Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.

Perception of worry of harm from air pollution: results from the Health Information National Trends Survey (HINTS).

BACKGROUND: Air pollution exposure has been associated with a multitude of diseases and poses a significant concern to public health. For targeted environmental risk communication and interventions to be effective, it is important to correctly identify characteristics associated with worry of harm from air pollution. METHODS: Using responses from 3,630 participants of the Health Information National Trends Survey 4 Cycle 2, we assessed worry of harm from exposure to indoor (IAP) and outdoor (OAP) air pollution separately. Multinomial logistic regression models were used to calculate odds ratios and 95% confidence intervals. RESULTS: Hispanics were more likely to worry about harm from IAP and OAP compared to non-Hispanic whites. Participants who lived in metropolitan counties were more likely to worry about harm from IAP and OAP compared to those who lived in rural counties. Finally, those who believed their chance of getting cancer was high were more likely to worry about harm from IAP and OAP compared to those who thought their likelihood of getting cancer was low. CONCLUSIONS: Worry of harm from IAP and OAP varied across sociodemographic and cancer-related characteristics. Public health professionals should consider these characteristics when developing targeted environmental risk communication and interventions.

Opportunities for Gene and Environment Research in Cancer: An Updated Review of NCI's Extramural Grant Portfolio.

BACKGROUND: The study of gene-environment (GxE) interactions is a research priority for the NCI. Previously, our group analyzed NCI's extramural grant portfolio from fiscal years (FY) 2007 to 2009 to determine the state of the science in GxE research. This study builds upon our previous effort and examines changes in the landscape of GxE cancer research funded by NCI. METHODS: The NCI grant portfolio was examined from FY 2010 to 2018 using the iSearch application. A time-trend analysis was conducted to explore changes over the study interval. RESULTS: A total of 107 grants met the search criteria and were abstracted. The most common cancer types studied were breast (19.6%) and colorectal (18.7%). Most grants focused on GxE using specific candidate genes (69.2%) compared with agnostic approaches using genome-wide (26.2%) or whole-exome/whole-genome next-generation sequencing (NGS) approaches (19.6%); some grants used more than one approach to assess genetic variation. More funded grants incorporated NGS technologies in FY 2016-2018 compared with prior FYs. Environmental exposures most commonly examined were energy balance (46.7%) and drugs/treatment (40.2%). Over the time interval, we observed a decrease in energy balance applications with a concurrent increase in drug/treatment applications. CONCLUSIONS: Research in GxE interactions has continued to concentrate on common cancers, while there have been some shifts in focus of genetic and environmental exposures. Opportunities exist to study less common cancers, apply new technologies, and increase racial/ethnic diversity. IMPACT: This analysis of NCI's extramural grant portfolio updates previous efforts and provides a review of NCI grant support for GxE research.

Increasing Incidence of Testicular Germ Cell Tumors among Racial/Ethnic Minorities in the United States.

BACKGROUND: The incidence of testicular germ cell tumors (TGCT) has been rising in the United States and is notably higher among white men. Previously, our group reported that rates were rising among Hispanic men in certain areas. This study sought to determine whether the patterns noted in our prior publication remained evident in more recent years and to determine whether any new patterns have emerged. METHODS: Data from 51 U.S. cancer registries were examined. Racial/ethnic-specific incidence rates per 100,000 man-years were calculated overall and by census region. Annual percent changes (APC) were estimated, and joinpoint models were fit. Differences in regional incidence were examined using the Wald test. RESULTS: During the time period 2001 to 2016, 126,575 TGCTs were recorded. TGCT incidence was highest among non-Hispanic whites (NHW; 6.63/100,000), followed by Hispanics (4.20), American Indian/Alaska Natives (AI/AN; 3.27), Asian/Pacific Islanders (A/PI; 1.72), and non-Hispanic blacks (NHB; 1.27). TGCT incidence increased significantly among all men; the greatest increase was experienced by A/PIs (APC: 2.47), followed in order by Hispanics (2.10), AI/ANs (1.71), NHBs (1.28), and NHWs (0.41). Significant differences in rates by region were seen for all men except NHBs, with the highest rates among Hispanics (5.38/100,000), AI/ANs (4.47), and A/PIs (2.37) found in the West, and among NHWs (7.60) and NHBs (1.51) found in the Northeast. CONCLUSIONS: Although TGCT incidence remained highest among NHWs between 2001 and 2016, the greatest increase was experienced by A/PI men. IMPACT: Rising rates of TGCTs among men of all racial/ethnic backgrounds in the United States suggest that future attention is warranted.

