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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.

PURPOSE Ototoxicity is a prominent side effect of cisplatin-based chemotherapy. There are few reports, however, estimating its prevalence in well-defined cohorts and associated risk-factors. METHODS Testicular cancer (TC) survivors given first-line cisplatin-based chemotherapy completed validated questionnaires. Descriptive statistics evaluated ototoxicity prevalence. We compared patients with and without tinnitus or hearing loss using Chi-square test, two-sided Fisher's Exact test, or two-sided Wilcoxon Rank Sum test. To evaluate ototoxicity risk factors, a backward selection logistic regression procedure was performed. RESULTS Of 145 TC survivors, 74% reported ototoxicity: 68%-tinnitus; 59% hearing loss; and 52% reported both. TC survivors with tinnitus were more likely to indicate hypercholesterolemia (P=0.008), and difficulty hearing (PCONCLUSIONS Ototoxicity risk factors included age, cisplatin dose, cardiovascular risk factors, and family-history of hearing loss. Three of four TC survivors report some type of ototoxicity; thus, follow-up of cisplatin-treated survivors should include routine assessment for ototoxicity with provision of indicated treatments. IMPLICATIONS FOR CANCER SURVIVORS Survivors should be aware of risk factors associated with ototoxicity. Referrals to audiologists before, during, and after cisplatin treatment is recommended.

Purpose:Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (>1) severe neurotoxicities.Experimental Design:The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case–control genome-wide association study (GWAS; cases, n = 104 and controls, n = 196) was also performed.Results:Age at clinical examination (P = 6.4 × 10−16) and cumulative cisplatin dose (P = 5.4 × 10−4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension (P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P = 0.01), Raynaud phenomenon (P = 3.7 × 10−9), and symptoms consistent with peripheral motor neuropathy (P = 4.3 × 10−14) after age and dose adjustment. These patients also reported poorer overall health (P = 2.7 × 10−5) and a greater use of psychotropic medications (P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P = 3.9 × 10−5) and FAM20C (P = 5.5 × 10−5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines.Conclusions:Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor.

The Platinum Study CAO GWAS results for SNPs previously implicated in cisplatin-associated hearing loss.

Supplementary data from Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms

The design of the study, GWAS results, clinical characteristics are included in the supplemental data.

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

Supplementary Table S1 and S2

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.

Purpose:Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy.Experimental Design:TCS (n = 762) were dichotomized to cases (moderate/severe tinnitus; n = 154) and controls (none; n = 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed.Results:Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P = 0.007) and cumulative cisplatin dose (P = 0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared with 300 (P = 0.41), but doses >400 mg/m2 (median 580, range 402–828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25–12 kHz, P < 0.0001), and reported more vertigo (OR = 6.47; P < 0.0001) and problems hearing in a crowd (OR = 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR = 2.4; P = 0.003). GWAS suggested a variant near OTOS (rs7606353, P = 2 × 10−6) and OTOS eQTLs were significantly enriched independently of that SNP (P = 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q = 0.007).Conclusions:CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.

Purpose:Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1–35 years after CBC and evaluate genetic contributions to these levels.Experimental Design:Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model.Results:Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P = 2.13 × 10−3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P = 6.58 × 10−3). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; P = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, P = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P = 4.6 × 10−8, a SNP intronic to MYH14).Conclusions:This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.

Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO).Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4–12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding.Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 1.4 × 10−8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P values in the GWAS (P = 0.048).Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. Clin Cancer Res; 23(13); 3325–33. ©2016 AACR.

Purpose: Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs).Experimental Design: TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial.Results: Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; P = 2 × 10−9), smoking (OR, 1.54; P = 0.004), excess drinking (OR, 1.83; P = 0.007), and hypertension (OR, 1.61; P = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; P = 2.6 × 10−9) and weight gain adjusted for years since treatment (OR per Δkg/m2, 1.05; P = 0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5 expression as associated with CisIPN (P value for each < 5 × 10−6) with replication of RPRD1B meeting significance criteria (Fisher combined P = 0.0089).Conclusions: CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of RPRD1B. Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. Clin Cancer Res; 23(19); 5757–68. ©2017 AACR.

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).

Deficits in speech understanding constitute one of the most severe consequences of hearing loss. Here we investigate the clinical and genetic risk factors for symmetric deterioration of speech recognition thresholds (SRT) among cancer survivors treated with cisplatin.SRT was measured using spondaic words and calculating the mean of measurements for both ears with symmetric SRT values. For clinical associations, SRT-based hearing disability (SHD) was defined as SRT≥15 dB hearing loss and clinical variables were derived from the study dataset. Genotyped blood samples were used for GWAS with rank-based inverse normal transformed SRT values as the response variable. Age was used as a covariate in association analyses.SHD was inversely associated with self-reported health (p = 0.004). Current smoking (p = 0.002), years of smoking (p = 0.02), BMI (p 0.001), and peripheral motor neuropathy (p = 0.003) were positively associated with SHD, while physical activity was inversely associated with SHD (p = 0.005). In contrast, cumulative cisplatin dose, peripheral sensory neuropathy, hypertension, and hypercholesterolemia were not associated with SHD. Although no genetic variants had an association p value 5 × 10Current results improve our understanding of risk factors for SRT deterioration in cancer survivors. Higher BMI, lower physical activity, and smoking are associated with SHD. Larger samples would allow for expansion of the current findings on the genetic architecture of SRT.

