Disparities in peripheral sensory neuropathy (PSN) have been studied in taxane-treated breast cancer and vincristine-treated leukemia survivors, but not addressed in cisplatin. Both platinum compounds and environmental heavy metals are associated with vascular toxicity, and there is genetic variation in single nucleotide polymorphisms (SNPs) associated with metal burden, which may be due to adaptation to exposures across geographies. We hypothesize that disparities may exist in cisplatin-induced neurotoxicities related to differences in population allele frequency and variants’ impact on gene expression. In a study of 1663 genotyped testicular cancer survivors, logistic regression between multidimensional scaling-calculated geographic ancestry and neurotoxicities (400-450 mg/m2 cisplatin) and clinical/lifestyle factors was assessed. SNPs with Fst > 0.25 in 1000 Genomes were filtered using GTEx and LDmatrix to find independent expression/splicing trait loci (eQTL/sQTL) in nerve/brain tissue or cisplatin-associated genes. Logistic regression was conducted between genotype and toxicity with age and 10 genetic principal components as covariates. Spearman correlation between gene expression (DepMap) and cisplatin sensitivity (GDSC) in cell lines was calculated for genes of interest from association analysis. Survivors of African (AFR) ancestry had significantly higher PSN incidence versus European (EUR) (p=0.049) and Asian (ASN)-axis (p=0.034) ancestry and higher vertigo incidence versus EUR (p=5.2x10-3) and ASN-axis ancestry (p=0.04), with significant differences in self-reported health. Clinical factors did not show disparities, although ASN-axis survivors were significantly less likely to be on antihypertensives. 19,992 SNPs passed filtering. While genotype-toxicity associations did not hit Bonferroni threshold, six SNPs had suggestively significant p<1.0x10-4. One SNP had increased frequency of the risk allele in the AFR population for PSN and four SNPs for vertigo. rs34904346 (p=2x10-5) was a RNF24 eQTL in the nerve, with 3 other RNF24 eQTLs also associated with PSN (p<0.05). For vertigo, rs3777909 (p=3.1x10-5) was an eQTL for MFSD4B in the nerve and REV3L in the brain, with other independent eQTLs associated with vertigo (p<0.05) and MFSD4B (3) and REV3L (4). For vertigo, rs56819906 (p=7.6x10-5) and rs73626678 (p=1.8x10-4) were DDX25 eQTLs in the nerve. MFSD4B (p=0.0058) and REV3L (p=5.1x10-5) expression in cancer cell lines were significantly correlated with cisplatin sensitivity, matching direction of effect in toxicity association analyses. We show evidence for the contribution of differential risk allele frequencies to disparities in cisplatin-induced PSN and vertigo. If results are confirmed, genotyping risk alleles to identify at-risk patients may benefit cisplatin-treated populations. Swetha Nakshatri, Paul C. Dinh, Darren R. Feldman, Robert J. Hamilton, David J. Vaughn, Chunkit Fung, Christian Kollmannsberger, Robert Huddart, Lawrence H. Einhorn, Nancy J. Cox, Lois B. Travis, M. Eileen Dolan. Disparities in neurotoxicities in cisplatin-treated cancer patients: a population pharmacogenomics approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4357.

BACKGROUND:To comprehensively evaluate the longitudinal progression of cumulative burden of morbidity (CBM) in testicular cancer survivors (TCS) following standard-dose cisplatin-based chemotherapy and the impact of modifiable risk factors on morbidity and early mortality. METHODS:Participants completed first-line chemotherapy at or longer than 6 months before baseline assessments with comprehensive questionnaires and physical examinations. Based on follow-up assessments (median: 7 years later), longitudinal progression of adverse health outcomes (AHOs) and CBM score (encompassing AHO number and severity) were examined. Baseline health behaviors and AHOs were evaluated for associations with mortality using mixed-effects parametric proportional-hazards regression to identify modifiable risk factors. RESULTS:Among 616 TCS longitudinally assessed, 23% experienced worsening CBM postchemotherapy (median = 11 years, interquartile range = 7-15). Declines were driven by worsening treatment-related AHOs: tinnitus (29.7%), hearing loss (24.4%), Raynaud's disease (22.6%), neuropathy (18.5%), and neuropathic pain (10.7%). Baseline factors associated with worsening neuropathy included lack of aerobic physical activity (odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.06 to 3.72), and obesity (OR = 1.85, 95% CI = 1.17 to 2.92). These were also related to worsening neuropathic pain (OR = 2.82, P = .009 and OR = 2.29, P = .023). Twenty-nine deaths occurred among 1830 5-year TCS (4.2% cumulative hazard) (median age = 48 years, range = 22-74). Participants reporting neuropathic pain (hazard ratio [HR] = 3.64, 95% CI = 1.45 to 9.10), no aerobic (HR = 6.56, 95% CI = 2.73 to 15.8), or no low-impact physical activity (HR = 3.96, 95% CI = 1.40 to 11.2) had significantly higher mortality, as did TCS indicating fair (HR = 9.23, 95% CI = 3.08 to 27.8) or poor (HR = 18.5, 95% CI = 3.30 to 103) health. Relationships between pain and mortality were mediated through lowered physical activity (P = .036). CONCLUSIONS:Clinically actionable factors associated with early mortality identify high-risk TCS in need of closer monitoring and targeted interventions. The significant relationship between neuropathic pain and mortality, mediated by low physical activity, is the first to our knowledge in TCS.

