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e24020 Background: Transcatheter aortic valve replacement (TAVR) is a widely adopted treatment for severe aortic stenosis, but outcomes in cancer survivors with prior chest radiation therapy (C-XRT) remain uncertain. This study compares the clinical outcomes of TAVR between patients with a history of C-XRT and those without prior radiation exposure (control group). Methods: Patients with prior chest radiation therapy (C-XRT) were compared to a control group without radiation exposure to evaluate key clinical endpoints. For each endpoint, odds ratios (OR) and 95% confidence intervals (CI) were determined, and heterogeneity was analyzed using the I² statistic. A p-value of <0.05 was considered statistically significant. Results: Nine studies were included in the meta-analysis, encompassing 3083 C-XRT and 8891 control patients. Patients with prior C-XRT showed significantly higher long-term mortality (OR 1.84, 95% CI [1.08, 3.13], p=0.02) compared to controls. Other outcomes, including access-related vascular complications, Acute Kidney Injury, Congestive heart failure, major bleeding, need for pacemaker, short-term mortality, and stroke, did not demonstrate significant differences between the groups. Conclusions: Cancer survivors with prior chest radiation therapy undergoing TAVR may experience higher long-term mortality compared to patients without radiation exposure. However, no significant differences were observed in other major outcomes. These findings suggest that while TAVR is a viable treatment for C-XRT patients, long-term risks require further investigation to optimize patient selection and management strategies. Outcomes. Outcome OR 95% Confidence Interval P value Access related vascular complications 1.12 [0.85, 1.48] 0.43 Acute kidney injury 0.54 [0.20, 1.50] 0.24 Congestive heart failure 1.38 [0.88, 2.17] 0.16 Long term mortality 1.84 [1.08, 3.13] 0.02 Major bleeding 0.96 [0.78, 1.17] 0.67 Need for pacemaker 1.05 [0.88, 1.26] 0.57 Short term mortality 1.66 [0.97, 2.84] 0.06 Stroke 1.25 [0.74, 2.11] 0.39

e24024 Background: Patients with active cancer undergoing trans catheter aortic valvular replacement (TAVR) face a higher risk of adverse outcomes due to the interplay between cancer and cardiovascular disease. Although TAVR is increasingly used in high-risk populations, data on outcomes for these patients remain limited. This systematic review and meta-analysis aim to evaluate the clinical outcomes associated with TAVR in patients with active cancer compared to non-cancer controls, providing insights to inform clinical decision-making in this unique group. Methods: A systematic search of major databases (PubMed, Embase, OVID, Web of Science, Scopus) was conducted to identify studies comparing clinical outcomes of TAVR between patients with active cancer and those without cancer. Key outcomes included measures of mortality, procedural complications, and post-procedure adverse events. The Mantel-Haenszel method was used for pooled analysis, applying random-effects or fixed-effects modeling based on heterogeneity assessed by Higgins I². Statistical significance was set at a p-value < 0.05. Results: Twelve studies involving 5,73,192 patients (67,684 active cancer, 505508 control) were included. Patients with active cancer undergoing TAVR have significantly higher risks of short-term mortality (OR 1.31, 95% CI [1.15, 1.49], p < 0.0001), long-term mortality (OR 2.24, 95% CI [1.85, 2.70], p < 0.0001), and major bleeding complications (OR 1.80, 95% CI [1.68, 1.92], p < 0.0001). There were no statistically significant differences in cardiovascular mortality (OR 1.33, 95% CI [0.94, 1.89], p = 0.11), myocardial infarction (OR 1.60, 95% CI [0.82, 3.11], p = 0.17), stroke (OR 0.61, 95% CI [0.28, 1.35], p = 0.22), AKI (OR 0.92, 95% CI [0.49, 1.73], p = 0.80), or the need for permanent pacemaker implantation (OR 1.12, 95% CI [0.85, 1.48], p = 0.42). Conclusions: Patients with active cancer undergoing TAVR face significantly higher risks of mortality and major bleeding compared to non-cancer controls. However, the risks of cardiovascular mortality, MI, stroke, AKI, and the need for permanent pacemaker implantation are comparable to those of non-cancer controls. Careful risk assessment and management are crucial for optimizing outcomes in this vulnerable population, and further studies are needed to refine treatment strategies. Odds ratios of all outcomes. Outcomes OR Confidence Interval (95% CI) p-value Short term mortality 1.31 [1.15, 1.49] < 0.0001 Long term mortality 2.24 [1.85, 2.70] < 0.00001 Major bleeding 1.8 [1.68, 1.92] < 0.00001 Cardiovascular mortality 1.33 [0.94, 1.89] 0.11 Myocardial Infarction 1.6 [0.82, 3.11] 0.17 Stroke 0.61 [0.28, 1.35] 0.22 Acute Kidney Injury 0.92 [0.49, 1.73] 0.8 Need for permanent pacemaker implantation 1.12 [0.85, 1.48] 0.42

1051 Background: Hispanics or Latinos (HL) and African Americans or Black (AA) have a higher prevalence of advanced-stage breast cancer (BC) at diagnosis compared to Non-Hispanic Whites (NHW). To understand the role of immune system, we evaluated the tumor immune microenvironment (TIME) by race/ethnicity among HL, AA, and NHW BC patients. Methods: 15544BC samples were tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). Race/ethnicity data is self-reported. Immune cell were estimated using WTS deconvolution (Quantiseq). Gene expression profiles were analyzed for T-cell inflammation score (TIS) and interferon-gamma (IFN-gamma) score. Real-world overall survival (OS) was obtained from insurance claims and calculated from date of tumor biopsy to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney U test with p -values adjusted for multiple comparisons (q < .05). Results: 7170 NHW (35.3%, N = 2528) biopsied (bx) from primary breast cancer (pBC), 64.7% (N = 4642) metastatic bx (mBC), 1,508 AA (pBC 39.3% N = 592, mBC 60.7% N = 916), and 1,754 HL (pBC 44.1% N = 774, mBC 55.9% N = 980) cases were included. By subtype, there were 1,956 (60.4% NHW, 20.7% NHB, 18.9% HL) TNBC, 3425 HR+/HER2- (72.6% NHW, 11.9% NHB, 15.6% HL), and 694 HER2+ (64.6% NHW, 15.7% NHB, 19.7% HL). Across all cases, AA (20.5%) and HL (20.4%) had greater incidence (%) of PD-L1+ cases versus (vs) NHW (17.4%), all q < .05. TMB-High (³10 mut/Mb) was similar in NHW (11.5%), AA (10.8%), and HL (10.9%). AA tumors had lower median % cell infiltration of M2-like macrophages (M2 Mφ), B cells, and neutrophils vs NHW (Table). HL had a lower fraction of M2 Mφ and higher CD8+ T cells (Table). AA had lower TIS (-8 vs 1, p = .02) while HL had lower IFN-gamma (-0.38 vs. -0.35, q < .05) vs NHW. By subtype, AA had lower neutrophils (4% vs 4.3%) and increased DC fractions (3.1% vs 2.8%) in TNBC vs NHW, all q < .05; no significant changes seen in HL vs NHW. AA had worse mOS than NHW overall (31.8 vs 36.8 months (mo)), HR 1.1, 95% CI 1 – 1.2, p = < .01), in pBC (40.3 vs 49.9 mo, HR 1.3, 95% CI 1.1 – 1.5, p = < .01), but not mBC (27.4 vs 29.1 mo, HR 1, p = 0.2). HL had similar mOS vs NHW overall (37.4 vs 36.8 mo, HR 0.9, p = 0.9) and in mBC (29.1 vs 31 mo, HR 0.96, p = 0.4), but worse mOS in pBC (44.7 vs 50.0 mo, HR 1.1, 95% CI 1 – 1.3, p = .01). Conclusions: Our study shows worse mOS in AA and HL pBC cases vs NHW, possibly from a less inflamed TIME in AA and HL and lower fraction of neutrophils and M2 Mφ despite higher % of PD-L1+. Targeting Mφ and CD8+ T cells and converting cold to hot TIME may lessen race/ethnic disparities, especially in early-stage BC. Immune cell fraction of NHW, AA and HL BC. NHW (median %) AA (median %) HL (median %) q-valueNHW vs AA q-value NHW vs HL B cell 5.2 4.8 5.0 <.05 0.7 DC 2.6 2.7 2.6 0.08 0.4 M1 Mφ 2.5 2.4 2.4 0.4 0.9 M2 Mφ 4.6 3.7 4.2 <.05 <.05 Neutrophils 3.7 3.5 3.4 <.05 <.05 NK cell 2.9 2.9 2.9 0.7 0.6 CD8+ T cell 0.1 0.15 0.26 0.8 <.05 Treg 1.5 1.5 1.6 0.6 <.05