Background It is unknown how body fat distribution modulates the cardiometabolic risk of testicular cancer survivors after cisplatin-based chemotherapy. Methods For 455 patients enrolled in the Platinum Study at Memorial Sloan Kettering Cancer Center, visceral (VAT) and subcutaneous (SAT) adipose tissue was quantified on prechemotherapy computed tomography. The VAT-to-SAT ratio was calculated as a quantitative measure of central adiposity. Endpoints were incidence of new posthemotherapy cardiometabolic disease (new antihypertensive, lipid-lowering, or diabetes medication), and postchemotherapy Framingham risk scores. Cox models and linear regression with interaction terms were applied. Postchemotherapy body fat distribution was analyzed in 108 patients. All statistical tests were 2-sided. Results The baseline median age was 31 years (interquartile range [IQR] = 26-39 years), body mass index (BMI) was 26 kg/m2 (IQR = 24-29 kg/m2), and the VAT-to-SAT ratio was 0.49 (IQR = 0.31-0.75). The median follow-up was 26 months (IQR = 16-59 months). Higher prechemotherapy VAT-to-SAT ratios inferred a higher likelihood of new cardiometabolic disease among patients with a BMI of 30 kg/m2 or greater (age-adjusted hazard ratio = 3.14, 95% confidence interval = 1.02 to 9.71, P = .047), but not other BMI groups. The prechemotherapy VAT-to-SAT ratio was associated with postchemotherapy Framingham risk scores in univariate regression analysis (exp(β)-estimate: 2.10, 95% confidence interval = 1.84 to 2.39, P Conclusions In testicular cancer survivors, central adiposity is associated with increased cardiometabolic risk after cisplatin-based chemotherapy, particularly in obese or young men. Weight gain after chemotherapy occurs preferentially in the visceral compartment, providing insight into the pathogenesis of cardiovascular disease in this population.

Purpose: Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (>1) severe neurotoxicities. Experimental Design: The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case–control genome-wide association study (GWAS; cases, n = 104 and controls, n = 196) was also performed. Results: Age at clinical examination (P = 6.4 × 10−16) and cumulative cisplatin dose (P = 5.4 × 10−4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension (P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P = 0.01), Raynaud phenomenon (P = 3.7 × 10−9), and symptoms consistent with peripheral motor neuropathy (P = 4.3 × 10−14) after age and dose adjustment. These patients also reported poorer overall health (P = 2.7 × 10−5) and a greater use of psychotropic medications (P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P = 3.9 × 10−5) and FAM20C (P = 5.5 × 10−5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines. Conclusions: Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor.

To provide new information on factors associated with discrepancies between patient-reported and audiometrically defined hearing loss (HL) in adult-onset cancer survivors after cisplatin-based chemotherapy (CBCT) and to comprehensively investigate risk factors associated with audiometrically defined HL.A total of 1410 testicular cancer survivors (TCS) ≥6 months post-CBCT underwent comprehensive audiometric assessments (0.25 to 12 kHz) and completed questionnaires. HL severity was defined using American Speech-Language-Hearing Association criteria. Multivariable multinomial regression identified factors associated with discrepancies between patient-reported and audiometrically defined HL and multivariable ordinal regression evaluated factors associated with the latter.Overall, 34.8% of TCS self-reported HL. Among TCS without tinnitus, those with audiometrically defined HL at only extended high frequencies (EHFs) (10 to 12 kHz) (17.8%) or at both EHFs and standard frequencies (0.25 to 8 kHz) (23.4%) were significantly more likely to self-report HL than those with no audiometrically defined HL (8.1%) [odds ratio (OR) = 2.48; 95% confidence interval (CI), 1.31 to 4.68; and OR = 3.49; 95% CI, 1.89 to 6.44, respectively]. Older age (OR = 1.09; 95% CI, 1.07 to 1.11, p0.0001), absence of prior noise exposure (OR = 1.40; 95% CI, 1.06 to 1.84, p = 0.02), mixed/conductive HL (OR = 2.01; 95% CI, 1.34 to 3.02, p = 0.0007), no hearing aid use (OR = 5.64; 95% CI, 1.84 to 17.32, p = 0.003), and lower education (OR = 2.12; 95% CI, 1.23 to 3.67, p = 0.007 for high school or less education versus postgraduate education) were associated with greater underestimation of audiometrically defined HL severity, while tinnitus was associated with greater overestimation (OR = 4.65; 95% CI, 2.64 to 8.20 for a little tinnitus, OR = 5.87; 95% CI, 2.65 to 13.04 for quite a bit tinnitus, and OR = 10.57; 95% CI, 4.91 to 22.79 for very much tinnitus p0.0001). Older age (OR = 1.13; 95% CI, 1.12 to 1.15, p0.0001), cumulative cisplatin dose (300 mg/m2, OR = 1.47; 95% CI, 1.21 to 1.80, p = 0.0001), and hypertension (OR = 1.80; 95% CI, 1.28 to 2.52, p = 0.0007) were associated with greater American Speech-Language-Hearing Association-defined HL severity, whereas postgraduate education (OR = 0.58; 95% CI, 0.40 to 0.85, p = 0.005) was associated with less severe HL.Discrepancies between patient-reported and audiometrically defined HL after CBCT are due to several factors. For survivors who self-report HL but have normal audiometric findings at standard frequencies, referral to an audiologist for additional testing and inclusion of EHFs in audiometric assessments should be considered.

Significantly increased risks of cardiovascular disease occur in testicular cancer survivors given cisplatin-based chemotherapy. The postulated mechanism of platinum-based chemotherapy’s vascular toxicity has been thought secondary to its different early- and late- effects on vascular injury, endothelial dysfunction, and induction of a hypercoagulable state. We highlight for the first time the similarities between platinum-associated vascular adverse events and the vascular toxicity associated with other xenobiotic-metal contaminants. The vascular toxicity seen in large epidemiologic studies of testicular cancer survivors may in part be similar and mechanistically linked to the risk seen in environmental heavy metal contaminants linked to cardiovascular disease. Future research should be directed to better understand the magnitude of the adverse cardiovascular effects of platinum and to elucidate the underlying mechanisms of action.

Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1–35 years after CBC and evaluate genetic contributions to these levels. Experimental Design: Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires, and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a biexponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model. Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted P = 2.13 × 10−3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted P = 6.58 × 10−3). Patients with high residual platinum levels experienced greater Raynaud phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; P = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, P = 0.07). GWAS identified one single-nucleotide polymorphism (SNP) meeting genome-wide significance, rs1377817 (P = 4.6 × 10−8, a SNP intronic to MYH14). Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels.

