aHSILs. Recent data suggest that early detection and treatment of aHSILs could prevent the development of invasive cancer in this population. The objective of the study was to describe the implementation of an office-based screening program for anal cancer prevention in a Comprehensive Cancer Center in Brazil. Training included participation in the International Anal Neoplasia Society (IANS) HRA course at UCSF Medical Center Mount Zion in San Francisco, CA, USA, by three colorectal cancer surgeons. In-person and hands-on training was provided by a specialist through the AIDS Malignancy Consortium (AMC) of the US NIH. Equipment purchased and provided by the AMC included a colposcope with a digital camera, a hands-free mouse pedal, and a photo documentation imaging software program that allows images to be recorded for documentation and training purposes. The program was implemented in 2022 after a delay of more than two years due to the COVID-19 pandemic. An average of 24 exams are performed monthly. Patients with HIV aged 35 years or older who are undergoing antiretroviral therapy were recruited from the metropolitan area of Rio de Janeiro and referred by primary care providers for screening. Patients diagnosed with aHSILs are scheduled for in-office ablative treatment in the clinic. From March 2022 to June 2024, 324 exams were performed, and aHSIL was found in 38.2% of 220 high-risk patients, including 45 of 129 MSMs (34.9%), 6 of 19 transgender women (31.6%), and 33 of 72 women living with HIV (45.8%). A total of 69 treatments for aHSIL were performed in 62 patients. Patients are followed on a regular basis and long-term results are awaited, including the effectiveness of local therapy for aHSIL. The screening and treatment program was successfully implemented in a tertiary comprehensive Cancer Center. Team training and external proctorship were decisive for the achievement of benchmark standards. The program aims to permanently provide screening for the prevention of anal cancer through the detection and treatment of aHSIL within the National Cancer Institute of Brazil for populations considered at-risk for anal cancer.

Hyperthermic intraperitoneal chemotherapy for recurrent ovarian cancer (CHIPOR): a randomised, open-label, phase 3 trial.

Hyperthermic intraperitoneal chemotherapy (HIPEC) at interval cytoreductive surgery for ovarian cancer improves overall survival but its role in recurrent disease is uncertain. We aimed to compare outcomes in patients treated with or without HIPEC during surgery for recurrent ovarian cancer. The multicentre, open-label, randomised, phase 3 CHIPOR trial was conducted at 31 sites in France, Belgium, Spain, and Canada, and enrolled patients with first relapse of epithelial ovarian cancer at least 6 months after completing platinum-based chemotherapy. Eligible patients were aged 18 years or older with WHO performance status of less than 2. After six cycles of platinum-based chemotherapy (and optional bevacizumab), patients amenable to complete cytoreductive surgery were randomly assigned centrally in a 1:1 ratio, using a web-based system and a minimisation procedure, during surgery to receive HIPEC (cisplatin 75 mg/m2 in 2 L/m2 of serum at 41±1°C for 60 min) or not, stratified by centre, completeness of cytoreduction score, platinum-free interval, and latterly, planned poly(ADP-ribose) polymerase inhibitor use. The primary endpoint was overall survival, analysed on an intention-to-treat basis in all randomly assigned patients. This ongoing trial is registered with ClinicalTrials.gov, NCT01376752. Between May 11, 2011, and May 14, 2021, 415 female patients were randomly assigned (207 HIPEC, 208 no HIPEC). At the primary analysis (median follow-up 6·2 years, IQR 4·1-8·1), 268 (65%) patients had died (126 [61%] of 207 in the HIPEC group; 142 [68%] of 208 in the no-HIPEC group). Overall survival was significantly improved with HIPEC (stratified hazard ratio 0·73, 95% CI 0·56-0·96; p=0·024). Median overall survival was 54·3 months (95% CI 41·9-61·7) with HIPEC versus 45·8 months (38·9-54·2) without. Grade 3 or worse adverse events within 60 days after surgery occurred in 102 (49%) of 207 patients receiving HIPEC versus 56 (27%) of 208 receiving no HIPEC, the most common being anaemia (47 [23%] vs 30 [14%]), hepatotoxicity (23 [11%] vs 18 [9%]), electrolyte disturbance (28 [14%] vs two [1%]), and renal failure (20 [10%] vs three [1%]). There were three deaths within 60 days of surgery, all in the no-HIPEC group. Adding HIPEC to cytoreductive surgery after response to platinum-based chemotherapy at first epithelial ovarian cancer recurrence significantly improved overall survival. When treating patients with late first relapse of high-grade serous or high-grade endometrioid ovarian cancer amenable to complete cytoreductive surgery at specialist centres, platinum-based HIPEC should be considered to extend overall survival. French National Cancer Institute and French League Against Cancer.