BACKGROUND:Cisplatin is a commonly used chemotherapeutic across numerous cancer types that can cause neurotoxicities in patients, including peripheral sensory neuropathy, tinnitus, hearing loss, and vertigo. OBJECTIVE:We aimed to evaluate, for the first time, how genetic ancestry impacts cisplatin-induced neurotoxicities and if disparities are related to population differences in allele frequency. METHODS:In a cohort of cisplatin-treated testicular cancer survivors, relationships between genetic ancestry and neurotoxicities, medications, and lifestyle factors were assessed using logistic regression and Kruskal-Wallis tests and multiple pairwise comparisons using the Wilcoxon rank-sum test (Benjamini-Hochberg adjustment). Associations between single nucleotide polymorphism (SNP) genotypes and neurotoxicities with significant inter-population disparities were calculated to identify independent, functional variants with population allele frequency differentiation associated with toxicities. RESULTS:Following four cycles of cisplatin-based chemotherapy, African ancestry survivors were significantly more likely to have neuropathy and vertigo versus European and Asian-axis ancestry survivors, although Asian axis survivors were significantly younger at evaluation than other ancestries. Following filtering for population allele frequency differentiation, functional relevance, and independence, 19,992 SNPs were tested for association with toxicities. Although none passed the Bonferroni threshold, two and four SNPs were associated with neuropathy and vertigo, respectively, at suggestively significant p < 1.0 × 10-4. For neuropathy, rs34904346 (p = 2.0 × 10-5) was an expression quantitative trait locus (eQTL) for RNF24 in nerve tissue, with three other RNF24 eQTLs associated with neuropathy (p < 0.01). For vertigo, rs3777909 (p = 3.1 × 10-5) was an eQTL for MFSD4B in nerve and REV3L in brain tissue, along with three other eQTLs for MFSD4B and four for REV3L associated with vertigo (p < 0.05). In silico, higher MFSD4B and REV3L expression in cancer cell lines were associated with significantly greater cisplatin sensitivity. CONCLUSION:African ancestry was associated with increased cisplatin-induced peripheral sensory neuropathy and vertigo versus European ancestry. Population allele frequency differences and expression levels of RNF24, MFSD4B, and REV3L were potentially implicated.

Transcriptome-wide association studies (TWASs) have the potential to identify susceptibility genes associated with testicular germ cell tumors (TGCTs). We conducted a comprehensive TGCT TWAS by integrating genome-wide association study (GWAS) summary data with predicted expression models from normal testis, TGCT tissues, and a cross-tissue panel that encompasses shared regulatory features across 22 normal tissues, including the testis. Gene associations were evaluated while accounting for variant-level effects from GWASs, followed by fine-mapping analyses in regions exhibiting multiple TWAS signals, and finally supplemented by colocalization analysis. Expression and protein patterns of identified TWAS genes were further examined in relevant tissues. Our analysis tested 19,805 gene- disease links, revealing 165 TGCT-associated genes with a false discovery rate of less than 0.01. We prioritized 46 candidate genes by considering GWAS-inflated signals, correlations between neighboring genes, and evidence of colocalization. Among these, 23 genes overlap with 22 GWAS loci, with 7 being associations not previously implicated in TGCT risk. Additionally, 23 genes located within 21 loci are at least 1 Mb away from published GWAS index variants. The 46 prioritized genes display expression levels consistent with expected expression levels in human gonadal cell types and precursor tumor cells and significant enrichment in TGCTs. Additionally, immunohistochemistry revealed protein-level accumulation of two candidate genes, ARID3B and GINM1, in both precursor and tumor cells. These findings enhance our understanding of the genetic predisposition to TGCTs and underscore the importance of further functional investigations into these candidate genes.