Background: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. Patients and Methods: Eligible TCS were Results: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7–68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to 2 (OR, 2.08; P= .011) or ≥30 kg/m2 (OR, 2.36; P= .005) compared with 2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; PP= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed. Conclusions: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.

10550 Background: Cranial radiation therapy (CRT) for pediatric cancer often results in ototoxicity in the form of hearing loss and tinnitus. We sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with cranial radiation. Methods: Relationships between age at last observation, sex, cumulative CRT dose and self-reported ototoxicity were evaluated for hearing loss and tinnitus among 1,991 (tinnitus) and 2,198 (hearing loss) survivors in the Childhood Cancer Survivor Study who received CRT. Logistic regression evaluated associations with non-genetic risk factors and comorbidities as well as SNP dosages in GWAS of CRT-related tinnitus (cases: 146; controls: 1,845) and hearing loss (cases: 270; controls: 1,928). Results: Males were more likely to report CRT-related tinnitus (9.4% vs. 5.4%; p = 5.81x10−4) and hearing loss (14.0% vs. 10.7%; p = 0.02) than females after adjusting for dose and age at last observation. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: p < 2.00x10−16; hearing loss: p = 6.35x10−9), take antidepressants (tinnitus: p = 0.02; hearing loss: p = 0.01) and report poorer overall health (tinnitus: p = 9.40x10−7; hearing loss: p = 1.30x10−6) compared to survivors without tinnitus or hearing loss after age-adjustment. GWAS of CRT-related tinnitus revealed a prominent signal in chromosome 1 led by rs203248 (p = 1.50x10−9), while GWAS of CRT-related hearing loss identified rs332013 (p = 5.79x10−7) in chromosome 8 and rs67522722 (p = 7.78x10−7) in chromosome 6 as approaching genome-wide significance. Replication analysis in an independent cohort of pediatric cancer survivors (SJLIFE) indicated that rs67522722, intronic to ATXN1, a gene associated with the neurodegenerative disorder spinocerebellar ataxia type 1, was significantly associated with CRT-related hearing loss (p = 0.03). Enrichment analysis and LD score regression with previous GWAS results of cisplatin-related hearing loss and tinnitus in testicular cancer survivors showed no detectable enrichment in genetic architecture with CRT-related hearing loss and tinnitus, respectively. Conclusions: Radiation-associated ototoxicity was associated with sex, several neuro-otological symptoms, increased antidepressant use and poorer self-reported health. GWAS of CRT-related hearing loss identified rs67522722 that was replicated in an independent cohort of pediatric cancer survivors.

e24089 Background: Cisplatin is one of the most used cytotoxic drugs worldwide, but few studies have comprehensively evaluated CIS-TINN in adult-onset cancer survivors. It is critical to identify survivors with high degrees of handicap and related risk factors, as tinnitus (TINN) is strongly related to adverse health outcomes (AHO) including reduced quality of life, and poorer physical and mental health. Methods: Eligible cisplatin-treated testicular cancer survivors (TCS) (aged < 60 y at diagnosis) completed comprehensive, validated health surveys, including the 20-item Tinnitus Primary Function Questionnaire (TPFQ). TPFQ assesses the 4 main TINN-impaired domains (see Table), each with a response metric of 0% (no interference) to 100% interference by TINN, with final impairment groupings of 0-16% (none/minimal), 17-42% (mild/moderate), and 43-100% (significant). TPFQ measures were compared by 2-sided signed-rank tests. Multinomial logistic regression models (adjusted for age, income, education, yrs since therapy, cisplatin dose, BMI, smoking, hypertension, and hearing loss (HL)) tested for associations with TINN severity. Results are shown as OR [95% CI], p-value. Results: Among 213 TCS [median age 46 y (IQR: 38-52 y); median time since therapy: 10.6 y (IQR: 6.8-16.6 y)], the most common AHOs were CIS-TINN (60%), and HL (60%). For TCS with CIS-TINN, the mean degree of reported interference across all TPFQ domains was 21% (median: 15, IQR: 3-33). TCS with CIS-TINN reported significantly greater interference with emotion (median: 22, range 5-40) than with concentration (median 13, IQR: 1.0-37, p = .004), hearing (median: 10, IQR: 0-30, p < .001), and sleep (median: 2.4, IQR: 0-21, p < .001). Conclusions: Following cisplatin chemotherapy, CIS-TINN is a leading AHO and often reported with HL and reduced quality of life. Severe CIS-TINN was associated with greater handicap on the TPFQ as well as with depression, cognitive dysfunction, and hearing aid use. Overall, however, TCS with CIS-TINN and HL reported underutilization of hearing aids.[Table: see text]

12080 Background: No study has systematically evaluated the impact of AHOs on PROMIS-validated measures of physical and mental health in TCS. Patient-reported outcomes are increasingly recognized as crucial in TCS follow-up, given their young age at diagnosis and high cure rates. Methods: Eligible TCS (age < 60 yr at diagnosis, given first-line cisplatin-based chemotherapy (CHEM)) completed comprehensive health surveys, prescription drug usage, and PROMIS global physical health and global mental health measures. PROMIS scores were compared to US subpopulation norms for similar-age men. 2017-2018 NHANES data were compared with select survey responses. Linear regression examined the relationship between individual AHOs (pain, obesity, cisplatin-induced peripheral neuropathy (CIPN)), cisplatin-related AHOs (CIPN, hearing loss, vertigo, tinnitus, renal disease), cardiovascular (CVD) AHOs (7 AHO), and all AHOs taken together (24 AHOs), with PROMIS global physical and mental health measures. Regression models were adjusted for age, cisplatin dose, time since CHEM, education, income, smoking, and alcohol. Results: Among 213 TCS (median age at evaluation: 46 yr; IQR: 38-52 yr; median time since CHEM completion: 10.6 yr; IQR: 6.8-16.6 yr), the most common AHOs were tinnitus (60%), self-reported hearing loss (60%), CIPN (55%), and Raynaud Phenomenon (43%). The median number of AHOs was 5 (IQR: 3-7), and 12% of TCS had ≥10 AHOs. Only 1.4% of TCS had no AHOs. Compared to NHANES men without cancer, controlling for age, education, and race, fewer TCS currently smoked (3% vs. 22%; P

