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

Abstract

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. 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, ), 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. We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; <.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; <.001) or abdominal obesity (28.2% vs 40.1%; <.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; =.59), did not differ by treatment (=.20), and was not related to rs523349 (=.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%; <.001), total cholesterol levels (26.3% vs 11.1%; <.001), and body mass index ≥25 kg/m (75.1% vs 69.1%; =.04). On multivariate analysis, age at evaluation (<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; =.005), and elevated sICAM-1 level (OR, 3.58; =.001) were significantly associated with MetS. 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.

Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors

“…7 The prevalence of metabolic syndrome in TCS and its risk factors have been reviewed in detail elsewhere. 17 In our investigation, the cumulative dose of cisplatin did not correlate with the prevalence of hypogonadism. Other studies 41,42 have reported a higher prevalence of hypogonadism in TCS who received higher doses of cisplatin.…”

“…Data on the prevalence of metabolic syndrome and its risk factors in this cohort have been previously described. 17…”

Relationship of Cisplatin-Related Adverse Health Outcomes With Disability and Unemployment Among Testicular Cancer Survivors

“…Our study thus addresses an important gap by identifying, specifically, cisplatin-related AHOs associated with SRH among a relatively young group of cancer survivors. Other AHOs not included in our CBM Pt score such as cardiovascular disease ( 52 , 53 ) and those related to metabolic syndromes ( 54 ) may also relate in part to cisplatin exposure; however, it is difficult to isolate cisplatin’s contribution from genetic and lifestyle factors.…”

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy

“…Hypogonadism was defined as testosterone levels 3 ng/mL based on crude measurement or whether the patient was on testosterone therapy. All patients who had testosterone levels > 3 ng/mL and were not on testosterone therapy were labeled as normal or high, and were grouped together as controls for the linear regression analysis, as described previously (30).…”