AimsTo resolve the ongoing controversy surrounding the impact of teratoma (TER) in the primary among patients with metastatic testicular non-seminomatous germ-cell tumours (NSGCT).Patients and methodsUsing the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium database, we compared the survival probabilities of patients with metastatic testicular GCT with TER (TER) or without TER (NTER) in their primaries corrected for known prognostic factors. Progression-free survival (5y-PFS) and overall survival at 5 years (5y-OS) were estimated by the Kaplan-Meier method.ResultsAmong 6792 patients with metastatic testicular NSGCT, 3224 (47%) had TER in their primary, and 3568 (53%) did not. In the IGCCCG good prognosis group, the 5y-PFS was 87.8% in TER versus 92.0% in NTER patients (p = 0.0001), the respective 5y-OS were 94.5% versus 96.5% (p = 0.0032). The corresponding figures in the intermediate prognosis group were 5y-PFS 76.9% versus 81.6% (p = 0.0432) in TER and NTER and 5y-OS 90.4% versus 90.9% (p = 0.8514), respectively. In the poor prognosis group, there was no difference, neither in 5y-PFS [54.3% in TER patients versus 55.4% (p = 0.7472) in NTER], nor in 5y-OS [69.4% versus 67.7% (p = 0.3841)]. NSGCT patients with TER had more residual masses (65.3% versus 51.7%, p < 0.0001), and therefore received post-chemotherapy surgery more frequently than NTER patients (46.8% versus 32.0%, p < 0.0001).ConclusionTeratoma in the primary tumour of patients with metastatic NSGCT negatively impacts on survival in the good and intermediate, but not in the poor IGCCCG prognostic groups.

You have accessJournal of UrologyPenile & Testicular Cancer I (MP01)1 May 2024MP01-10 THE LANDSCAPE OF RACIAL AND ETHNIC DISPARITY IN TESTICULAR CANCER STAGE PRESENTATION: A NATIONAL HOSPITAL-BASED STUDY Khalid Y. Alkhatib, Ian Mitchell Harmatz, John Pluta, Morgan Leff, Brian D. Cortese, Nathaniel McLaughlan, Thomas Guzzo, Katherine L. Nathanson, David J. Vaughn, Phillip M. Pierorazio, and Daniel J. Lee Khalid Y. AlkhatibKhalid Y. Alkhatib , Ian Mitchell HarmatzIan Mitchell Harmatz , John PlutaJohn Pluta , Morgan LeffMorgan Leff , Brian D. CorteseBrian D. Cortese , Nathaniel McLaughlanNathaniel McLaughlan , Thomas GuzzoThomas Guzzo , Katherine L. NathansonKatherine L. Nathanson , David J. VaughnDavid J. Vaughn , Phillip M. PierorazioPhillip M. Pierorazio , and Daniel J. LeeDaniel J. Lee View All Author Informationhttps://doi.org/10.1097/01.JU.0001008660.87408.90.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Testicular cancer's (TC) high curability presents a significant challenge in assessing racial and ethnic disparities using mortality outcomes. Examining the stage of presentation may provide valuable insights into existing disparities. We used the National Cancer Database to evaluate racial and ethnic differences in TC stage of presentation. METHODS: We analyzed TC patients between 2004 and 2016 using multivariable logistic regression analysis to investigate predictors of disease stage. Using a multivariable multinomial logistic regression, we calculated the marginal predicted probability for stage I, II, and III disease. We then estimated the adjusted risk difference (ARD) for each racial and ethnic group vs non-Hispanic white (NHW). RESULTS: We identified 70,757 TC patients for analysis. Descriptors and predictors are found in Table 1. Non-Hispanic black race (NHB) (OR: 1.21, 95%CI: [1.09, 1.35], p<0.01) and Hispanic ethnicity (OR: 1.16, 95%CI: [1.09, 1.23], p<0.01) were significant predictors of late stage (stage II/III) presentation. We also found a significant decrease in the adjusted predicted probability for stage I presentation in both NHB (ARD: -0.04, 95%CI: [-0.06, -0.02], p<0.01) and Hispanics (ARD: -0.03, 95%CI: [-0.04 , -0.01] , p<0.01) and a significant increase in the adjusted predicted probability of stage III presentation in NHB (ARD: 0.03, 95%CI: [0.01, 0.05], p<0.01), Hispanics (ARD: 0.03, 95%CI: [0.02, 0.04], p<0.01), and Asian American and Native Hawaiian/Pacific Islanders (AANHPI) (ARD: 0.02, 95%CI: [0.00, 0.04], p=0.02) compared to NHW (Figure 1). CONCLUSIONS: As compared to NHW, NHB and Hispanic are more likely to present with late stage disease and less likely to present with stage I disease. Additionally, NHB, Hispanics, and AANHPI are more likely to present with stage III disease. Our findings indicate an under-recognition of early stage TC in non-whites. Further investigating the drivers behind this could significantly impact TC care at the national level. Download PPT Source of Funding: N/A © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e5 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Khalid Y. Alkhatib More articles by this author Ian Mitchell Harmatz More articles by this author John Pluta More articles by this author Morgan Leff More articles by this author Brian D. Cortese More articles by this author Nathaniel McLaughlan More articles by this author Thomas Guzzo More articles by this author Katherine L. Nathanson More articles by this author David J. Vaughn More articles by this author Phillip M. Pierorazio More articles by this author Daniel J. Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