ABSTRACTBackgroundIn this study, we compared outcomes of intensified myeloablative conditioning regimens using large registry data from Japan (Japanese Society for Transplantation and Cellular Therapy) and the United States (Center for International Blood and Marrow Transplant Research).MethodsAdult patients who underwent their first myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for acute leukemia in remission between 2010 and 2018 using conditioning regimens of cyclophosphamide plus total‐body irradiation (CY/TBI), CY/TBI+cytarabine (AraC), or CY/TBI+etoposide (VP16) were included.ResultsThe acute myeloid leukemia (AML) cohort (N = 480, 38.8%) indicated that overall survival (OS) was poorer in CY/TBI+AraC (hazard ratio [HR] 1.46, p < 0.001) and CY/TBI+VP16 (HR 1.39, p = 0.059) compared to CY/TBI. Relapse was not suppressed, while treatment‐related mortality (TRM) was significantly higher (HR 1.78 and 1.74, p < 0.001 and 0.018, respectively). In the acute lymphoblastic leukemia (ALL) cohort (N = 3901, 61.2%), OS was comparable among these regimens. With intensified regimens, relapse was significantly suppressed in CY/TBI+VP16 (HR 0.74, p = 0.005), while TRM was higher (HR 1.21, p = 0.077). No interactions were observed regarding the country.ConclusionIn AML adding AraC and VP16 to CY/TBI had an adverse effect on OS. Conversely, in ALL, adding VP16 or AraC to CY/TBI did not affect survival, but the addition of VP16 reduced the risk of relapse.Clinical Trial RegistrationThe authors have confirmed clinical trial registration is not needed for this submission.

6037 Background: The incidence of HPV-associated head and neck squamous cell carcinoma (HNSCC) continues to rise with over 90% of cases being driven by HPV16. Median overall survival (OS) with pembrolizumab in first-line recurrent/metastatic (R/M) HNSCC is 12.3 months in subjects with CPS ≥1, 10.8 months for CPS ≥1-19, and 14.9 months for CPS ≥20. There is an urgent need to improve survival rates in the growing population of HPV16-positive R/M HNSCC. PDS0101 (Versamune HPV) is an investigational T cell stimulating immunotherapy that unleashes a potent, durable attack against HPV16-positive cancers and is being studied in combination with pembrolizumab. Preliminary results were presented at ASCO 2023. (Price KAR, et al. ASCO 2023. Abstract 6012). Methods: VERSATILE-002 is a single-arm phase 2 study evaluating PDS0101 and pembrolizumab for first-line HPV16-positive R/M HNSCC with CPS ≥1. Subjects received pembrolizumab 200 mg IV Q3W with PDS0101 1 mL SC administered concurrently during Cycles 1, 2, 3, 4, and 12 and pembrolizumab alone for all other Cycles up to Cycle 35 (approx. 2 years). The primary study endpoint is confirmed objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free survival (PFS), OS, and safety. Results: The median follow-up is 18.4 months (range 0.2-42.7 months). The efficacy population consists of 53 subjects: 32 (60%) with CPS ≥1-19 and 21 (40%) with CPS ≥20. The median OS for subjects with CPS ≥1 is 30 months (95% CI 23.9, NE). For the CPS ≥1-19 subgroup, the median OS is 29.5 months (95% CI 15.3, NE). For the CPS ≥20 subgroup, the median OS is 39.3 months (95% CI 18.4, NE). Confirmed response rates by investigator assessment are shown in the Table. Twenty-three subjects are still on study: 3 on treatment and 20 in long-term follow-up. No new safety signals have emerged. The most common TRAEs are injection site reactions, fatigue, headache, and pruritus. Only 19% of subjects experienced Grade ≥3 TRAEs. No subject