12120 Background: Cisplatin is one of the most commonly used ototoxic drugs, but no study has quantified the handicap imposed by CIHL in U.S. adult-onset cancer survivors. Identification of survivors with high degrees of handicap and related risk factors is vital, as hearing loss (HL) in the general population is strongly related to adverse health outcomes, including cognitive decline, dementia, and poor mental health and social well-being. Methods: Eligible testicular cancer survivors (TCS) (age < 60 y at diagnosis, given first line cisplatin) completed comprehensive health surveys, including the validated 25-item Hearing Handicap Inventory for Adults (HHIA). HHIA quantifies emotional (13 items) and social difficulties (12 items) related to HL; for each scale (0-100%), based on their responses, TCS were grouped into 3 handicap levels: 0-16% (none/minimal), 17-42% (mild/moderate), and 43-100% (significant) following HHIA recommendations. A Spearman correlation evaluated the associations between increasing HL severity and HHIA group. The association between HL and reported cognitive dysfunction was evaluated by a logistic regression analysis adjusted for age, income, education, yrs since therapy, cisplatin dose, BMI, smoking, and hypertension, with results presented as OR[CI], p-value. Results: Among 213 TCS [median age at evaluation, 46 y (IQR: 38-52 y); median time since cisplatin completion, 10.6 y (IQR: 6.8-16.6 y)], CIHL was reported by 127 TCS (60%). Of TCS with CIHL, 31% reported some degree of related handicap (for total HHIA scale: 13% TCS and 18% TCS reporting mild/moderate and significant handicap, respectively). HL severity was significantly correlated with handicap level in all domains (social, ρ = 0.85, p

12083 Background: Patients with relapsed/refractory germ cell tumors are often cured with tandem platinum-based HDCT followed by autologous stem cell transplant in the ≥2nd line treatment setting. A comprehensive assessment of long-term AHO (adverse health outcomes) in TCS cured with HDCT has not been previously described. Methods: Testis cancer survivors (TCS) at least 1 year after HDCT and treated at Indiana University were eligible. TCS were asked to complete a comprehensive, well validated survey regarding 19 different AHO. TCS demographics, disease characteristics, treatment received, and AHO were collected. Results: From 2/2021-1/2022, 118 eligible TCS were invited. 70 TCS completed the survey (59.3% completion rate). TCS received HDCT followed by autologous stem cell transplant in the 2nd (91.4%), 3rd (7.1%) or 4th line (1.4%) setting. At the time of survey completion, 93% of respondents were at least two years from HDCT (range 1.6-16.2 y) with a median age of 42 y (range 24.8-66.6 y). Median age at the time of original germ cell tumor diagnosis was 32 y (range 17.4-56.8 y). TCS reported a median of 3 AHO with 37% of participants reporting 5 or more AHO. 90% of participants reported tinnitus, 91% experienced hearing impairment, and 52% required the use of hearing aids. Additionally, 46% TCS noted peripheral neuropathy and 26% reported problems with balance/vertigo/dizziness. Prevalence of kidney disease was 10%, and 24% TCS experienced erectile dysfunction. In regards to physical activity, 47% of participants were not participating in vigorous physical activity (defined as > 6 mets/week). 16% TCS reported use of medications to treat anxiety and/or depression, and 19% required testosterone replacement therapy. The prevalence of hypertension, coronary artery disease, Raynaud phenomenon, hypercholesterolemia, diabetes, and thyroid disease were 13%, 1%, 17%, 12%, 4%, and 6% respectively. Conclusions: Despite the high cure rate of HDCT, TCS report a substantial burden of morbidity with the majority experiencing ototoxicity, and with half of the TCS requiring hearing aids. Special attention to these AHO and efforts to develop ototoxicity prevention approaches are urgently needed for this patient population.

e24066 Background: Cisplatin treatment is used for many cancers, including testicular, ovarian, and head and neck malignancies. Cancer survivors with multiple cisplatin-related toxicities can have poor health-related quality of life (HRQOL). Identification of clinical and genetic factors that predict the risk of these neurotoxicities is critical. Methods: Testicular cancer survivors (TCS) enrolled in the Platinum Study completed surveys, underwent physical examination, extensive audiometric testing, and phlebotomy for genotyping and serum platinum analysis. Cases included TCS with two or more severe toxicities (hearing loss [HL], tinnitus, and peripheral sensory neuropathy [PSN]), defined as follows: hearing threshold > 40dB based on geometric mean of 4-12kHz, responding yes to “Do you have ringing or buzzing in the ears?” and/or EORTC-CIPN20 scores in the severe range for items related to sensory neuropathy. Controls were restricted to TCS without any toxicities. TCS with a single toxicity were excluded from analyses. Penalized logistic regression lasso method was used to create the model to predict the binary outcome. Creatinine clearance and residual serum platinum levels were calculated. Polygenic risk scores (PRS) for traits commonly associated with pharmacokinetics and HL, tinnitus, and PSN were calculated for TCS in the training (n = 284) and validation (n = 157) data sets using PRS publicly available in The Polygenic Score Catalog using PRSice 2.3.3. Models were trained and tested in R 4.1.2. Results: A model to assess the risk of developing multiple severe neurotoxicities that could be used without blood work and additional analysis was developed. Clinical predictors incorporated into the model were age at testicular cancer diagnosis, age at phlebotomy, weight and height. PRS incorporated were age-related sensorineural hearing loss (PGS000762), body fat percentage (PGS002133), creatinine in urine (PGS001944), and peripheral nervous system disease (PGS002039). The accuracy of this model was 77.71%, which was significantly greater than the no information rate (NIR) of 65.61% (p = .00067). The positive and negative predictive values (PPV and NPV) were 72.09% and 79.82%, respectively. The AUC-ROC was 0.804. Adding residual platinum levels and creatinine clearance increased the accuracy of the model to 78.34%, which was significantly greater than the NIR (p = .00035). The PPV was 75.00% and the NPV was 79.49%. The area under the receiver operating characteristic curve (AUC-ROC) was 0.832. Conclusions: TCS are often faced with multiple severe neurotoxicities such as HL, tinnitus, and PSN, which impact HRQOL for many decades. If confirmed, a penalized regression model using clinical and genetic characteristics can predict the risk of developing these phenotypes to guide clinicians in treatment and post-treatment management plans.

