Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

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  • a From Indiana University, Melvin and Bren Simon Cancer Center, and Indiana University School of Nursing, Indianapolis, Indiana; University of Rochester Medical Center, James P. Wilmot Cancer Institute, Rochester, New York; Department of Medicine, University of Chicago, Chicago, Illinois; Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York; Division of Urology, Princess Margaret Cancer Centre, Toronto, Ontario; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Radiation Oncology, Dana-Farber Cancer Institute, and Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.

Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ≥25 kg/m2 (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (ORhighest vs lowest quartile, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment–associated MetS requires further characterization.

Testicular cancer (TC) is the most common cancer among men aged 18 to 39 years, with increasing incidence over the past 20 years.1 Cisplatin-based chemotherapy has resulted in unprecedented survival rates among patients with metastatic disease,2 with cure expected in 80%.3 Overall, the 5-year relative survival rate for all patients with TC is 95%.4 As a result, 1 in 600 men in the United States is now a TC survivor (TCS),5 with a gain of upwards of 40 years of life.6 Thus, TCS comprise a unique population in which to study the long-term adverse effects of cancer treatment in survivors of adult-onset cancer.7 In particular, TCS treated with chemotherapy experience up to a 7-fold increased long-term risk for cardiovascular disease (CVD) compared with controls.813

In the general population, metabolic syndrome (MetS) is a major risk factor for CVD.14 MetS is a constellation of interrelated CVD risk factors, including insulin resistance, hypertension, elevated triglyceride levels, decreased high-density lipoprotein (HDL) cholesterol levels, and obesity.14 Using various definitions, European studies of TCS have reported a wide variation in the prevalence of MetS, ranging from 13% to 39%.1519 Some investigations have demonstrated MetS risk to be higher among TCS compared with controls,1518 but others have not.19 Boer et al20 reported MetS to be more prevalent in TCS carrying the minor allele of a single nucleotide polymorphism (SNP), rs523349 (V89L), compared with wild-type (33% vs 19%; P=.032). This SNP is a nonsynonymous coding variant in the SRD5A2 gene, encoding steroid 5-α-reductase type II. The prevalence of MetS was particularly high (66.7%) in TCS who had low testosterone levels (<4.3 ng/mL) and carried a minor allele (homozygous or heterozygous) genotype.

Given the conflicting data on MetS prevalence in European studies of TCS and the lack of information in North American patients, we evaluated for the first time MetS and associated risk factors among a large cohort of North American TCS.21 We also examined the reported association of the rs523349 SNP with MetS in our patients.

Patients and Methods

Participants

The ongoing Platinum Study is evaluating the late consequences of platinum-based chemotherapy and has been approved by Institutional Review Boards at all participating institutions.21,22 Each participant provided written informed consent allowing access to medical records since cancer diagnosis. Eligibility criteria included a diagnosis of germ cell tumor (GCT) at age <55 years, treatment with first-line platinum-based chemotherapy, no salvage chemotherapy, no radiotherapy, and no antecedent chemotherapy for another primary cancer. All participants were disease-free at the time of clinical evaluation. We included in this analysis all TCS for whom blood samples had been analyzed and who had complete data on all MetS components.

Assessments

Sociodemographic, Lifestyle, and Behavioral Factors: TCS completed a questionnaire regarding health outcomes, lifestyle behaviors, and current prescription medications (including antihypertensive, diabetic, and lipid-lowering medications). Demographic information included age at cancer diagnosis and clinical evaluation, race, education, employment, and marital status. Smoking status was categorized as current, former, or never-smoker. Physical activity was reported as the average time per week engaged in various forms of exercise.23 Moderate- and vigorous-intensity physical activity were defined as participating in at least one activity per week with a metabolic equivalent of 3 to <6, or ≥6 metabolic equivalents, respectively.24,25

Data Collection From Medical Records: Study staff abstracted data according to a uniform protocol, using forms adapted from a prior study.22 Data included date of GCT diagnosis, histology and site of GCT, and, for each cytotoxic drug, name, dose, dates of administration, number of cycles, and cumulative dose. All data were entered into the eClinicalWorks system (Westborough, MA), supported by the study coordinating center.