had a Grade 5 TRAE. Conclusions: These data represent one of the most extended follow-up periods to date of subjects receiving an HPV16-targeted therapy for HPV16-positive R/M HNSCC. The PDS0101 and pembrolizumab combination is well tolerated and has demonstrated deep and durable clinical responses. Median OS is promising in light of historic expectations, both overall and relative to PD-L1 subgroup, and remains durable with continued follow up. The results support further evaluation in a randomized phase 3 study with OS as the primary endpoint. Clinical trial information: NCT04260126 . Summary of results. CPS ≥1-19 (N=32) CPS ≥20 (N=21) CPS ≥1 (N=53) ORR, % 28.1 47.6 35.8 DCR, % 75.0 81.0 77.4 Median DOR, months (95 % CI) 21.8 (4.2, NE) NE (5.6, NE) 21.8 (11.5, NE) Median PFS, months (95% CI) 5.1 (2.4, 8.1) 14.1 (2.1, NE) 6.3 (3.5, 9.0) Median OS, months (95% CI) 29.5 (15.3, NE) 39.3 (18.4, NE) 30.0 (23.9, NE)

e17064 Background: Analyses of clinical trials data suggest thatBlack men have equal or even improved overall survival (OS) with certain treatments for mCRPC compared with other races. Moreover, retrospective analysis of the PROCEED registry indicated that Black men who received Sip-T, an autologous cellular immunotherapy, had longer survival compared with other men with mCRPC. The Abi Race and PANTHER clinical trials prospectively assessed the effect of ARPIs on clinical outcomes among Black and White patient (pt) cohorts, and included pts who had received Sip-T either prior to or during study. We combined data from Abi Race and PANTHER to investigate associations between OS, Sip-T and race. Methods: Data from the Abi Race (N=100) and PANTHER (N=93) studies were retrospectively pooled for this analysis. Propensity scores for Sip-T treatment were calculated based on Karnofsky performance status, race, Gleason score, and study. Kaplan-Meier estimates for OS, with and without inverse propensity score weighting, were generated and stratified by Sip-T use. This analysis was stratified by race to examine whether the relationship between Sip-T use and OS differed by race. Results: Of the 93 Black pts and 100 White patients included from both studies, 123 patients did not receive Sip-T, while 70 patients did (60 before study, 10 on study). Pts who received Sip-T had a median OS (mOS) of 44 months (95% Confidence Interval (CI) 39, NR) compared to 36 months (95% CI 31, 48) for those who did not. Weighted by propensity scores, Black men who received Sip-T had a mOS of 72 months (95% CI 43, NR), while those who did not had a mOS of 38 months (95% CI 30, NR). Among White men, patients who received Sip-T had a mOS of 39 months (95% CI 30, NR), while those who did not had a mOS of 32 months (95% CI 29, 48) (see Table). Conclusions: Our findings from an investigator-led retrospective analysis independent of sponsors provide independent clinical trial support of prior retrospective findings that suggest Black men with mCRPC who receive Sip-T may have a greater OS than White men. While our analysis controlled for factors that may influence the use of Sip-T, it is limited by potential unmeasured confounders or timing of Sip-T. Further, adequately powered prospective trials specifically evaluating outcomes with Sip-T by race in earlier clinical settings are needed. Drug support and funding for Abi Race and PANTHER were provided by Janssen Scientific Affairs, LLC. Death counts and median overall survival (mOS) in months by race and Sipuleucel-T use. Black Men White Men Sipuleucel-T use Deaths / Total N No 36 / 64 38 / 59 Yes 12 / 29 24 / 41 Unweighted mOS (95% CI) No 36 (29, NR) 32 (29, 48) Yes 72 (43, NR) 39 (31, NR) Weighted mOS (95% CI) No 38 (30, NR) 32 (29, 48) Yes 72 (43, NR) 39 (30, NR) NR = not reached, mOS = median overall survival, CI = confidence interval.