Testicular cancer among US men aged 50 years and older.

BACKGROUND: The incidence of testicular cancer in the United States (US) has substantially increased in recent decades. The majority of testicular cancers are germ cell tumors (TGCT), which are the most commonly occurring malignancies among men aged 15-44 years in the US. To date, few studies have focused on testicular cancer among men aged ≥ 50 years. Thus, we sought to examine detailed descriptive features, including incidence rates and age patterns, of tumors that arise in the testes among men aged ≥ 50 years. METHODS: Data from forty-one US cancer registries were included for the years 1999-2014. Incidence rates per 100,000 person-years and their 95% confidence intervals (CI) were calculated by race/ethnicity, histology, and age at diagnosis. Estimates of annual percent change (APC) were also calculated. RESULTS: Age-specific incidence rates of spermatocytic tumors, sex cord stromal tumors and lymphomas rose with age, while age-specific incidence rates of seminomas and nonseminomas declined. Between 1999 and 2014, the incidence of nonseminoma (APC = 3.26, 95% CI: 2.27-4.25) increased more than any other tumor type. The incidence of seminoma (APC: 1.15, 95% CI: 0.59-1.71) also increased, while rates of testicular lymphoma (APC: -0.66, 95% CI: -1.16 to -0.16), spermatocytic tumors (APC: 0.42, 95% CI: -1.42 to 2.29), and sex cord stromal tumors (APC: 0.60, 95% CI: -3.21 to 4.55) remained relatively unchanged. CONCLUSION: Given the distinct time-trends and age-specific patterns of testicular cancer in men aged ≥50 years, additional investigation of risk factors for these tumors is warranted.

Placental Weight and Risk of Cryptorchidism and Hypospadias in the Collaborative Perinatal Project.

Cryptorchidism and hypospadias are the most common congenital anomalies of the genitourinary tract in males, but their etiology remains unclear. Placental insufficiency has been suggested to be linked to both conditions. Placental weight is a commonly used proxy measure for placental insufficiency; thus, we examined placental weight and other placental characteristics in relation to cryptorchidism and hypospadias in the Collaborative Perinatal Project, a US mother-child cohort study. Pregnant women were recruited between 1959 and 1965. The analysis contrasted boys with cryptorchidism (n = 413) and boys with hypospadias (n = 145) with boys without cryptorchidism (n = 23,799) and boys without hypospadias (n = 22,326). Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. In categorical analyses in which the middle tertile was the referent, cryptorchidism was inversely associated with placental weight (odds ratio = 0.66, 95% confidence interval: 0.46, 0.95) among white boys and positively associated with the lowest tertile of placental weight among black boys (odds ratio = 1.70, 95% confidence interval: 1.11, 2.59). We conclude that lower placental weight may be related to risk of cryptorchidism. Further investigation of placental functioning may offer insights into the etiology of cryptorchidism.

Maternal use of personal care products during pregnancy and risk of testicular germ cell tumors in sons.