Background: Testicular germ cell tumor (TGCT) is the most common cancer among young White men. TGCT is highly heritable, although there are no known highpenetrance predisposition genes. CHEK2 is associated with moderate TGCT risk. Objective: To identify coding genomic variants associated with predisposition to TGCT. Design, setting, and participants: The study involved 293 men with familial or bilateral (high risk; HR)-TGCT representing 228 unique families and 3157 cancer-free controls. Outcome measurements and statistical analysis: We carried out exome sequencing and gene burden analysis to identify associations with TGCT risk. Results and limitations: Gene burden association identified several genes, including lossof-function variants of NIN and QRSL1. We identified no statistically significant association with the sex- and germ-cell development pathways (hypergeometric overlap test: p = 0.65 for truncating variants, p = 0.47 for all variants) or evidence of associations with the regions previously identified via genome-wide association studies (GWAS). When considering all significant coding variants together with genes associated with TGCT on GWAS, there were associations with three major pathways: mitosis/cell cycle (Gene Ontology identity GO:1903047: observed/expected variant ratio [O/E] 6.17, false discovery rate [FDR] 1.53 x 10 -11 ), co -translational protein targeting (GO:0006613: O/ E 18.62, FDR 1.35 x 10 -10 ), and sex differentiation (GO:0007548: O/E 5.25, FDR 1.90 x 10 -4 ). Conclusions: To the best of our knowledge, this study is the largest to date on men with HR-TGCT. As in previous studies, we identified associations with variants for several genes, suggesting multigenic heritability. We identified associations with cotranslational protein targeting, and chromosomal segregation and sex determination, identified via GWAS. Our results suggest potentially druggable targets for TGCT prevention or treatment. Patient summary: We searched for gene variations that increase the risk of testicular cancer and found numerous new specific variants that contribute to this risk. Our results support the idea that many gene variants inherited together contribute to the risk of testicular cancer.

Background:Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in men with prostate cancer; however, data on racial disparities in CVD outcomes are limited. Objectives:We quantified the disparities in CVD according to self-identified race and the role of the structural social determinants of health in mediating disparities in prostate cancer patients. Methods:A retrospective cohort study of 3,543 prostate cancer patients treated with systemic androgen deprivation therapy (ADT) between 2008 and 2021 at a quaternary, multisite health care system was performed. The multivariable adjusted association between self-reported race (Black vs White) and incident major adverse cardiovascular events (MACE) after ADT initiation was evaluated using cause-specific proportional hazards. Mediation analysis determined the role of theme-specific and overall social vulnerability index (SVI) in explaining the racial disparities in CVD outcomes. Results:Black race was associated with an increased hazard of MACE (HR: 1.38; 95% CI: 1.16-1.65; P < 0.001). The association with Black race was strongest for incident heart failure (HR: 1.79; 95% CI: 1.32-2.43), cerebrovascular disease (HR: 1.98; 95% CI: 1.37-2.87), and peripheral artery disease (HR: 1.76; 95% CI: 1.26-2.45) (P < 0.001). SVI, specifically the socioeconomic status theme, mediated 98% of the disparity in MACE risk between Black and White patients. Conclusions:Black patients are significantly more likely to experience adverse CVD outcomes after systemic ADT compared with their White counterparts. These disparities are mediated by socioeconomic status and other structural determinants of health as captured by census tract SVI. Our findings motivate multilevel interventions focused on addressing socioeconomic vulnerability.