e16072 Background: Gastric cancer is a leading cause of mortality worldwide, with pronounced variations in outcomes across populations. This study investigates U.S. trends in age-adjusted mortality rates (AAMRs) for gastric cancer from 1999 to 2023, examining differences by gender, race, region, and urbanization to uncover critical patterns and inequities. Methods: Data were extracted from the CDC WONDER database using ICD-10 code C16 to identify gastric cancer-related deaths in adults aged 25 and older. AAMRs per 1,000,000 population were calculated and stratified by year, gender, race/ethnicity, geographic region, and urban-rural classification. Trends were analyzed using Joinpoint regression to determine annual percentage changes (APC) and 95% confidence intervals (CI). Statistical significance was set at p < 0.05. Results: From 1999 to 2023, there were 312,300 gastric cancer deaths (185,391 men, 126,909 women). Overall, AAMRs declined consistently, with APCs of -3.4 for the period 1999 to 2007, -2.2 for 2007 to 2018, and -1.2 for 2018 to 2023. Men showed a more pronounced decline, with APCs of -3.6 for 1999 to 2009 and -2.2 for 2009 to 2023, compared to women, who had APCs of -3.1 for 1999 to 2008, -1.9 for 2008 to 2018, and -0.8 for 2018 to 2023. Non-Hispanic Black populations experienced a decline in AAMR with an APC of -3.3 for 1999 to 2020, while Hispanic/Latino and Asian/Pacific Islander populations showed declines with APCs of -2.8 for 1999 to 2011 and -3.8 for 1999 to 2020, respectively. Metropolitan areas saw AAMR reductions with APCs of -3.3 for 1999 to 2008 and -2.2 for 2008 to 2020, while non-metropolitan areas had larger initial declines with an APC of -3.6 for 1999 to 2006 but slower decreases with an APC of -2.0 for 2006 to 2020. Geographically, the Northeast had the highest AAMR (62.9), followed by the West (61.7), South (57.4), and Midwest (50.9). Hawaii recorded the highest state-level AAMR (96.5), while Wyoming had the lowest (36.6). States in the top 90th percentile included Alaska, California, and New York, whereas Utah, Idaho, and Iowa were among the lowest. Conclusions: Gastric cancer mortality in the U.S. has declined over the past two decades, but the pace of reduction has slowed in recent years. Significant disparities persist across gender, racial, and geographic groups, underscoring the need for targeted interventions to address these inequities and improve outcomes in vulnerable populations.