Clinical Evaluation: TCS underwent a physical examination measuring height, weight, and waist circumference. Body mass index (BMI) was calculated as kg/m2. Blood pressure was measured twice after resting for 5 minutes and then averaged. Blood samples were drawn, time of last meal was recorded, and the samples were frozen and shipped to the central laboratory. Serum levels of testosterone, luteinizing hormone, lipids, creatinine, and soluble cell adhesion molecule-1 (sICAM-1), a known CVD biomarker,2628 were measured using commercial assays. Hypogonadism was defined using the FDA definition (total serum testosterone ≤3.0 ng/mL),29 which is commonly used in clinical practice.

DNA Genotyping and Imputation: DNA was extracted from blood samples collected at clinical evaluation. SNPs were genotyped on the HumanOmniExpressExome-8 BeadChip (Illumina, Inc., San Diego, CA) at the RIKEN Center for Integrative Medical Sciences. Because the SNP of interest is not called on this chip, we performed genotype imputation following standard quality control measures as previously described.30 Imputation was performed on the University of Michigan Imputation Server31 with the following parameters: 1000 Genomes Phase 1 (version 3) Shapeit2 (no singletons) reference panel, SHAPEIT phasing, and the EUR (European) population. Linkage disequilibrium (LD) structures around the variant of interest were determined using NIH's LDlink32 using the CEU (European) population.

Definition of MetS

MetS was defined using a modification of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III) Guidelines14 as the presence of ≥3 of the following (Table 1): (1) systolic blood pressure ≥130 mm Hg and/or diastolic blood pressure ≥85 mm Hg or use of antihypertensive medication; (2) abdominal obesity (waist circumference ≥102 cm); (3) self-reported diabetes and medication use; (4) HDL cholesterol level <40 mg/dL or lipid-lowering medication; and/or (5) serum triglyceride level ≥150 mg/dL (fasting) or ≥175 mg/dL (nonfasting). These MetS criteria were developed by several major organizations to represent one harmonized definition.14 Criteria for HDL and triglyceride cut points were adapted from recent guidelines.33

Control Group

Matched controls for selected comparisons were chosen from the National Health and Nutrition Examination Survey (NHANES) using 2 consecutive data sets (2011–2012 and 2013–2014), following methods applied by the St. Jude's Lifetime Cohort study.34 Controls (restricted to men without cancer) were matched 1:1 on race, age (within 5 years), and educational level.

Table 1.

Criteria Used to Define MetS

Table 1.

Statistical Analyses

Data were summarized, with medians (ranges) for continuous variables and proportions for categorical variables in 2 TCS subgroups defined by the presence or absence of MetS. The 2 groups were compared using the Pearson chi-square and 2-sided Wilcoxon rank sum tests on categorical and continuous variables, respectively. TCS were compared with controls using the Pearson chi-square test with regard to the prevalence of various MetS components, as well as other CVD risk factors not included in the NCEP ATP III criteria. A composite score was calculated based on the cut points for the individual MetS components, with a range of 0 to 5 (0 indicated no abnormal components). Based on MetS diagnostic criteria,14 participants with a composite score of 3 to 5 were classified with MetS.

To determine factors associated with MetS in TCS, a 2-step approach was used. First, logistic regression models were used to estimate the odds ratios (ORs), 95% confidence intervals (CIs), and P values for all clinical, demographic, behavioral, and laboratory measures. Second, factors that were significantly associated with MetS in univariate analyses were included in the multivariable model. All statistical analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC). All tests were 2-sided, with P values <.05 considered statistically significant.