5033 Background: Given the young age at diagnosis and effective therapies (cisplatin-based chemotherapy and/or surgical approaches), most TCS gain many decades of life. Attention has been drawn to the potential downsides of these treatment successes, including the accelerated development of age-related diseases. Previous studies have suggested that cytotoxic treatment and carcinogenesis are associated with epigenetic changes, leading to premature biological aging processes. Methods: We recruited 24 TCS managed with surgical approaches alone and 24 cisplatin-treated TCS (all also treated with surgical removal of the cancerous testis) and who had histologic/serological germ cell tumor diagnosis before 55 years, and were disease-free at routine follow up. We also included 310 cancer-free race- and age-matched (+/- 5 years) males from a normative cohort, i.e., the Coronary Artery Risk Development in Young Adults (CARDIA) Study. We undertook genome-wide interrogation of blood DNA methylation (DNAm) using the Illumina Infinium Methylation EPIC BeadChip (EPIC array). We quantified aging using DNAm GrimAge, a validated, composite biomarker consisting of DNAm surrogate biomarkers of seven plasma proteins associated with various age-related conditions plus a DNAm surrogate of smoking pack-years. The comparison analysis was adjusted for age, race, smoking status, blood cell type proportions estimated using DNA methylation batch effect, and other laboratory-related technical factors. Results: The median chronological age of TCS was 28 years (range 19-64) with 25% smokers. Compared to their chronological age, TCS managed with surgical approaches alone had a mean GrimAge of 39.4 years (i.e., 9.2 years older, paired t-test P = 0.001), and cisplatin-treated TCS had a mean GrimAge of 45.2 years (i.e., 14.9 years older, paired t-test P < 0.001). Compared to the matched CARDIA controls, TCS managed with surgical approaches alone were on average 3.0 years epigenetically older (P = 0.093), and cisplatin-treated TCS were on average 11.2 years epigenetically older (P < 0.001), suggesting an increasing trend with treatment burden (P-trend < 0.001). Conclusions: Our data showed a faster epigenetic aging process in TCS. Consistent with previous studies, our data is in line with the hypothesis that TC cytotoxic treatment may induce premature aging. Although TCS managed with surgical approaches alone had no exposure to cytotoxic drugs, their epigenetic age may also be accelerated due to TC development and/or risk factors that contributed to it as well as post-therapy factors.

Background: This study examined sociodemographic factors, cisplatin-related adverse health outcomes (AHO), and cumulative burden of morbidity (CBMPt) scores associated with medication use for anxiety and/or depression in testicular cancer survivors (TCS). Methods: A total of 1,802 TCS who completed cisplatin-based chemotherapy ≥12 months previously completed questionnaires regarding sociodemographic features and cisplatin-related AHOs [hearing impairment, tinnitus, peripheral sensory neuropathy (PSN), and kidney disease]. A CBMPt score encompassed the number and severity of cisplatin-related AHOs. Multivariable logistic regression models assessed the relationship of individual AHOs and CBMPt with medication use for anxiety and/or depression. Results: A total of 151 TCS (8.4%) used medications for anxiety and/or depression. No cisplatin-related AHOs were reported by 511 (28.4%) participants, whereas 622 (34.5%), 334 (18.5%), 287 (15.9%), and 48 (2.7%), respectively, had very low, low, medium, and high CBMPt scores. In the multivariable model, higher CBMPt scores were significantly associated with medication use for anxiety and/or depression (P < 0.0001). In addition, tinnitus (P = 0.0009), PSN (P = 0.02), and having health insurance (P = 0.05) were significantly associated with greater use of these medications, whereas being employed (P = 0.0005) and vigorous physical activity (P = 0.01) were significantly associated with diminished use. Conclusions: TCS with higher CBMPt scores had a higher probability of using medications for anxiety and/or depression, and conversely, those who were employed and physically active tended to have reduced use of these medications. Impact: Healthcare providers should encourage TCS to increase physical activity to improve both physical and mental health. Rehabilitation programs should assess work-related skills and provide career development counseling/training.

Survivors of adolescent and young adult cancers (AYAs) often live 50 to 60 years beyond their diagnosis. This rapidly growing cohort is at increased risk for cancer- and treatment-related ‘late effects’ that persist for decades into survivorship. Recognition of similar issues in pediatric cancer survivors has prompted the development of evidence-based guidelines for late effects screening and care. However, corresponding evidence-based guidelines for AYAs have not been developed. We hosted an AYA survivorship symposium for a large group of multidisciplinary AYA stakeholders (approximately 200 were in attendance) at Princess Margaret Cancer Centre (Toronto, Ontario, Canada) to begin addressing this disparity. The following overview briefly summarizes and discusses the symposium’s stakeholder-identified high-priority targets for late effects screening and care and highlights knowledge gaps to direct future research in the field of AYA survivorship. This overview, although not exhaustive, is intended to stimulate clinicians to consider these high-priority screening and care targets when seeing survivors in clinical settings and, ultimately, to support the development of evidence-based late effects screening and care guidelines for AYAs.