e13808 Background: Cancer is a leading cause of death for Latinos. They experience higher rates than their white peers of preventable, infectious-agent-causing-cancers, such as stomach & liver cancer. Latina women have experienced a 1% rise in cancer cases since 2011 & Latino children & adolescents experience higher rates of leukemia than any other racial/ethnic group. Latinos face disparities in access to healthcare, cancer screening & treatment, medical representation & experience lower rates of survival due to late-stage cancer diagnosis. Methods: To combat these inequities & identify equitable interventions for Latino health, the Institute of Health Promotion Research & the Mays Cancer Center established the Advancing the Science of Cancer in Latinos (ASCL) Conference. The fourth ASCL Conference convened in San Antonio, TX from February 21-23, 2024. The conference objectives were 1) Examine the intersection of health equity & biological underpinnings in cancer control, prevention, and treatment 2) Foster collaborative initiatives among attendees aimed at addressing cancer-related health disparities within the Latino community. The conference hosted 286 participants (speakers, researchers, physicians, healthcare professionals, patient advocates & students). It comprised of 23 sessions (3 keynotes, 6 plenaries, 6 breakouts, 3 general sessions, 1 special session, 1 lunch panel session) featuring insights from 51 speakers, a poster session highlighting 80 research abstracts & a rapid-fire session tailored for early-career investigators. Sessions focused on multiple topics relevant to Latino cancer research, clinical trials, survivorship, patient advocacy, climate change impacts on cancer, precision medicine, health policy & social determinants of health. Results: A post-conference survey from a cohort of 48 respondents underscored high levels of satisfaction, with 90% expressing contentment regarding the conference experience. Nearly all respondents (98%) rated the relevance of conference content to Latino cancer science as excellent, with 93% regarding the conference as an exceptional platform for information exchange. Impressions regarding session quality were positive, with 90% of respondents indicating a high level of satisfaction, & all survey respondents acknowledging the objectivity, balance & absence of commercial bias in the session content. Conclusions: Results showed that the resounding positivity in attendee feedback reflects the conference's success in fostering meaningful engagement among attendees. The ASCL conference facilitated an understanding of cultural nuances and barriers specific to the Latino community, stimulating collaborative efforts aimed at enhancing Latino health outcomes. Overall, this analysis affirms the conference's success in achieving its stipulated objectives and underscores the need of having consistently coordinated research endeavors to reduce Latino health disparities.

e12562 Background: Previous research has suggested that breast cancer (BC) diagnosed during pregnancy or the postpartum period exhibits more aggressive clinical features, possibly due to pregnancy-related hormonal changes, immune modulation, and alterations in the mammary microenvironment compared to nulligravid or women many years out from pregnancy. Emerging data have demonstrated potential worse outcomes for patients (pts) diagnosed in post-partum. This study evaluated the influence of timing of diagnosis in relation to pregnancy history and recency of childbirth on long-term outcomes in a modern cohort of young pts with early-stage BC. Methods: Pts with stage I–III BC age < 40y in the prospective Young Women’s Breast Cancer Study (YWBCS) were categorized at diagnosis as Nulligravid (no prior pregnancy), Nulliparous (prior pregnancy without live birth), Currently Pregnant, or Parous (subdivided by time since last childbirth: within 5 years [≤ 5y PP], and 5–10 years postpartum [5–10y PP]). Baseline characteristics and outcomes were compared across BC subtypes (estrogen receptor+/HER2- [ER+/HER2-], HER2+, and triple-negative BC [TNBC]). Prognostic analyses for distant recurrence-free survival (DRFS) used Cox models. Results: 859 pts were included, 257 (30%) nulligravid, 50 (6%) nulliparous, 37 (4%) pregnant, and 515 (60%) parous (348 [68%] were ≤5y PP, and 167 [32%] were 5–10y PP). Median follow-up was 133 (6–209) months. Median age at diagnosis was lower in nulligravid pts (33 vs. 35–38 years); T1 tumors were most common in