Results

TCS Characteristics

Median time from chemotherapy completion to study enrollment was 4.7 years (range, 0.4–23.9). TCS with MetS (n=102) were significantly older at clinical evaluation compared with those without MetS (n=384; median, 44.4 vs 36.6 years; P<.001) (supplemental eTable 1, available with this article at JNCCN.org). TCS received either bleomycin/etoposide/cisplatin (BEP; 54.7%) or etoposide/cisplatin (EP; 33.1%), but MetS prevalence did not differ by treatment regimen nor by cumulative dose of cisplatin or bleomycin. TCS with MetS had a significantly higher prevalence of obesity (60.8% vs 22.7%; P<.001), hypogonadism (46.1% vs 26.8%; P<.001), and elevated sICAM levels compared with those without MetS (supplemental eTable 2).

Comparison With Matched Controls

TCS were more likely to have hypertension (43.2% vs 30.7%; P<.001) but less likely to have low HDL levels (23.7% vs 34.8%; P<.001) and abdominal obesity (28.2% vs 40.1%; P<.001) compared with controls (Table 2). Although overall MetS prevalence in TCS and controls was comparable (21.0% vs 22.4%; P=.59), there were significant differences in other CVD risk factors not included in the NCEP ATP III definition. TCS were more likely to have low-density lipoprotein (LDL) cholesterol levels ≥160 mg/dL (17.7% vs 9.3%; P<.001), total cholesterol levels ≥240 mg/dL (26.3% vs 11.1%; P<.001), and BMI ≥25 kg/m2 (75.1% vs 69.1%; P=.04). Additionally, a larger proportion of TCS compared with controls reported participating in moderate- (93.8% vs 42.4%; P<.001) or vigorous-intensity (66.7% vs

Table 2.

Comparison of MetS, its Components, and Selected CVD Risk Factors

Table 2.
33.5%; P<.001) physical activity, and were less likely to be current smokers (9.3% vs 25.9%; P<.001).

Factors Associated With MetS in TCS

Results of a univariate analysis of factors potentially associated with MetS are shown in Table 3. Factors statistically significant on univariate analysis were incorporated into a multivariate model, in which age, low serum testosterone level, and sICAM level remained significantly associated with MetS (Table 4). For every 10-year increase in age at clinical evaluation, MetS risk increased by 1.7-fold (95% CI, 1.33–2.30; P<.001). Testosterone level ≤3.0 ng/mL was associated with a significant 2-fold increased risk of MetS compared with higher levels (P=.005). MetS risk increased monotonically with increasing sICAM level (OR, 3.58 comparing highest vs lowest quartile; P=.001). Educational level, marital status, alcohol intake, and vigorous-intensity physical activity were not associated with MetS risk in the multivariate model.

Genetic Association of MetS With SRD5A2

The SNP rs523349 showed high imputation quality (R2=1), call rate (>0.99), and perfect Hardy-Weinberg equilibrium (P=1.0). This imputed SNP was in perfect LD with a nearby genotyped SNP, rs12467911. LDlink revealed that the expected LD R2 in a European population is 0.975. Genotype frequencies by MetS status are presented in Table 5. The variant genotype did not correlate with MetS (P=.61).

Discussion

Our investigation represents the largest to date to address the prevalence of metabolic abnormalities in TCS treated with contemporary platinum-based regimens and is the only investigation of North American patients. At a median age of only 38 years, 3 in 4 TCS were overweight or obese, 43% had hypertension, and a significantly higher proportion had elevated LDL or total cholesterol levels compared with matched controls. Overall, 1 in 5 TCS had MetS according to the NCEP ATP III definition.14 No difference was seen in the prevalence of MetS by treatment regimen (BEP vs EP) nor by cumulative dose of cisplatin or bleomycin. Significant risk factors for MetS included hypogonadism, increasing

Table 3.

Univariate Analysis of Potential Risk Factors for MetS

Table 3.
Table 4.

