Testicular cancer survivors (TCS) experience excess cardiovascular disease (CVD) incidence and mortality. To address the urgent need for new risk prediction tools, we evaluated the AHA's 2024 PREVENT-equation among 1,759 TC survivors (TCS; median baseline age = 37 years). Baseline median 10- and 30-year CVD risks were 1.3% and 9.1%. Among evaluated survivors with follow-up (N = 737; median age = 45), each 5% increase in 10-year PREVENT risk conferred 2.94-fold odds (95%CI = 1.99-4.35, P < .001) of incident CVD. Those with 10-year PREVENT absolute risk defined as intermediate-high (≥7.5% per AHA) had 12.11-fold higher odds (P < .001). Associations were strongest after four cycles of etoposide/cisplatin (EPX4) (OR = 4.93, P < .001), possibly driven by lower eGFR and slightly older age (P < .001 each), and among TCS without vigorous baseline physical-activity (OR = 4.25, P < .001). EPX4 patients were among those less engaged in activity (P = .005). PREVENT equations, utilizing routine measures, can identify high-risk TCS, highlighting physical-activity as a key modifiable factor for early intervention.

BACKGROUND:This study aimed to quantify, for the first time, cumulative burden of morbidity (CBM) scores-including renal function-in long-term testicular cancer survivors (TCS) treated with contemporary NCCN-endorsed regimens of 4 cycles of etoposide/cisplatin (EPx4) or 3 or 4 cycles of bleomycin/etoposide/cisplatin (BEPx3/BEPx4). PATIENTS AND METHODS:A total of 798 TCS underwent baseline clinical examinations and completed follow-up questionnaires. Severity grades for adverse health outcomes (AHOs) and CBM scores were calculated. Adjusted ordinal logistic regression estimated odds ratios (ORs) for AHOs and CBM scores by treatment regimen. Baseline estimated glomerular filtration rate (eGFR) was analyzed for associations with cumulative cisplatin dose and selected follow-up AHOs. RESULTS:Median age at follow-up was 45 years (median, 11 years postchemotherapy); 516 (65%) TCS survived ≥10 years. Chemotherapy consisted largely of BEPx3 (n=317; 39.7%), EPx4 (n=198; 24.8%), or BEPx4 (n=99; 12.4%); 27 (3.4%) received etoposide/ifosfamide/cisplatin (VIPx4). TCS receiving EPx4 (vs BEPx3) had significantly increased odds of worse renal impairment (adjusted OR [aOR], 1.55; P=.035), ototoxicity (aOR, 1.48; P=.04), and neuropathy (aOR, 1.77; P=.002). Reduced eGFR (<90 mL/min/1.73 m2), observed in 41% of TCS, was associated with cumulative cisplatin dose (r = -0.149; P<.0001) and with 2- to 20-fold increased odds of developing hypertension (60-89 mL/min/1.73 m2: OR, 2.01; P=.001; 45-59 mL/min/1.73 m2: OR, 2.84; P=.040; 30-44 mL/min/1.73 m2: OR, 20.0; P=.001). Moderate-to-severe eGFR reductions (30-44 mL/min/1.73 m2) were also associated with significantly increased odds of developing hyperlipidemia (OR, 6.10; P=.032) and/or cardiovascular disease (CVD) (OR, 7.09; P=.023). Significantly increased odds of Raynaud phenomenon were associated with β-blocker use (OR, 2.17; P=.036), peripheral artery disease (OR, 3.14; P=.002), reduced eGFR (OR per 10 mL/min/1.73 m2 increase in eGFR, 0.90; P=.027), and BEPx4 (OR vs EPx4, 2.18; P=.003). CBM scores were similar after EPx4 compared with BEPx3 (aOR, 1.04; P=.83) but worse after BEPx4 (aOR, 1.77; P=.016) or VIPx4 (aOR, 2.24; P=.038). Self-reported global physical health correlated strongly with CBM score (P<.001) and chemotherapy regimen (P<.001). CONCLUSIONS:This multicenter, real-world study shows that long-term CBM scores after NCCN-endorsed EPx4 or BEPx3 are comparable, but statistically significant differences in cisplatin-related toxicities exist. Cisplatin dose-dependent reductions in eGFR are followed by significant excesses of hypertension, hyperlipidemia, and CVD.