211 Background: Strategies to inform cardiovascular (CV) risk are needed for prostate cancer patients initiating androgen deprivation therapy (ADT). Reduced myocardial blood flow reserve (MBFR) and coronary microvascular dysfunction (CMD) represent functional counterparts of traditional CV risk factors, including hyperlipidemia, insulin-resistance, and the metabolic syndrome. Myocardial perfusion PET stress imaging quantifies MBFR and detects CMD. However, the potential utility of these measures to indicate adverse CV changes in prostate cancer patients receiving ADT is poorly understood. Methods: In this prospective study (NCT03535987), eligible prostate cancer patients were planned for at least 6 months of ADT and curative-intent radiation therapy. All patients had a Framingham 10-year general CV risk score of at least 10% and no prior ADT exposure. Myocardial perfusion PET stress imaging was performed within 3 weeks of ADT initiation and again following 6 months of ADT exposure. MBFR was calculated as the ratio of MBF during stress / MBF during rest, and CMD was defined per established criteria as reduced MBFR (ratio < 2.0) in patients without coronary artery disease. Study outcomes included the change in MBFR following 6 months of ADT exposure and the incidence of reduced MBFR and CMD. McNemar’s test and Wilcoxon signed rank test were used for comparison of paired data. Results: Fifteen patients completed baseline myocardial perfusion PET imaging, of whom 13 completed follow-up imaging at 6 months. At baseline, the median (IQR) Framingham CV risk score was 30.4% (19.6, 35.5). One patient (7.7%) had reduced MBFR at baseline, and 5 additional patients (46.2%) developed newly reduced MBFR (ratio < 2.0) within 6 months of ADT initiation (p = 0.025). While no patients had CMD at baseline, 3 patients (30%) developed incident CMD (p = 0.083). MBFR declined in 69% of patients [median decline -0.32 (IQR -0.51, -0.22)] over 6 months ADT exposure. Conclusions: Myocardial perfusion PET imaging demonstrated a high incidence of reduced MBFR and CMD within 6 months of ADT initiation. These findings support further investigation of myocardial PET imaging, a widely-available clinical tool, as a potential research and clinical strategy to inform CV risk assessment in prostate cancer patients receiving ADT. Clinical trial information: NCT03535987.

No study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) impacting cognitive function in long-term testicular cancer survivors (TC-survivors). TC-survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those which assessed cognition. Medical record abstraction provided cancer and treatment history. Multivariable logistic regression examined relationships between potential associated factors and cognitive impairment. Among 678 TC-survivors [median age: 46 (IQR: 38, 54); median time-since-chemotherapy: 10.9 years (IQR = 7.9, 15.9)], 13.7% reported cognitive dysfunction. Hearing loss (OR = 2.02; P = .040), neuropathic-pain (OR = 2.06; P = .028), fatigue (OR = 6.11; P<.001), and anxiety/depression (OR = 1.96; P = .029) were associated with cognitive impairment in multivariable analyses. Being on disability (OR = 9.57; P = .002) or retired (OR = 3.64; P = .029) were also associated with cognitive declines. Factors associated with impaired cognition identify TC-survivors requiring closer monitoring, counseling, and focused interventions. Hearing loss, neuropathic-pain, fatigue, and anxiety/depression constitute potential targets for prevention or reduction of cognitive impairment in long-term TC-survivors.

Abstract Background: Studies have shown that taxane-treated breast cancer patients with African (AFR) ancestry experience worse peripheral sensory neuropathy (PSN), while African American vincristine-treated leukemia patients have less PSN than Europeans (EUR). We hypothesized that ancestral disparities may exist for cisplatin-induced neurotoxicities and may relate to differences in allele frequency and resultant gene expression of SNPs associated with these toxicities. Methods: In our Platinum Study of 1680 genotyped testicular cancer survivors (TCS), multidimensional scaling scores were anchored by the 1000 Genomes population to classify geographic ancestry. PSN (EORTC-CIPN20) and other toxicities plus clinical and lifestyle variables were examined for associations between geographic ancestry and phenotypes using logistic regression and Wilcoxon rank sum test. Genotyped SNPs with Fst > 0.25 in 1000 Genomes were identified and evaluated with GTEx data to find expression or splicing quantitative trait loci in nerve/brain tissue or for cisplatin-associated candidate genes, across all tissues. LDmatrix was used to find linkage disequilibrium. If a block of SNPs had R2 > 0.75, one independent SNP was kept for association analysis. Logistic regression with age at questionnaire completion and 10 genetic principal components as covariates was used to calculate the association between genotype and toxicity. Results: In an analysis of patients who received 400-450 mg/m2 of cisplatin including EUR (n=681), Asian (ASN) axis (n=44) and AFR (n=13), the odds ratio (OR) for any neuropathy vs. none in the AFR vs. EUR was 7.8 (P=0.049) and in the AFR vs. ASN axis (including East Asian 1000 Genomes populations) was 10.0 (P=0.034). TCS with AFR ancestry had significantly more vertigo. There were 19,874 SNPs for analysis from the genome-wide approach and 118 SNPs from the candidate gene approach. While associations between genotype and toxicity did not reach Bonferroni threshold, some SNPs had p-values in the 10-5 range. For PSN, one SNP had increased frequency of a risk allele in the AFR population while the other had increased frequency of a protective allele, while for vertigo, four SNPs had increased frequency of risk alleles in the AFR population. Of interest was rs34904346, in which the TT vs. AA genotype had an OR of 1.9 (p=2x10-5) for any vs. no PSN, with the T allele having 90% frequency in AFR ancestry patients versus ∼60% in other populations. This SNP and three other independent SNPs associated with PSN incidence (p∼10-3) are eQTLs for RNF24 in nerve tissue, which interacts with membrane proteins that regulate intracellular calcium levels. Conclusions: We show preliminary evidence for the role of differing risk allele frequencies across populations in explaining disparities in cisplatin-induced PSN and vertigo, likely in combination with structural and environmental factors. Genotyping risk alleles could customize dosing, treatment, and post-treatment monitoring to benefit all cisplatin-treated patients. Citation Format: Swetha Nakshatri, Paul C. Dinh, Darren R. Feldman, Robert J. Hamilton, Chunkit Fung, David J. Vaughn, Christian Kollmannsberger, Robert Huddart, Lawrence H. Einhorn, Nancy J. Cox, Lois B. Travis, Eileen Dolan. Impact of population pharmacogenomics on cisplatin-induced neurotoxicities [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 C051.