Specialty Tobacco Treatment Implementation in Oncology: A Qualitative Study.

In 2017, the National Cancer Institute (NCI) funded the Cancer Center Cessation Initiative (C3I) to implement and expand tobacco treatment programs in routine oncology care. Many C3I programs developed specialty care programs staffed by tobacco treatment specialists (TTSs) to deliver evidence-based treatment to adult patients who smoke. People involved in specialty tobacco treatment programs can help to identify implementation strategies and adaptations that may enhance tobacco treatment reach and effectiveness in cancer care and help more patients with cancer quit using tobacco. We conducted semistructured interviews with TTSs from 21 C3I-funded cancer centers and applied content analysis to interview transcripts from 37 TTSs and 17 respondents in other program roles. We used the Consolidated Framework for Implementation Research to code interview data. We identified final themes and implementation strategies and adaptations recommended by respondents on the basis of these codes. Respondents shared that implementation of specialty tobacco treatment programs in cancer care settings could be facilitated by training staff to provide patient connection to services, incorporating prescription of no- or low-cost cessation medications, hiring additional staff to deliver tobacco treatment, allocating space to the program, and automating electronic health record workflows. TTSs and others involved in specialty tobacco treatment in NCI-designated cancer centers identified ways to improve tobacco treatment access, use, and effectiveness by (1) adapting specialty tobacco treatment delivery to meet patient needs; (2) facilitating referrals and pharmacotherapy coordination; and (3) committing staffing, space, and support resources to tobacco treatment programs. Key program participants suggested that these approaches would help more oncology patients connect with evidence-based tobacco treatment and quit smoking.

Abstract 4132212: Trends in Atrial Fibrillation or Flutter Related Mortality Among Adults in the United States: Insights from CDC WONDER Database from 1999-2020

Background: Atrial fibrillation or flutter (Afib/AFL) incidence rates continue to rise and are linked to significant mortality, particularly in older populations. Our analysis examines Afib/AFL mortality trends across different demographics and regions in the U.S. from 1999 to 2020, highlighting the importance of understanding these patterns. Aim: To guide preventive measures that alleviate the impact of Afib/AFL and identify high-risk populations and regions, we sought to quantify trends associated with Afib/AFL related mortality in the U.S. Methods: We conducted a comprehensive search of death certificates from 1999-2020 using Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research (CDC WONDER) database focusing on Afib/AFL mortality in adults with ICD-10 codes I48. Gender, race, geographical and urban-rural parameters were investigated by calculating annual percent change (APC) and age-adjusted mortality rates (AAMRs) per 100,000 persons using the Joinpoint Regression Program (Joinpoint V 4.9.0.0, National Cancer Institute). Results: A total of 2,581,488 deaths occurred in patients with Afib/AFL from 1999 to 2020. The AAMR displayed an abrupt rise from 2018 to 2020 (APC: 8.51; 95% CI: 4.84-10.47). Men consistently exhibited a higher AAMR (overall AAMR male: 79.4, 95% CI 79.3-79.6; female: 60.8, 95% CI 60.7-60.9). Non-metropolitan areas showed higher AAMRs than metropolitan areas (overall AAMR non-metropolitan areas: 74.9, 95% CI 74.7-75.1; metropolitan: 67.2, 95% CI 67.1-67.2). Disparities were also observed in AAMRs by region with the West region showing the highest mortality rate with a notable rise between 2010 and 2020 (APC: 3.70, 95% CI 3.30-5.37). Non-hispanic (NH) White population showed the highest mortality (overall AAMR: 74.2, 95% CI 74.1-74.3), followed by NH American Indian (AAMR: 50.3), NH Black (AAMR: 45.8), NH Asian (AAMR: 35.0) and Hispanic (AAMR: 37.9) populations. Conclusion: Mortality from Afib/AFL has risen from 1999 to 2020. Men, NH white populations, and residents in non-metropolitan areas and Western U.S. are at higher risk. Targeted interventions and strategic healthcare resource allocation are needed to address these disparities and improve outcomes.

A roadmap to reduce the incidence and mortality of breast cancer by rethinking our approach to women's health.