BackgroundFew data exist on the relationship of cisplatin-related adverse health outcomes (AHOs) with disability, unemployment, and self-reported health (SRH) among testicular cancer survivors (TCS).MethodsA total of 1815 TCS at least 1 year postchemotherapy underwent clinical examination and completed questionnaires. Treatment data were abstracted from medical records. A cumulative burden of morbidity score (CBMPt) encompassed the number and severity of platinum-related AHOs (peripheral sensory neuropathy [PSN], hearing loss, tinnitus, renal disease). Multivariable regression assessed the association of AHOs and CBMPt with employment status and SRH, adjusting for sociodemographic and clinical characteristics. Unemployment was compared with a male normative population of similar age, race, and ethnicity.ResultsAlmost 1 in 10 TCS was out of work (2.4%, disability leave; 6.8%, unemployed) at a median age of 37 years (median follow-up = 4 years). PSN (odds ratio [OR] = 2.89, 95% confidence interval [CI] = 1.01 to 8.26, grade 3 vs 0, P = .048), renal dysfunction defined by estimated glomerular filtration rate (OR = 12.1, 95% CI = 2.06 to 70.8, grade 2 vs 0, P = .01), pain (OR = 10.6, 95% CI = 4.40 to 25.40, grade 2 or 3 vs 0, P ConclusionsOur findings have important implications regarding treatment-associated productivity losses and socioeconomic costs in this young population. Survivorship care strategies should include inquiries about disability and unemployment status, with efforts made to assist affected TCS in returning to the workforce.

Background No large US population-based study focusing on recent decades, to our knowledge, has comprehensively examined risks of second malignant solid and hematological neoplasms (solid-SMN and heme-SMN) after testicular cancer (TC), taking into account initial therapy and histological type. Methods Standardized incidence ratios (SIR) vs the general population and 95% confidence intervals (CI) for solid-SMN and heme-SMN were calculated for 24 900 TC survivors (TCS) reported to the National Cancer Institute’s Surveillance, Epidemiology, and End Results registries (1973–2014). All statistical tests were two-sided. Results The median age at TC diagnosis was 33 years. Initial management comprised chemotherapy (n = 6340), radiotherapy (n = 9058), or surgery alone (n = 8995). During 372 709 person-years of follow-up (mean = 15 years), 1625 TCS developed solid-SMN and 228 (107 lymphomas, 92 leukemias, 29 plasma cell dyscrasias) developed heme-SMN. Solid-SMN risk was increased 1.06-fold (95% CI = 1.01 to 1.12), with elevated risks following radiotherapy (SIR = 1.13, 95% CI = 1.06 to 1.21) and chemotherapy (SIR = 1.36, 95% CI = 1.12 to 1.41) but not surgery alone (SIR = 0.83, 95% CI = 0.75 to 0.92). Corresponding risks for seminoma were 1.13 (95% CI = 1.06 to 1.21), 1.28 (95% CI = 1.02 to 1.58), and 0.87 (95% CI = 0.74 to 1.01) and for nonseminoma were 1.05 (95% CI = 0.67 to 1.56), 1.25 (95% CI = 1.08 to 1.43), and 0.80 (95% CI = 0.70 to 0.92), respectively. Thirty-year cumulative incidences of solid-SMN after radiotherapy, chemotherapy, and surgery alone were 16.9% (95% CI = 15.7% to 18.1%), 10.1% (95% CI = 8.8% to 11.5%), and 8.8% (95% CI = 7.8% to 9.9%), respectively (P Conclusions We report statistically significant excesses of solid-SMN affecting 1 in 6 TCS 30 years after radiotherapy, and 2.7-fold risks of leukemias after chemotherapy, mostly acute myeloid leukemia. Efforts to minimize chemotherapy and radiotherapy exposures for TC should continue. TCS should be counseled about cancer prevention and screening.

Purpose: Invasive cervical cancer (ICC) is one of the HIV-associated cancers with a high burden in Nigeria. ICC occurs at relatively younger age in HIV infected women, with HIV known to promote aging and related diseases, including cancer. DNA methylation changes with increasing age, various health-related exposures, and age-related health outcomes, suggesting a role of DNA methylation in biological aging and disease. We sought to understand the effect of HIV infection on epigenetic age acceleration (EpiAgeAccel) in Nigerian women with ICC. Methods: Epigenetic age (EpiAge) was estimated by Horvath's calculator using genome-wide methylation data in 116 cervical tissue samples from three groups of women: a) HIV positive with ICC (n=39); b) HIV positive and cancer-free (n=53); and c) HIV negative with ICC (n=24). EpiAgeAccel was computed as the regression residuals of EpiAge against chronological age (ChronAge), representing the independent deviation of EpiAge from ChronAge. We compared EpiAgeAccel across the 3 HIV/ICC groups using multiple linear regressions adjusting for ChronAge, education, parity, employment, cancer stage, body mass index, and study site. Among the ICC women, we compared EpiAgeAccel between 26 tumor tissues and their surrounding normal tissues using paired t-tests, stratified by HIV status. Results: EpiAgeAccel among HIV positive women with ICC was 4.5 years higher than HIV positive and cancer-free women (p=0.019). We did not find substantial differences in EpiAgeAccel between HIV-positive women with ICC and HIV-negative women with ICC. EpiAgeAccel was 7.9 and 2.9 years higher in tumor tissues compared to the surrounding normal tissues among HIV positive women (p=0.021) and negative women (p=0.295), respectively. Conclusion: EpiAge is accelerated in cervical tissue of HIV-infected women with ICC. EpiAgeAccel may be a potential biomarker for ICC screening and early detection for women living with HIV in low- and middle-income countries. Citation Format: Jonah Musa, Kyeezu Kim, Yinan Zheng, Yishu Qu, Brian Joyce, Jun Wang, Lois Travis, Demirkan Gursel, Olugbenga Silas, Fatimah Abdulkareem, Godwin Imade, Alani Akanmu, Jian-Jun Wei, Masha Kocherginsky, Kwnag-Youn Kim, Firas Wehbe, Chad Achenbach, Rose Anorlu, Melissa Simon, Atiene Sagay, Folasade Ogunsola, Robert Murphy, Lifang Hou. Accelerated Epigenetic Age among HIV-infected Nigerian Women with Invasive Cervical Cancer [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 71.