Background and objective Until recently, the standard first-line treatment for advanced urothelial carcinoma (UC) was platinum-based combination chemotherapy followed by avelumab maintenance therapy for patients without progressive disease (PD). For patients with advanced UC who experience PD or recurrence, standard-of-care treatment is pembrolizumab monotherapy based on the phase 3 KEYNOTE-045 study. This post hoc analysis of the KEYNOTE-045 study evaluated the efficacy of pembrolizumab compared with chemotherapy by the best response to prior platinum-based chemotherapy. Methods Patients with advanced UC that progressed or recurred after first-line platinum-based chemotherapy were randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 wk (Q3W) for ≤2 yr or investigator’s choice of chemotherapy (paclitaxel [175 mg/m2], docetaxel [75 mg/m2], or vinflunine [320 mg/m2], each Q3W). Endpoints included overall survival (OS) from the initiation of the last treatment prior to death, objective response rate (ORR), and duration of response (DOR) as per Response Evaluation Criteria in Solid Tumors version 1.1 from the date of the first response. Key findings and limitations An objective response to pembrolizumab was observed in all groups in terms of a prior response to first-line platinum-based chemotherapy. Median OS, ORR, and median DOR were numerically greater with pembrolizumab than with chemotherapy across subgroups. Patients with PD as the best response to prior platinum-based chemotherapy had the poorest OS outcomes. Limitations include a lack of formal hypothesis testing. Conclusions and clinical implications When compared with chemotherapy, prolonged OS and durable responses to second-line pembrolizumab were observed independently of the response to or type of prior platinum-based chemotherapy. These findings further support pembrolizumab as second-line treatment for advanced UC.

BACKGROUND:No study has quantified the impact of pain and other adverse health outcomes on global physical and mental health in long-term US testicular cancer survivors or evaluated patient-reported functional impairment due to pain. METHODS:Testicular cancer survivors given cisplatin-based chemotherapy completed validated surveys, including Patient-Reported Outcomes Measurement Information System v1.2 global physical and mental health, Patient-Reported Outcomes Measurement Information System pain questionnaires, and others. Multivariable linear regression examined relationships between 25 adverse health outcomes with global physical and mental health and pain-interference scores. Adverse health outcomes with a β^  of more than 2 are clinically important and reported below. RESULTS:Among 358 testicular cancer survivors (median age = 46 years, interquartile range [IQR] = 38-53 years; median time since chemotherapy = 10.7 years, IQR = 7.2-16.0 years), median adverse health outcomes number was 5 (IQR = 3-7). A total of 12% testicular cancer survivors had 10 or more adverse health outcomes, and 19% reported chemotherapy-induced neuropathic pain. Increasing adverse health outcome numbers were associated with decreases in physical and mental health (P < .0001 each). In multivariable analyses, chemotherapy-induced neuropathic pain (β^ = -3.72; P = .001), diabetes (β^ = -4.41; P = .037), obesity (β^ = -2.01; P = .036), and fatigue (β^ = -8.58; P < .0001) were associated with worse global mental health, while being married or living as married benefited global mental health (β^ = 3.63; P = .0006). Risk factors for pain-related functional impairment included lower extremity location (β^ = 2.15; P = .04) and concomitant peripheral artery disease (β^ = 4.68; P < .001). Global physical health score reductions were associated with diabetes (β^ = -3.81; P = .012), balance or equilibrium problems (β^ = -3.82; P = .003), cognitive dysfunction (β^ = -4.43; P < .0001), obesity (β^ = -3.09; P < .0001), peripheral neuropathy score (β^ = -2.12; P < .0001), and depression (β^ = -3.17; P < .0001). CONCLUSIONS:Testicular cancer survivors suffer adverse health outcomes that negatively impact long-term global mental health, global physical health, and pain-related functional status. Clinically important factors associated with worse physical and mental health identify testicular cancer survivors requiring closer monitoring, counseling, and interventions. Chemotherapy-induced neuropathic pain must be addressed, given its detrimental impact on patient-reported functional status and mental health 10 or more years after treatment.