Background:Cisplatin is broadly used, but it is nephrotoxic and ototoxic. No large-scale investigation has analysed cisplatin-related ototoxicity while considering quantified renal function, cumulative dose, comorbidities, and modifiable risk factors. Our aim was to fill this knowledge gap. Methods:The Platinum Study is a well-characterised multicentre cohort study of cisplatin-treated testicular cancer survivors enrolled 2012-18 in eight academic cancer centres in the USA, Canada, and the UK, with follow-up ongoing. Measures include audiometrically assessed hearing (0.25-12 kHz), real-world speech-in-noise perception, and hearing loss progression. Multivariable analyses evaluated associations of audiometrically-assessed hearing with estimated glomerular filtration rate (eGFR), comorbidities, health-behaviours, and cisplatin dose. Mediation analyses tested direct and indirect eGFR contributions to ototoxicity and eGFR-dose interactions. Findings:Among 1422 survivors (median age 38 years, IQR 31-47), ototoxicity affected 1061 (75%), and audiometrically-assessed hearing was significantly associated with cumulative cisplatin dose (β = 8.72 per 100 mg/m2, p = 0.0004), reduced eGFR (β = 3.90 per 20 mL/min/1.73 m2, p = 0.043), hypertension (β = 4.06, p = 0.0005), non-White race (β = 3.26, p = 0.014), physical inactivity (β = -0.24 per 1000 kCal/week, p = 0.034), and age (β = 5.21 per 5 years, p < 0.0001). Cisplatin dose significantly interacted with eGFR (p = 0.017); 7.2% (95% CI 0.9-18.8; p < 0.05) of cisplatin's ototoxicity was mediated through reduced eGFR and 5.6% (0.4-16.1; p < 0.05) through interaction effects. Poorer speech-in-noise perception was associated with cognitive dysfunction (β = 1.01, p = 0.026), hypercholesterolaemia without statin use (β = 0.71, p = 0.029), lower education (β = 0.91, p = 0.0098), and hearing loss severity (β = 0.08, p < 0.0001). Hearing loss progression was associated with age (β = 0.30, p < 0.0001), while statin use for hypercholesterolaemia was protective (β = -4.09, p = 0.0048). Interpretation:Cisplatin's dose-dependent ototoxicity is amplified by its nephrotoxicity, with the dose-response becoming stronger as eGFR worsens. Given age-related declines in both eGFR and hearing, follow-up of cisplatin-treated survivors should monitor both, and include strict control of cardiovascular risk factors. Statin use for hypercholesterolaemia appeared protective against hearing loss progression, suggesting a potential therapeutic intervention for reducing long-term auditory complications in this population. Funding:The National Cancer Institute.

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.

Cisplatin is an effective chemotherapeutic agent for treating many cancers. However, a major complication associated with cisplatin treatment is ototoxicity. Since the early 2000s, several genetic risk factors linked to cisplatin ototoxicity have been reported. However, the extent to which these genetic risk factors might be shared with those contributing to hearing difficulty in the general population remains unknown. In this study, we investigate if variants with reported links to increased risk of ototoxicity in cisplatin-treated cancer cohorts were also associated with hearing impairment in the general population in the results from a recent meta-analysis (Meta-study; 501,825 participants). Importantly, no significant associations were identified. We also compared association results from our recent genome-wide association study (GWAS) for hearing loss in male testicular cancer survivors (Pt-study; 1,071 participants) with those from both Meta-study and a meta-analysis of the male subset (Male-study; 223,081 participants). We observed evidence for colocalization at the rs7952909 locus across the Male-study and Pt-study results, however, with opposite directions of effects. Across pairwise comparisons, only two variants with matching directions of effects reached significance when relaxed selection cutoffs (10-3 or 10-4) were used. Collectively, our results suggest that genetic risk factors for cisplatin-induced ototoxicity and those for hearing difficulty in the general population are largely distinct.