BACKGROUND: The etiology of testicular germ cell tumors (TGCT) is poorly understood, however, exposure to endocrine disrupting chemicals (EDCs) may be related to increased risk. Personal care products, some of which contain EDCs, are widely used on a daily basis and are known to cross the placenta, be present in breastmilk, and are capable of inducing reproductive tract abnormalities. To determine the association between personal care product use during pregnancy and breastfeeding and TGCT risk, an analysis among mothers of TGCT cases and controls was conducted. METHODS: The US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study enrolled TGCT cases and controls and their mothers between 2002 and 2005. The current analysis examined personal care product use during pregnancy among 527 mothers of TGCT cases and 562 mothers of controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for identified covariates. RESULTS: Maternal use of face lotion more than one time per week was associated with a significantly increased risk of TGCT (OR: 1.42, 95% CI: 1.08-1.86, p-trend: 0.01). None of the other products examined (perfume, hairspray, nail polish, hair dye, permanent wave, body lotion, deodorant, sunscreen) were associated with TGCT risk. CONCLUSIONS: Frequent exposure to face lotion during pregnancy and while breastfeeding may be associated with increased TGCT risk. Further investigation into the endocrine disrupting effects of personal care products is warranted.

Future of testicular germ cell tumor incidence in the United States: Forecast through 2026.

BACKGROUND: Testicular germ cell tumors (TGCTs) are rare tumors in the general population but are the most commonly occurring malignancy among males between ages 15 and 44 years in the United States (US). Although non-Hispanic whites (NHWs) have the highest incidence in the US, rates among Hispanics have increased the most in recent years. To forecast what these incidence rates may be in the future, an analysis of TGCT incidence in the Surveillance, Epidemiology, and End Results program and the National Program of Cancer Registries was conducted. METHODS: TGCT incidence data among males ages 15 to 59 years for the years 1999 to 2012 were obtained from 39 US cancer registries. Incidence rates through 2026 were forecast using age-period-cohort models stratified by race/ethnicity, histology (seminoma, nonseminoma), and age. RESULTS: Between 1999 and 2012, TGCT incidence rates, both overall and by histology, were highest among NHWs, followed by Hispanics, Asian/Pacific Islanders, and non-Hispanic blacks. Between 2013 and 2026, rates among Hispanics were forecast to increase annually by 3.96% (95% confidence interval, 3.88%-4.03%), resulting in the highest rate of increase of any racial/ethnic group. By 2026, the highest TGCT rates in the US will be among Hispanics because of increases in both seminomas and nonseminomas. Rates among NHWs will slightly increase, whereas rates among other groups will slightly decrease. CONCLUSIONS: By 2026, Hispanics will have the highest rate of TGCT of any racial/ethnic group in the US because of the rising incidence among recent birth cohorts. Reasons for the increase in younger Hispanics merit further exploration. Cancer 2017;123:2320-2328. © 2017 American Cancer Society.

Review of the Gene-Environment Interaction Literature in Cancer: What Do We Know?

BACKGROUND: Risk of cancer is determined by a complex interplay of genetic and environmental factors. Although the study of gene-environment interactions (G×E) has been an active area of research, little is reported about the known findings in the literature. METHODS: To examine the state of the science in G×E research in cancer, we performed a systematic review of published literature using gene-environment or pharmacogenomic flags from two curated databases of genetic association studies, the Human Genome Epidemiology (HuGE) literature finder and Cancer Genome-Wide Association and Meta Analyses Database (CancerGAMAdb), from January 1, 2001, to January 31, 2011. A supplemental search using HuGE was conducted for articles published from February 1, 2011, to April 11, 2013. A 25% sample of the supplemental publications was reviewed. RESULTS: A total of 3,019 articles were identified in the original search. From these articles, 243 articles were determined to be relevant based on inclusion criteria (more than 3,500 interactions). From the supplemental search (1,400 articles identified), 29 additional relevant articles (1,370 interactions) were included. The majority of publications in both searches examined G×E in colon, rectal, or colorectal; breast; or lung cancer. Specific interactions examined most frequently included environmental factors categorized as energy balance (e.g., body mass index, diet), exogenous (e.g., oral contraceptives) and endogenous hormones (e.g., menopausal status), chemical environment (e.g., grilled meats), and lifestyle (e.g., smoking, alcohol intake). In both searches, the majority of interactions examined were using loci from candidate genes studies and none of the studies were genome-wide interaction studies (GEWIS). The most commonly reported measure was the interaction P-value, of which a sizable number of P-values were considered statistically significant (i.e., <0.05). In addition, the magnitude of interactions reported was modest. CONCLUSION: Observations of published literature suggest that opportunity exists for increased sample size in G×E research, including GWAS-identified loci in G×E studies, exploring more GWAS approaches in G×E such as GEWIS, and improving the reporting of G×E findings.