PURPOSE:The role of elective pelvic nodal irradiation in salvage radiotherapy (sRT) remains controversial. Utilizing 18F-DCFPyL PET/CT, this study aimed to investigate differences in disease distribution after whole pelvic (WPRT) or prostate bed (PBRT) radiotherapy and to identify risk factors for pelvic lymph node (LN) relapse. METHODS:This retrospective study included patients with PSA > 0.1 ng/mL post-radical prostatectomy (RP) or post-RP and sRT who underwent 18F-DCFPyL PET/CT. Disease distribution on 18F-DCFPyL PET/CT after sRT was compared using Chi-square tests. Risk factors were tested for association with pelvic LN relapse after RP and salvage PBRT using logistic regression. RESULTS:979 18F-DCFPyL PET/CTs performed at our institution between 1/1/2022 - 3/24/2023 were analyzed. There were 246 patients meeting criteria, of which 84 received salvage RT after RP (post-salvage RT group) and 162 received only RP (post-RP group). Salvage PBRT patients (n = 58) had frequent pelvic nodal (53.6%) and nodal-only (42.6%) relapse. Salvage WPRT patients (n = 26) had comparatively lower rates of pelvic nodal (16.7%, p = 0.002) and nodal-only (19.2%, p = 0.04) relapse. The proportion of distant metastases did not differ between the two groups. Multiple patient characteristics, including ISUP grade and seminal vesicle invasion, were associated with pelvic LN disease in the post-RP group. CONCLUSION:At PSA persistence or progression, salvage WPRT resulted in lower rates of nodal involvement than salvage PBRT, but did not reduce distant metastases. Certain risk factors increase the likelihood of pelvic LN relapse after RP and can help inform salvage RT field selection.

5042 Background: The focus of Testicular Cancer (TC) has shifted towards survivorship due to the high cure rates. With the increase in TC survivors population, long-term cardiovascular disease (CVD) have been suggested to be strongly linked with earlier treatment for TC by various hospital based small studies. As it is crucial to investigate this relationship at a population level to develop early prevention strategies to improve TC survivors' overall quality of life (QoL), we analyzed the U.S. The Behavioral Risk Factor Surveillance System (BRFSS) to describe the long-term outcomes of TC survivors in a real-world random population sample. Methods: Using BRFSS cycles between 2014 and 2022, we pulled all patients who reported having a history of TC and compared them to the rest of the men's population sample who had no history of cancer diagnosis. Using national complex weights, we estimated each group outcomes proportions. Further, we evaluated several complex-weighted logistic regression models adjusted for different covariates to describe the association of high blood pressure, high cholesterol, diabetes, BMI of >25, angina, myocardial infarction (MI), and coronary heart disease (CHD). Results: Out of 3,077,806 participants, we identified 308 with a history of TC and 1,169,061 men with no history of cancer. After calculating descriptive demographics, our modeling analysis showed a consistent significant association in reporting history of Angina (OR range from 3.84 to 4.27), CHD or MI (OR range from 2.92 to 3.14). see table. Conclusions: Real-world data indicate alarming results of high prevalence CVD in TC survivors; our results confirm previously reported results from hospital-based cohorts. Our findings support immediate actions to develop and implement preventative strategies in TC survivors. [Table: see text]