Despite progress, breast cancer remains the most feared disease among women. In the USA alone, the incidence is now almost 300,000 new cancers per year, a rate that has nearly doubled in the last 30years. Most women survive, but over 40,000 women a year still die of their disease National Cancer Institute [Internet]. [cited 2024 Nov 4]. Cancer of the Breast (Female) - Cancer Stat Facts. Available from: https://seer.cancer.gov/statfacts/html/breast.html. It is the most diagnosed cancer among women and the second leading cause of cancer death. Important disparities exist in breast cancer outcomes among African American women, where women die of breast cancer at higher rates, are diagnosed younger, and at a more advanced stage. We are proposing a radical shift in our thinking about breast cancer preventionwith an aspiration to dramatically lower breast cancerincidence. Most breast cancers are driven by steroid hormones. Throughout the life course, women are offered an array of hormonal treatments for menstrual cycle control, family planning, in vitro fertilization, postpartum weaning, and menopausal symptom management. There are mixed data on the extent to which each of these may contribute to increased or decreased risk for breast cancer. These endocrine manipulations could represent a great opportunity to potentially reduce breast cancer incidence and improve quality of life for survivors. To date, they have not been designed to explicitly reduce breast cancer risk. A new holistic approach will require scientists, drug developers, breast oncologists, obstetricians, gynecologists, endocrinologists,radiologists, and family medicine/internists to work together toward the common goal of reducing breast cancer risk while addressing othercritical issues in women's health.

BIOM-42. RESPONSE TO DABRAFENIB/TRAMETINIB IN A PATIENT WITH WHO-CNS GRADE 3 BRAF V600E-MUTATED PLEOMORPHIC XANTHOASTROCYTOMA

Abstract BACKGROUND Pleomorphic xanthoastrocytoma (PXA) is a rare central nervous system tumor. Mutations in BRAF V600E are present in 60-80% of cases. While traditionally managed with surgical resection and adjuvant radiation, emerging evidence suggests targeted therapies may be effective, particularly in cases harboring the BRAF V600E mutation. CASE SUMMARY A 35-year-old male with no significant medical history presented in November 2023 with diplopia and headache leading to the discovery of a large left temporal/parietal tumor. A partial resection was performed. Initial histopathological diagnosis was glioblastoma (GBM); thus, the patient was treated with concurrent radiation and temozolomide for 6 weeks. Molecular pathological analysis demonstrated the presence of BRAF V600E mutation and CDKN2A/B copy number loss. Methylation-based tumor profiling was performed at the National Cancer Institute, with composite methylation profile indicating a consensus match to pleomorphic xanthoastrocytoma. Following chemoradiation, a repeat brain MRI in March 2024 showed tumor progression, prompting the initiation of dabrafenib and trametinib therapy. After 1 month of targeted treatment, a repeat brain MRI demonstrated a partial response with a decrease in tumor size and enhancement. In April 2024, he underwent a planned repeat resection. Symptomatically, the patient experienced intermittent headaches and nausea that were responsive to oral steroids with no serious adverse effects to targeted therapy. DISCUSSION This case highlights the therapeutic potential of double BRAF/MEK blockade with dabrafenib and trametinib in BRAF V600E-mutant anaplastic PXA. The observed partial response on imaging suggests the efficacy of targeted therapy in this molecular subtype. These findings underscore the importance of molecular profiling in guiding treatment decisions.

Exploring the Incidence of Testicular Neoplasms in the Transgender Population: A Case Series.

The use of hormonal therapy and gender-affirming surgery in the transgender community has been rising during the last several years. Although it is generally safe, hormonal therapy's link to testicular cancer remains uncertain. To review the incidence of testicular cancer in specimens from gender-affirming orchiectomies at our institution and evaluate the tumors for histologic and genetic alterations. Pathology reports for gender-affirming orchiectomies (January 1, 2018, to August 1, 2023) were reviewed for testicular neoplasms, with additional analysis for chromosome 12 abnormalities. Incidence and chromosome variations were compared with those in the general population. Among 458 cases during 5.5 years, 5 germ cell neoplasms in 4 patients emerged. Our institution's annual incidence rate (159 per 100 000) is 26.5 times higher than the National Cancer Institute's previous report (6.0 per 100 000). Although they were morphologically no different from germ cell neoplasms in the general population, fluorescence in situ hybridization tests showed no i(12p) in 4 of 5 neoplasms (80%) in our cohort. The cause behind this rise in incidence remains uncertain but may be due to long term pretreatment with hormones or blockers. The lower isochromosome 12p frequency suggests an alternative mechanism driving tumor development, which requires more detailed molecular studies.

Core publications in drug discovery and natural product research

Natural products have long been a cornerstone of drug discovery, providing diverse and biologically relevant chemical scaffolds. This work aims to guide newcomers to natural product research and, specifically, drug discovery by presenting a curated list of 30 key publications selected through an international survey of experts and critical evaluation by the authors. The selected works span textbooks, review articles, and original research papers, covering various aspects of natural product research, including chemistry, pharmacology, analytical sciences, emerging open science, and computational approaches. We discuss historical milestones in natural product drug discovery, highlighting the specific contributions of the U.S. National Cancer Institute in developing anticancer and anti-HIV agents. The present work also addresses current challenges and innovations in the field, emphasizing the importance of data quality, interdisciplinary collaboration, and the integration of artificial intelligence. By providing this carefully selected reading list and accompanying analysis, we aim to offer a comprehensive yet accessible entry point for researchers new to natural product-based drug discovery and highlight future directions and opportunities in this dynamic field.