Importance Cisplatin is highly ototoxic but widely used. Evidence is lacking regarding cisplatin-related hearing loss (CRHL) in adult-onset cancer survivors with comprehensive audiologic assessments (eg, Words-in-Noise [WIN] tests, full-spectrum audiometry, and additional otologic measures), as well as the progression of CRHL considering comorbidities, modifiable factors associated with risk, and cumulative cisplatin dose. Objective To assess CRHL with comprehensive audiologic assessments, including the WIN, evaluate the longitudinal progression of CRHL, and identify factors associated with risk. Design, Setting, and Participants The Platinum Study is a longitudinal study of cisplatin-treated testicular cancer survivors (TCS) enrolled from 2012 to 2018 with follow-up ongoing. Longitudinal comprehensive audiologic assessments at Indiana University and Memorial Sloan Kettering Cancer Center included 100 participants without audiometrically defined profound hearing loss (HL) at baseline and at least 3.5 years from their first audiologic assessment. Data were analyzed from December 2013 to December 2022. Exposures Factors associated with risk included cumulative cisplatin dose, hypertension, hypercholesterolemia, diabetes, tobacco use, physical inactivity, body mass index, family history of HL, cognitive dysfunction, psychosocial symptoms, and tinnitus. Main Outcomes and Measures Main outcomes were audiometrically measured HL defined as combined-ears high-frequency pure-tone average (4-12 kHz) and speech-recognition in noise performance measured with WIN. Multivariable analyses evaluated factors associated with risk for WIN scores and progression of audiometrically defined HL. Results Median (range) age of 100 participants at evaluation was 48 (25-67) years; median (range) time since chemotherapy: 14 (4-31) years. At follow-up, 78 (78%) TCS had audiometrically defined HL; those self-reporting HL had 2-fold worse hearing than TCS without self-reported HL (48 vs 24 dB HL; P < .001). A total of 54 (54%) patients with self-reported HL showed clinically significant functional impairment on WIN testing. Poorer WIN performance was associated with hypercholesterolemia (beta = 0.88; 95% CI, 0.08 to 1.69; P = .03), lower-education (F1 = 5.95; P = .004), and severity of audiometrically defined HL (beta = 0.07; 95% CI, 0.06 to 0.09; P < .001). CRHL progression was associated with hypercholesterolemia (beta = -4.38; 95% CI, -7.42 to -1.34; P = .01) and increasing age (beta = 0.33; 95% CI, 0.15 to 0.50; P < .001). Importantly, relative to age-matched male normative data, audiometrically defined CRHL progression significantly interacted with cumulative cisplatin dose (F1 = 5.98; P = .02); patients given 300 mg/m2 or less experienced significantly less progression, whereas greater temporal progression followed doses greater than 300 mg/m(2). Conclusions and Relevance Follow-up of cisplatin-treated cancer survivors should include strict hypercholesterolemia control and regular audiological assessments. Risk stratification through validated instruments should include querying hearing concerns. CRHL progression relative to age-matched norms is likely associated with cumulative cisplatin dose; investigation over longer follow-up is warranted.

Tinnitus is a common sensorineural complication that can occur de novo or after cancer treatments involving cisplatin or radiotherapy. Considering the heterogeneous etiology and pathophysiology of tinnitus, the extent to which shared genetic risk factors contribute to de novo tinnitus and cancer treatment-induced tinnitus is not clear. Here we report a GWAS for de novo tinnitus using the UK Biobank cohort with nine loci showing significantly associated variants (p < 5 x 10-8). To our knowledge, significant associations in four of these loci are novel, represented by rs7336872, rs115125870, rs1532898 and rs2537, with UBAC2, NUDT9, TGM4 and MPP2 as their nearest protein coding genes, respectively. Through quantitative comparison of results from GWAS of de novo tinnitus with GWAS of radiation-induced tinnitus, two intronic variants (rs7023227 and rs3780395) from a locus within immunoregulatory gene PD-L1 (CD274) reached the replication threshold using comparison thresholds of 10-5 and 10-4, with no other shared genetic risk factors identified. We did not observe shared genetic risk factors between de novo and cisplatin-induced tinnitus. Our results suggest that genetic risk factors are mainly distinct based on etiology of tinnitus and future efforts to study, prevent or treat tinnitus are expected to benefit from strategies that allow for distinction of cases based on the primary environmental risk factor.