Purpose: Cisplatin is one of the most commonly used chemotherapy drugs worldwide and one of the most ototoxic. We sought to identify genetic variants that modulate cisplatin-associated ototoxicity (CAO). Experimental Design: We performed a genome-wide association study (GWAS) of CAO using quantitative audiometry (4–12 kHz) in 511 testicular cancer survivors of European genetic ancestry. We performed polygenic modeling and functional analyses using a variety of publicly available databases. We used an electronic health record cohort to replicate our top mechanistic finding. Results: One SNP, rs62283056, in the first intron of Mendelian deafness gene WFS1 (wolframin ER transmembrane glycoprotein) and an expression quantitative trait locus (eQTL) for WFS1 met genome-wide significance for association with CAO (P = 1.4 × 10−8). A significant interaction between cumulative cisplatin dose and rs62283056 genotype was evident, indicating that higher cisplatin doses exacerbate hearing loss in patients with the minor allele (P = 0.035). The association between decreased WFS1 expression and hearing loss was replicated in an independent BioVU cohort (n = 18,620 patients, Bonferroni adjusted P < 0.05). Beyond this top signal, we show CAO is a polygenic trait and that SNPs in and near 84 known Mendelian deafness genes are significantly enriched for low P values in the GWAS (P = 0.048). Conclusions: We show for the first time the role of WFS1 in CAO and document a statistically significant interaction between increasing cumulative cisplatin dose and rs62283056 genotype. Our clinical translational results demonstrate that pretherapy patient genotyping to minimize ototoxicity could be useful when deciding between cisplatin-based chemotherapy regimens of comparable efficacy with different cumulative doses. Clin Cancer Res; 23(13); 3325–33. ©2016 AACR.

We evaluated for the first time, to our knowledge, adverse health outcomes (AHOs) among US testicular cancer survivors (TCS) given chemotherapy (n = 381) vs surgery-only patients (n = 98) managed at a single institution, accounting for non-treatment-related risk factors to delineate chemotherapy’s impact. Chemotherapy consisted largely of bleomycin-etoposide-cisplatin (BEP) administered in three or four cycles (BEPx3, n = 235; BEPx4, n = 82). Incidence of at least 3 AHOs was lowest in surgery-only TCS and increased with BEPx3, BEPx4, and other cisplatin-based regimens (12.2%, 40.8%, 52.5%, 54.8%; P

Testicular cancer (TC) is the most common cancer among men aged 18 to 39 years. It is highly curable, with a 10-year relative survival approaching 95% due to effective cisplatin-based chemotherapy. Given the increasing incidence of TC and improved survival, TC survivors (TCS) now account for approximately 4% of all US male cancer survivors. They have also become a valuable cohort for adult-onset cancer survivorship research, given their prolonged survival. Commensurately, long-term treatment-related complications have emerged as important survivorship issues. These late effects include life-threatening conditions, such as second malignant neoplasms and cardiovascular disease. Moreover, TCS can also experience hearing loss, tinnitus, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, infertility, anxiety, depression, cognitive impairment, and chronic cancer-related fatigue. Characterization of the number and severity of long-term adverse health outcomes among TCS remains critical to develop risk-stratified, evidence-based follow-up guidelines and to inform the development of preventive measures and interventions. In addition, an improved understanding of the long-term effects of TC treatment on mortality due to noncancer causes and second malignant neoplasms remains paramount. Future research should focus on the continued development of large, well-characterized clinical cohorts of TCS for lifelong follow-up. These systematic, comprehensive approaches can provide the needed infrastructure for further investigation of long-term latency patterns of various medical and psychosocial morbidities and for more in-depth studies investigating associated etiopathogenetic pathways. Studies examining premature physiologic aging may also serve as new frontiers in TC survivorship research.

12004 Background: Cisplatin is an essential component of first-line chemotherapy for many cancers, but causes neurotoxicity, including hearing loss (CisHL), tinnitus (CisTinn), and peripheral sensory neuropathy (CisPNeuro). However, few opportunities exist to identify risk factors and comorbidities for cisplatin-induced neurotoxicities among large numbers of homogenously treated patients without the confounding effect of cranial radiotherapy. Methods: Within a well-characterized clinical cohort of 1,680 cisplatin-treated testicular cancer survivors, linear and logistic regression analysis were utilized to analyze associations of CisHL (n = 1,258), CisTinn (n = 1,217), and CisPNeuro (n = 1,653) with non-genetic risk factors. Genome-wide association studies and gene-based analysis were performed on each phenotype. Results: Cisplatin-induced neurotoxicities (CisHL CisTinn, CisPNeuro), adjusting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension (CisTinn: OR = 2.62, p < 0.0001; CisHL: β = 0.25, p = 8.5 x10-4; CisPNeuro: OR = 1.86, p < 0.0001) and were more likely to report their health as poor (CisTinn: OR = 0.54, p < 0.0001; CisHL: β = -0.11, p < 0.0001; CisPNeuro: OR = 0.61, p < 0.0001). Persistent vertigo was significantly associated with both CisTinn (OR = 7.18, p < 0.0001) and CisPNeuro (OR = 4.29, p < 0.0001). In addition, CisTinn was significantly associated with hypercholesterolemia (OR = 1.78, p = 0.01). Importantly, gene-based association analyses identified significant associations between CisTinn and WNT8A (n = 1,037, p = 2.52x10-6) , encoding a signaling protein important in germ cell tumors; and marginal significance between CisHL and TXNRD1 (n = 1,071, p = 4.21x10-6) , thioredoxin reductase-1, which plays a key role in redox regulation. In silico analysis showed high expression levels of TXNRD1 were significantly correlated with cellular resistance to cisplatin in central nervous system tumor cells (Spearman Rho = 0.35, p = 0.04; R2= 0.14, p = 0.03), indicating TXNRD1 is protective for cisplatin-induced cytotoxicity. Previously, rs62283056 in WFS1 found to be significantly associated with CisHL (n = 511; subset of current population), was marginally significant in an independent replication cohort (p = 0.06; n = 606; subset of current population). Conclusions: Cisplatin-induced neurotoxicities are significantly associated with multiple clinical characteristics, including hypertension and self-reported poor health. WNT8A and TXNRD1 are notable risk factors for CisTinn and CisHL, respectively . Future studies should further investigate these genes and their potential impact on chemotherapy strategies. This study, based on the largest number of testicular cancer survivors investigated to date, highlights the clinical importance of these iatrogenic toxicities and their associated risk factors.