pts >5y PP (62%), and N0 status was highest in nulligravid pts (64%) (all p < 0.0001). Pregnant pts had higher rates of TNBC (27%), and T3 tumors (14%), N1 status, N1 (41%), and Grade 3 (81%) tumors compared to other groups (all p < 0.0001). Overall, only tumor size (T2-T4 vs T1, HR 2.03; 95% CI 1.37–3.03) and nodal status (N1 vs N0, HR 2.22; 1.48–3.34; N2/3 vs N0, HR 3.23; 1.96-5.33) were independently associated with worse DRFS; pregnancy history was not: nulligravid + nulliparous pts had no significant differences in DRFS compared to Pregnant (HR 1.46; 0.75–2.86), Parous <5y PP (HR 0.86; 0.58–1.26), and Parous 5–10y PP (HR 0.89; 0.54–1.48). Subgroup analyses by BC subtype (Table) and sensitivity analyses (excluding currently pregnant pts or separating nulligravid and nulliparous pts) demonstrated no significant associations between pregnancy history and DRFS. Conclusions: In this cohort study of very young patients with early breast cancer with contemporary treatment including management of breast cancer during pregnancy, pregnancy history and recency of pregnancy were not independent predictors of long-term disease outcomes. DRFS results by subgroup. Pregnancy Group N (%) HR (95% CI) ER+/HER2- Nulligravid + Nulliparous 173 (38.1) Ref Pregnant 16 (3.5) 0.93 (0.32–2.70) Parous ≤5y PP 177 (39.0) 0.77 (0.45–1.29) Parous 5–10y PP 88 (19.4) 0.78 (0.39–1.53) HER2+ Nulligravid + Nulliparous 77 (30.8) Ref Pregnant 11 (4.4) 3.27 (0.80–13.38) Parous ≤5y PP 113 (45.2) 1.50 (0.60–3.75) Parous 5–10y PP 49 (19.6) 1.45 (0.45–4.66) TNBC Nulligravid + Nulliparous 56 (36.8) Ref Pregnant 10 (6.6) 1.92 (0.61–6.09) Parous ≤5y PP 57 (37.5) 0.68 (0.28–1.63) Parous 5–10y PP 29 (19.1) 1.16 (0.43–3.14)

e23101 Background: Liver cell carcinoma (LCC) and hepatic failure (HF) are major contributors to global adult mortality. Identifying trends and disparities in LCC and HF-related deaths is critical for addressing public health challenges and guiding prevention strategies. This study examines national trends in LCC and HF-related mortality from 1999 to 2023, with an emphasis on demographic, geographic, and temporal disparities in age-adjusted mortality rates (AAMRs). Methods: Using the CDC WONDER database (1999–2023), this descriptive study identified deaths attributed to LCC (ICD-10 code C22.0) and HF (ICD-10 code K72.9) among adults aged 25 and older. Mortality data were stratified by gender, race/ethnicity, census region, urban-rural classification, and state. Age-adjusted mortality rates (AAMRs) per 1,000,000 individuals were calculated, and trends were analyzed using Joinpoint regression to determine annual percent changes (APCs) with 95% confidence intervals (CIs). Statistical significance was set at p < 0.05, and the study followed STROBE guidelines. Results: From 1999 to 2023, there were 22,963 deaths attributed to LCC and HF (Men: 17,822; Women: 5,141). Overall, AAMRs declined from 1999 to 2007 (APC: -2.4), stabilized between 2007 and 2017 (APC: 0.2), and declined again from 2017 to 2023 (APC: -3.5). Men experienced a steady AAMR decline from 1999 to 2010 (APC: -2.1), followed by stabilization (2010–2017, APC: 0.7), and further decline (2017–2023, APC: -4.4). Women showed a sharp AAMR decrease from 1999 to 2006 (APC: -3.8) and a relatively stable trend thereafter (APC: -0.1). Non-Hispanic Blacks people experienced an overall AAMR decline from 1999 to 2020 (APC: -0.9). Among Non-Hispanic Whites people, AAMRs decreased initially (1999–2006, APC: -2.6), rose slightly (2006–2018, APC: 0.5), and declined further (2018–2020, APC: -7.3). Regional AAMRs varied, with the West having the highest overall AAMR (5.6; 95% CI: 5.4–5.7) and the Midwest the lowest (3.2; 95% CI: 3.1–3.3). Hawaii reported the highest state AAMR (10.3; 95% CI: 8.9–11.6), while Arkansas had the lowest (2.4; 95% CI: 2.0–2.9). Urban-rural disparities revealed a sharper AAMR decline in metropolitan areas (1999–2005, APC: -3.9) and the non-metropolitan areas showed a slight increase (1999–2020, APC: 1.3). Conclusions: LCC and HF-related mortality rates have shown significant declines over the past two decades, with variations across gender, race, and geographic locations. Men and urban populations experienced steeper reductions in AAMRs, while rural populations exhibited slower improvements or slight increases in mortality. These findings highlight the need for targeted public health interventions to address disparities and further reduce LCC and HF-related mortality in vulnerable populations.