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: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.

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.

Supplementary Figures and Tables for Clinical and Genome Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer Figure S1. Diagram of Data Collection Pipeline. Table S1. EORTC-CIPN20 questionnaire. Figure S2. Flow diagram of GWAS Quality Control Pipeline. Table S2. Additional Diagnosis and Treatment Characteristics of TCS cohort. Figure S3. Response frequencies for the EORTC-CIPN20 questionnaire from 680 patients. Figure S4. Principal Component Analysis (PCA) of EORTC-CIPN20 items. Figure S5. SNP-level GWAS. Table S3. Top 100 GWAS Results (p < 2.25 x 10-5) Table S4. Review of candidate gene studies implicating SNPs in cisplatin-induced neuropathy and their replication in the TCS study. Table S5. Review of previous GWAS of CIPN implicating SNPs and their replication in the TCS study. Table S6. Top PrediXcan results (P < 0.001).

PURPOSE Cisplatin is widely used and highly ototoxic, but patient-reported functional impairment because of cisplatin-related hearing loss (HL) and tinnitus has not been comprehensively evaluated. PATIENTS AND METHODS Testicular cancer survivors (TCS) given first-line cisplatin-based chemotherapy completed validated questionnaires, including the Hearing Handicap Inventory for Adults (HHIA) and Tinnitus Primary Function Questionnaire (TPFQ), each of which quantifies toxicity-specific functional impairment. Spearman correlations evaluated associations between HL and tinnitus severity and level of functional handicap quantified with the HHIA and TPFQ, respectively. Associations between HL or tinnitus and five prespecified adverse health outcomes (cognitive dysfunction, fatigue, depression, anxiety, and overall health) were evaluated. RESULTS HL and tinnitus affected 137 (56.4%) and 147 (60.5%) of 243 TCS, respectively. Hearing aids were used by 10% TCS (14/137). Of TCS with HL, 35.8% reported clinically significant functional impairment. Severe HHIA-assessed functional impairment was associated with cognitive dysfunction (odds ratio [OR], 10.62; P < .001), fatigue (OR, 5.48; P = .003), and worse overall health (OR, 0.19; P = .012). Significant relationships existed between HL severity and HHIA score, and tinnitus severity and TPFQ score ( P < .0001 each). TCS with either greater hearing difficulty or more severe tinnitus were more likely to report cognitive dysfunction (OR, 5.52; P = .002; and OR, 2.56; P = .05), fatigue (OR, 6.18; P < .001; and OR, 4.04; P < .001), depression (OR, 3.93; P < .01; and OR, 3.83; P < .01), and lower overall health (OR, 0.39; P = .03; and OR, 0.46; P = .02, respectively). CONCLUSION One in three TCS with HL report clinically significant functional impairment. Follow-up of cisplatin-treated survivors should include routine assessment for HL and tinnitus. Use of the HHIA and TPFQ permit risk stratification and referral to audiologists as needed, since HL adversely affects functional status and is the single largest modifiable risk factor for cognitive decline and dementia in the general population.

Top SNPs (P < 1 x 10-5) in the meta-analysis of The Platinum Study and St. Jude cohorts.

Supplemental Figures and Tables Supplemental Figure 1. GWAS and Quality Control Pipeline. Abbreviations: IBD: identity by descent; SD: standard deviation; MAF: minor allele frequency. Supplemental Table 1. Additional Clinical and Sociodemographic Characteristics for 1,010 Testicular Cancer Survivors According to Residual Platinum Values. Supplemental Table 2. Univariate Multinomial Regression of the Association Between Residual Platinum Values and Clinical Phenotypes Relevant to Cisplatin-Based Chemotherapy. Supplemental Table 3. Multinomial Regression of the Association Between Residual Platinum Values and Phenotypes Relevant to Cisplatin-Based Chemotherapy with Age at Diagnosis as a Covariate. Supplemental Table 4. GWAS Results (P < 0.0001).

Robustness of the enrichment of top GWAS SNPs in Mendelian deafness genes.

Supplementary Table S1 and S2