12063 Background: Platinum levels are measurable in the serum for decades after cisplatin therapy and higher levels may be related to chemotherapy-induced toxicities. Since cisplatin is cleared exclusively by the kidney, we hypothesized that a genetic predictor of kidney function, an estimated glomerular filtration rate polygenic risk score (eGFR PRS), would significantly associate with serum platinum levels and could improve prediction models. Methods: Within a large well-characterized, multicenter clinical cohort of cisplatin-treated testicular cancer survivors (TCS), we conducted analyses on all patients with genetic data and serum platinum levels. Genotyping was performed on the HumanOmniExpressExome chip and standard QC measures were included. Serum platinum concentrations were quantified by inductively coupled plasma mass spectrometry. For all TCS, time since therapy (TIME) and cumulative cisplatin dose were collected. The eGFR PRS was developed from the Chronic Kidney Disease Genetics (CKDGen) consortium meta-analysis summary statistics using PRS-CS. Using principal component analysis, we restricted the analysis to TCS of genetically determined European ancestry, then calculated the genome-wide PRS for all participants. We performed Cox regression analyses to evaluate prediction models of serum platinum that included cumulative dose and TIME, as well as a model including eGFR PRS. Data are presented as median(interquartile range). Results: 901 patients were included in our analysis with a median diagnosis age of 31 (26 - 38) years, cumulative cisplatin dose of 400 (300-400) mg/m2, and time since first cisplatin dose of 4.6 (2.3-9.5) years. The median serum platinum level for all TCS was 305 (121-981) ng/L. When stratified into quartiles by eGFR PRS, TCS in the lowest quartile had a median serum platinum level of 316 (139-1014) ng/L while TCS in the highest had a median of 268 (106-731) ng/L. Comparison of two Cox regression models for serum platinum prediction, one including only cumulative dose and TIME as predictors and a second including dose, TIME, eGFR PRS, and an eGFR PRS*TIME interaction term, we determined the model including eGFR PRS had a lower AIC (14350 vs 16180) suggesting a more parsimonious model. Further, eGFR PRS was a significant independent predictor of serum platinum levels (p = 0.02) and the impact of eGFR PRS varies over time (eGFR PRS*TIME, p = 0.05). Conclusions: The genetic predictor of kidney function circumvents the use of renal function measures that may have been impaired by initial cisplatin administration. It is a significant independent predictor of serum platinum levels and consistent with expectation: TCS with higher genetically predicted kidney function had lower serum platinum levels. Our results suggest kidney function inferred by genetics may improve the prediction of serum platinum levels.

5025 Background: Cancer survivors are at increased risk of anxiety and depression that can affect health-related quality of life. There is no study to date that has examined the characteristics of testicular cancer survivors (TCS) taking medications for anxiety or depression since pharmacological interventions are typically reserved for more severe cases of these disorders. In this study, we aimed to examine sociodemographic factors, cisplatin-related adverse health outcomes (AHOs), and cumulative burden of morbidity (CBMPt) scores associated with medication use for anxiety and/or depression in TCS. Methods: A total of 1,802 TCS who completed CBCT ≥12 months previously completed validated questionnaires regarding sociodemographic features and cisplatin-related AHOs (hearing impairment, tinnitus, peripheral sensory neuropathy (PSN), kidney disease). Patients were recognized as users of medications for anxiety and/or depression if they used pharmacological classes of these medications and also indicated that the reason for use was for anxiety or depression. Individual AHOs were graded 0-to-4 based on severity according to NCI Common Terminology Criteria for Adverse Events version 4.03. A CBMPt score encompassed the number and severity of cisplatin-related AHOs. Multivariable logistic regression models assessed the relationship of individual AHOs and CBMPt with medication use for anxiety and/or depression. Results: A total of 151 TCS (8.4%) used medications for anxiety and/or depression. Any grade of HL, tinnitus, PSN, and kidney disease were reported by 37.9%, 39.5%, 55.2%, and 2.4% of 1,802 participants, respectively. No cisplatin-related AHO were reported by 511 (28.4%) participants, whereas 622 (34.5%), 334 (18.5%), 287 (15.9%), and 48 (2.7%), respectively, had very low, low, medium, and high CBMPt scores. Higher CBMPt scores were significantly associated with greater medication use for anxiety and/or depression (CBMPt scores of low (OR = 2.96, 95%CI, 1.67-5.24), medium (OR = 3.47, 95%CI, 1.95-6.18), and high (OR = 3.18, 95%CI, 1.22-8.3). A multivariable model including individual AHOs indicated that tinnitus ( P= 0.0009), PSN ( P= 0.02), and having health insurance (OR = 2.15, 95%CI, 1.01-4.56) were associated with significantly greater use of these medications; whereas being employed (OR = 0.39, 95%CI, 0.23-0.66) and vigorous physical activity (OR = 0.63, 95%CI,0.44-0.89) were associated with significantly diminished use. Conclusions: We found that TCS with higher CBMPt scores had a higher probability of using medications for anxiety and/or depression and conversely, those who were employed and physically active tended to have reduced use. These findings deserve further investigation in longitudinal studies. In the interim, healthcare providers should be aware of these associations in formulating survivorship care plans.