Incidence of testicular germ cell tumors among US men by census region.

BACKGROUND: The incidence of testicular germ cell tumors (TGCTs) in the United States is notably higher among white men versus other men. Previously, however, it was reported that rates were rising among Hispanics in certain areas. To determine whether this finding was evident in a wider area of the United States, data from 39 US cancer registries were examined. METHODS: Racial/ethnic-specific incidence rates per 100,000 man-years were calculated overall and by census region for the period of 1998-2011. Annual percentage changes (APCs) were estimated, and joinpoint models were fit. Differences in incidence by region were examined with the Wald test. RESULTS: From 1998 to 2011, 88,993 TGCTs were recorded. The TGCT incidence was highest among non-Hispanic whites (6.57 per 100,000), who were followed by Hispanics (3.88), American Indians/Alaska Natives (2.88), Asians/Pacific Islanders (A/PIs; 1.60), and non-Hispanic blacks (1.20). The incidence significantly increased among Hispanics (APC, 2.31; P < .0001), with rates rising in all regions except the South. Rates rose slightly among non-Hispanic whites (APC, 0.51; P = .0076). Significant differences in rates by region were seen for Hispanics (P = .0001), non-Hispanic whites (P < .0001), and A/PIs (P < .0001), with the highest rates among Hispanics in the West and with the highest rates among non-Hispanic whites and A/PIs in the Northeast. CONCLUSIONS: Although the incidence of TGCTs remained highest among non-Hispanic whites between 1998 and 2011, the greatest increase was experienced by Hispanics. Rising rates of TGCTs among Hispanics in the United States suggest that future attention is warranted. Reasons for the increase may include variability in birthplace, changing exposures, genetic susceptibility, and the length of US residence.

Urinary bisphenol A and age at menarche among adolescent girls: evidence from NHANES 2003-2010.

BACKGROUND: Bisphenol A (BPA) is an environmental estrogen used in the manufacture of polycarbonate plastics and epoxy resins used to make food and beverage packaging. Increasing evidence suggests that BPA mimics estrogens in the body and may be associated with putative markers of breast cancer risk. OBJECTIVES: We analyzed the National Health and Nutrition Examination Survey (NHANES) 2003-2010 data to investigate the association of BPA with age at menarche in adolescent girls. We hypothesized that urinary BPA, as a surrogate biomarker for BPA exposure, is associated with earlier age at menarche, and that body mass index (BMI) may modulate this association. METHODS: We conducted cross-sectional analyses of urinary BPA, BMI and age of menarche in a subsample of 987 adolescent girls aged 12-19, using pooled data from the 2003-2010 NHANES. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between urinary BPA and early onset of menarche, with adjustment for sampling design. We additionally assessed interaction of BPA with BMI. RESULTS: Adolescent girls with moderate BPA levels appeared to be less likely to have early onset of menarche than those with the lowest levels (OR=0.57; 95% CI=0.30, 1.08) after adjusting for age, race/ethnicity, parental education, country of birth, NHANES cycle, BMI and creatinine. BMI appeared to modify the BPA-menarche association. CONCLUSIONS: Although a non-significant trend suggests increasing urinary BPA may be associated with delayed menarche in adolescent girls, these results are based on cross-sectional data. Results should be clarified in carefully designed longitudinal cohort studies.

Area-level attributes and esophageal adenocarcinoma in surveillance, epidemiology and end results registries.