Multinomial Logistic Regression Analyses of Potential Correlates With Metabolic Syndromea

Table 4.
age, and increasing sICAM level. No association with MetS was observed with the variant genotype for rs523349.

Westerink et al35 recently pointed out that the etiology of cancer treatment-induced MetS (CTIMetS) differs from MetS in the general population, where sedentary lifestyle, along with excess caloric intake, are the primary causes.14 In contrast, CTIMetS is multifactorial and differs by cancer diagnosis, treatment, and patient characteristics. Surgery,36,37 radiotherapy,38 chemotherapy,18,19,39 and hormonal therapy4044 have each been shown to induce CTIMetS. In TCS, hypogonadism and chemotherapy, rather than sedentary behavior, are likely the main causes for metabolic abnormalities. The TCS in our study were at least twice more likely than controls to engage in moderate- or vigorous-intensity physical activity. Despite this, we did not find a significant difference in the prevalence of MetS between TCS and NHANES controls, likely because MetS criteria originally developed for the general population14 does not reflect the full spectrum of metabolic abnormalities seen in TCS.

The relationships between hypogonadism with MetS and CVD in the general population4550 and TCS13,1619 are well-established. In our study, approximately one-third of survivors were hypogonadal, which is higher than reported in the general population51 but not unexpected because our participants had undergone orchiectomy. In our cohort, TCS with hypogonadism were twice as likely to have MetS in multivariate analysis. Hypogonadism also correlated with obesity, hypertension, and high LDL and total cholesterol levels in univariate analysis (data not shown). Hypogonadism may also explain the lower prevalence of low HDL in TCS compared with controls because androgens can have a suppressive effect on HDL.52 In addition, the smaller waist circumference in TCS compared with controls, while having a higher BMI, may be explained by increased femoral adipose tissue deposition observed in hypogonadal compared with eugonadal patients.53

Table 5.

Comparison of Prevalence of MetS in Genotype Groups for SNP rs523349 (V89L) in SRD5A2 Gene

Table 5.

Studies of the effect of testosterone replacement on MetS and CVD risk in TCS are sparse. Although such investigations in older men in the general population showed favorable effects on lipid metabolism, bone mineral density, muscle mass, and fat-free body mass,54,55 the effects of testosterone replacement on CVD risk have been conflicting.56 One clinical trial showed an excess of CVD adverse events in older men treated with testosterone compared with placebo,57 but another trial in a similar population did not.58 However, these findings may not apply to young and physically active TCS. For young TCS with symptomatic hypogonadism, testosterone replacement should be considered, and future research is needed to address both the benefits and risks of testosterone replacement therapy.

Inflammation is considered a critical pathogenic component of atherosclerosis.59 de Haas et al17 provided a comprehensive assessment of proinflammatory markers in chemotherapy-treated TCS, finding significantly elevated levels of several markers in patients with MetS versus those without. Herein, we found that sICAM levels increased with increasing MetS risk even after adjustment for age and additional risk factors in multivariate analysis. sICAM is an adhesion molecule that serves a critical role in the adhesion and transmigration of leucocytes across the endothelial wall, an early step in the formation of the atherosclerotic plaque.60 Epidemiologic studies have shown strong, positive associations between sICAM levels and future CVD events in apparently healthy men and women.2628 Vaughn et al61 reported sICAM levels to be higher in TCS treated with chemotherapy than with surgery alone, suggesting a direct mechanism for CVD through chemotherapy-induced endothelial dysfunction. In vitro studies further support this hypothesis.6264

There has been increasing interest in personalizing care for cancer survivors. One approach is to identify genetic variants that can predispose survivors to selected adverse health outcomes.7 In this study, we evaluated an SNP (rs523349) in the steroid 5-α-reductase type II gene recently associated with MetS in TCS.20 This SNP decreases enzyme activity and thus the conversion of testosterone to the more active metabolite dihydrotestosterone.65 The frequencies of the wild-type and variant rs523349 in our cohort were comparable to those in Boer et al20 (Table 5); however, in our cohort, with more than twice the sample size, we found no association with MetS. An approach that accounts for multiple genes involved in relevant pathways may better identify clinically actionable results that could inform risk-adapted management approaches.