CTNI-64. TRIAL IN PROGRESS: DIET2TREAT -- A RANDOMIZED MULTICENTER PHASE 2 TRIAL OF A KETOGENIC DIET VS STANDARD DIETARY GUIDANCE IN COMBINATION WITH STANDARD-OF-CARE TREATMENT FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Many glioblastoma (GBM) patients inquire about the potential therapeutic benefits of a high fat / low carbohydrate ketogenic diet (KD). Preclinical models and early-phase trials have shown encouraging results, but definitive evidence of clinical efficacy is lacking. METHODS We are conducting a multicenter randomized controlled phase 2 clinical trial (NCT05708352) of KD vs standard dietary guidance (SD) for patients with newly diagnosed GBM. All patients receive standard-of-care chemoradiation. Inclusion criteria: newly diagnosed GBM, age ≥ 18 years, Karnofsky Performance Status ≥ 70. Exclusion criteria: inability to wean steroids below 8 mg dexamethasone/day, Body Mass Index &amp;lt; 21 kg/m2, food preferences incompatible with KD. Patients are randomized 1:1 to implement either KD or SD for a study period of 18 weeks, starting alongside chemoradiation. The primary outcome is overall survival for patients randomized to the KD arm compared to those randomized to the SD arm. Secondary outcomes include progression-free survival, health-related quality-of-life (FACT-BR, FACIT-F), cognitive performance (HVLT-R, Trail-Making Test A/B), and physical activity (modified Godin leisure questionnaire, continuous activity monitoring (Fitbit)). Patients randomized to the KD arm will be provided a fingerstick monitor to check blood ketone and glucose levels twice daily. Glucose and ketone levels are also periodically monitored for patients on the SD arm. Blood, tumor, and stool samples are being collected for high throughput profiling to assess the effects of KD on metabolic markers and immune response. Target accrual is 170 patients over 5 years. Enrollment began in July 2023 and is ongoing. As of May 2024, the trial is open for enrollment at Cedars-Sinai and UCSF, and will be opening soon at Duke, St. John’s Cancer Institute, and the Medical College of Wisconsin. 13 patients have been randomized to date. Funding provided by NIH R01CA276919 and the Foundation for Metabolic Cancer Therapies.

EXTH-53. THE PHARMACOLOGICAL ATLAS OF MENINGIOMAS

Abstract No systemic treatment options exist for recurrent or refractory meningioma patients. This study aimed to create a pharmacological atlas of all FDA-approved oncology drugs in a large cohort of patient-derived meningioma organoids (TOs). TOs were generated from single cell suspensions from freshly resected meningiomas and were treated with semi-logarithmic concentrations spanning from 10 nM to 30 µM by the automated liquid handler Hamilton MicroLAB STAR®. The drug library AODX from the National Cancer Institute consisted of 179 FDA-approved anticancer drugs. The viability was measured with the RealTimeGlo (Promega). Half-maximal inhibitory concentrations (IC50) were calculated by GraphPad Prism software. We created a pharmacological atlas of meningiomas by generating 8,413 dose-response curves of 179 current FDA-approved oncology drugs in patient-derived tumor organoids from 47 meningioma patients. The cohort consisted of 35 grade 1, 11 grade 2, and 1 grade 3 meningiomas, including 10 recurrent tumors. In total, 21% (n=39/179) of the drugs exhibited sensitivity (median IC50 &amp;lt; 30 µM), with significant enrichment for topoisomerase, RNA/protein synthesis, proteasome, and HDAC inhibitors. The top five drugs with the lowest IC50 values were romidepsin, dactinomycin, carfilzomib, plicamycin, and omacetaxine with median values of 10, 31, 145, 303, and 400 nM. Hierarchical clustering of IC50 data revealed at least two distinct drug response clusters defined by sensitivity to tyrosine kinase inhibitors. When considering the Cmax/IC50 ratio as a potential predictive marker of treatment response (&amp;gt;1), the HDAC inhibitors belinostat (74.5), romidepsin (69.7), the proteasome inhibitor carfilzomib (34.6), and the anthracyclines epirubicin (2.6), and doxorubicin (1.8), and the PI3K inhibitor idelalisib (1.6) are the most promising drug candidates for further in vivo evaluation. We provide the first comprehensive insight into the pharmacological landscape of meningiomas. This data might serve as the foundation for future clinical studies on the systemic treatment of aggressive meningiomas.