e17088 Background: The SPPORT trial demonstrated that salvage whole pelvic radiotherapy (sWPRT) after radical prostatectomy (RP) reduced prostate cancer progression compared to salvage prostate bed radiotherapy (sPBRT), at the expense of greater toxicity. To identify pts most appropriate for sWPRT, we studied the incidence of and risk factors associated with radiologic relapse after sPBRT on 18F-DCFPyL PET, a sensitive new imaging modality. Methods: We analyzed 538 18F-DCFPyL PET/CTs performed at our large academic institution and screened for pts who had biochemical recurrence (BCR), defined as PSA > 0.2 ng/mL, after receiving sPBRT for persistent or recurrent PSA. Risk factors including pathologic T stage (pT), pathologic Gleason score (pGS), seminal vesicle invasion (SVI), positive margins, perineural invasion (PNI), PSA at RP (PSA1), prior to RT (PSA2), and at time of scan (PSA3), and PSA doubling time after sPBRT (PSADT) were obtained. Associations between risk factors and radiographic relapse were quantified with logistic regression, with a p < 0.05 defined as significant. Results: 38 pts with BCR after sPBRT were identified. Median values were: pt age = 69.5 years (interquartile range 64 – 74), PSA1 = 7.83 ng/mL (4.7 – 11.5), PSA2 = 0.26 (0.1 – 0.8), PSA3 = 0.71 (0.5 – 2.2), PSA DT = 9.8 (5.3 – 18.2). Pt characteristics were: pT (pT2, 46% of pts; pT3a/b, 54%), pGS ( < 7, 11%; 3+4, 32%; 4+3, 39%; > 7, 18%), 19% w/ SVI, 68% w/ positive margins, 93% w/ PNI and 80% (of evaluable pts) w/ high-risk decipher score. 42% of pts received salvage ADT with sPBRT. 68% of pts had detectable disease on 18F-DCFPyL PET. Radiologic relapse in pelvic LNs was present in 47% of all pts, and 32% of pts had relapse only in the pelvic nodes. 26% of pts had distant metastases (DM) on imaging. Only 13% of pts had DM without pelvic LN involvement. Between pts with pelvic LN only relapse (n = 12) and pts without radiographic disease (n = 12), age, pT, pGS, SVI, margins, ADT, PSA1-3 and PSADT did not differ on univariate or multivariate analyses. On the univariate analysis between pts with DM (n = 10) and without DM (n = 28), only PSA3 (p < 0.05) was associated with radiographic relapse, and pT trended toward a negative association (p< 0.10) with DM. Only PSA3 (p < 0.10) trended toward association with DM in a multivariate analysis using age, pT, margins, ADT, and PSA2-3. Conclusions: Pts with biochemical relapse after sPBRT had frequent high-risk pathology. Aside from PSA3, no risk factors were predictive of detectable pelvic nodal or DM disease. However, most pts with detectable disease had pelvic LN involvement, suggesting that a substantial portion of these high-risk pts may have benefited from whole-pelvic RT. Further data on risk factors will help inform selection of pts appropriate for salvage whole pelvic RT.

12092 Background: Taxane-treated breast cancer patients with genetically African ancestry have worse PSN than other groups. However, no study has examined the association between ancestry and PSN after cisplatin-based chemotherapy. Increased risk could be partially explained by differing risk allele frequencies across populations for alleles increasing the general vulnerability to PSN or altering drug metabolism. Methods: The Platinum Study enrolled cisplatin-treated testicular cancer survivors (TCS) who completed clinical exams and surveys. A PSN score was derived from the mean of 8 sensory items (using EORTC-CIPN20), assigning severity on a 0-2 scale. Multidimensional scaling scores for each TCS were calculated, plotted and anchored by data from the 1000 Genomes Reference population to determine genetic ancestry. Multinomial logistic regression assessed the association between genetic ancestry and PSN. To determine risk alleles for PSN and allele frequencies across populations, risk allele panels were created, including ancestry-informative markers (AIMs) determined by the AncestrySNPMiner tool. Allele frequencies were calculated in each group; SNPs with frequency differences > 0.3 in the African (AFRAFR) population vs. others were included. For filtering the AIMs, GTEx data was used to identify expression quantitative trait loci (eQTL) or splicing quantitative trait loci (sQTL) in nerve/brain tissue. Multinomial logistic regression assessed associations between SNP genotype and PSN phenotype for SNPs with differing allele frequencies across populations. Results: Despite small numbers of non-Europeans, TCS with African ancestry had increased incidence and severity of PSN vs. TCS with European ancestry. In a subset analysis of EUR (n = 681) and AFRAFR (n = 13) patients who received 400-450 mg/m 2 of cisplatin, the relative risk ratio (RRR) in the AFRAFR vs. EUR TCS of severe neuropathy vs. none was 7.96 (P = 0.074) and the RRR for any neuropathy vs. none was 7.79 (P = 0.049). There were 394 independent AIMs with significant ( > 0.3) allele frequency differences between the AFRAFR and other populations that were eQTLs and/or sQTLs in nerve/brain tissue. Using multinominal logistic regression between genotype and phenotype for all TCS (n = 1513) with covariates for age at survey and 10 genetic principal components: 16 SNPs had P-values < 0.05 for severe PSN vs. none and/or any PSN vs. none. Although not statistically significant with multiple testing corrections, these suggestively significant SNPs could be potentially validated in additional populations. Conclusions: These results are preliminary evidence for the potential importance of differing risk allele frequencies across populations in explaining some disparities in cisplatin-related PSN. If confirmed, genotyping for risk variants could impact treatment decisions and enable monitoring to mitigate PSN.