The prevalence of MetS in our patients is within the range (17%–41%) reported in European studies of platinum-treated TCS (summarized in supplemental eTable 3).13,1519 Although each European series used slightly different criteria for MetS than applied in this study, it is still possible to compare the prevalence of individual MetS components. The most pronounced component of MetS among our TCS was hypertension (43%). Haugnes et al19 found significantly increased risks of hypertension in patients treated with cisplatin compared with those treated surgically (≥45% vs 34%, respectively), as did Willemse et al18 (31% vs 14%, respectively). The association between cisplatin-based chemotherapy, hypertension, and CVD in TCS is well-established, and is reviewed elsewhere.7,64

Strengths and Limitations

Strengths of our study include the large number of patients, detailed medical chart abstraction, and use of contemporary and homogeneous platinum-based chemotherapy regimens. We used a definition for hypogonadism that is clinically relevant and easily applicable to clinical practice.

However, any cross-sectional design has potential limitations and does not allow us to infer causation of evaluated risk factors to MetS, although prospective data collection is planned for this cohort. Additionally, the SNP of interest was imputed and not genotyped, although it was in perfect LD with a nearby genotyped SNP. Our study participants also largely represent well-educated TCS followed at major academic institutions, and the prevalence of MetS may be higher in community-based settings. Moreover, participants in the population-based NHANES cohort may not be comparable to our TCS in terms of all relevant sociodemographic and lifestyle variables.

Conclusions and Recommendations

There is a high prevalence of metabolic abnormalities in TCS treated with chemotherapy at a relatively young age and shortly after completion of cancer treatment. The etiology of MetS in cancer survivors likely differs from the general population,35 thus, applying criteria developed for the general population to cancer survivors may underestimate CVD risk. Importantly, longitudinal cohort studies of survivors are needed to develop more accurate risk prediction models for CVD. Meanwhile, it is reasonable to assume that management strategies for components of MetS may have similar positive effects on CVD prevention. Providers are encouraged to screen and adequately treat TCS for hypertension, dyslipidemia, and hypogonadism. Further, all TCS should be encouraged to adopt practices consistent with a healthy lifestyle, including maintenance of ideal body weight, avoidance of tobacco use, and engagement in regular exercise.

The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

This study was funded by NCI (R01 CA157823, to Dr. Travis). Dr. Gathirua-Mwangi is supported by 3R01CA196243-02S1 and K05CA175048. The NCI had no role in the design of the study; the collection, analysis, or interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication.

Presented in part as an oral presentation at the 2017 Cancer Survivorship Symposium: Advancing Care and Research; January 27–28, 2017; San Diego, California. Research was also featured in a video interview in The ASCO Post Newsreels and in an article with an accompanying editorial in The ASCO Post on March 10, 2017.

See JNCCN.org for supplemental online content.

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If the inline PDF is not rendering correctly, you can download the PDF file here.

To view members of the Platinum Study Group and Platinum Study Group Advisory Committee, see eAppendices 1 and 2 (available with this article at JNCCN.org).

Author contributions: Study concept and design: Sesso, Einhorn, Travis. Financial support: Travis. Administrative support: Travis. Provision of study materials or patients: Fung, Feldman, Hamilton, Vaughn, Beard, Einhorn, Travis. Data acquisition: Abu Zaid, Feldman, Cook, Althouse, Travis. Data analysis and interpretation: All authors. Manuscript preparation: All authors. Final approval of manuscript: All authors.

Correspondence: Lois B. Travis, MD, ScD, Indiana University, Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, RT433, Indianapolis, IN 46202. E-mail: lbtravis@iu.edu

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