PURPOSE: To examine the associations between area-level socioeconomic attributes and stage of esophageal adenocarcinoma diagnoses in 16 SEER cancer registries during 2000-2007. METHODS: Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression models to assess the relationship between distant-stage esophageal adenocarcinoma and individual, census tract, and county-level attributes. RESULTS: Among cases with data on birthplace, no significant association was seen between reported birth within versus outside the United States and distant-stage cancer (adjusted OR=1.02, 95% CI: 0.85-1.22). Living in an area with a higher percentage of residents born outside the United States than the national average was associated with distant-stage esophageal adenocarcinoma; census tract level: >11.8%, (OR=1.10, 95% CI:1.01-1.19), county level: >11.8%, (OR=1.14, 95% CI:1.05-1.24). No association was observed between median household income and distant-stage cancer at either census tract or county levels. CONCLUSION: The finding of greater odds of distant-stage esophageal adenocarcinoma among cases residing in SEER areas with higher proportion of non-U.S. Natives suggests local areas where esophageal cancer control efforts might be focused. Missing data at the individual level was a limitation of the present study. Furthermore, inconsistent associations with foreign birth at individual- versus area-levels cautions against using area-level attributes as proxies for case attributes.

A review of NCI's extramural grant portfolio: identifying opportunities for future research in genes and environment in cancer.

BACKGROUND: Genetic and environmental factors jointly influence cancer risk. The NIH has made the study of gene-environment (GxE) interactions a research priority since the year 2000. METHODS: To assess the current status of GxE research in cancer, we analyzed the extramural grant portfolio of the National Cancer Institute (NCI) from Fiscal Years 2007 to 2009. Publications attributed to selected grants were also evaluated. RESULTS: From the 1,106 research grants identified in our portfolio analysis, a random sample of 450 grants (40%) was selected for data abstraction; of these, 147 (33%) were considered relevant. The most common cancer type was breast (20%, n = 29), followed by lymphoproliferative (10%, n = 14), colorectal (9%, n = 13), melanoma/other skin (9%, n = 13), and lung/upper aerodigestive tract (8%, n = 12) cancers. The majority of grants were studies of candidate genes (68%, n = 100) compared with genome-wide association studies (GWAS) (8%, n = 12). Approximately one-third studied environmental exposures categorized as energy balance (37%, n = 54) or drugs/treatment (29%, n = 43). From the 147 relevant grants, 108 publications classified as GxE or pharmacogenomic were identified. These publications were linked to 37 of the 147 grant applications (25%). CONCLUSION: The findings from our portfolio analysis suggest that GxE studies are concentrated in specific areas. There is room for investments in other aspects of GxE research, including, but not limited to developing alternative approaches to exposure assessment, broadening the spectrum of cancer types investigated, and conducting GxE within GWAS. IMPACT: This portfolio analysis provides a cross-sectional review of NCI support for GxE research in cancer.

Research opportunities for cancer associated with indoor air pollution from solid-fuel combustion.

BACKGROUND: Indoor air pollution (IAP) derived largely from the use of solid fuels for cooking and heating affects about 3 billion people worldwide, resulting in substantial adverse health outcomes, including cancer. Women and children from developing countries are the most exposed populations. A workshop was held in Arlington, Virginia, 9-11 May 2011, to better understand women's and children's potential health effects from IAP in developing countries. Workshop participants included international scientists, manufacturers, policy and regulatory officials, community leaders, and advocates who held extensive discussions to help identify future research needs. OBJECTIVES: Our objective was to identify research opportunities regarding IAP and cancer, including research questions that could be incorporated into studies of interventions to reduce IAP exposure. In this commentary, we describe the state of the science in understanding IAP and its associations with cancer and suggest research opportunities for improving our understanding of the issues. DISCUSSION: Opportunities for research on IAP and cancer include studies of the effect of IAP on cancers other than lung cancer; studies of genetic factors that modify susceptibility; studies to determine whether the effects of IAP are mediated via germline, somatic, and/or epigenetic changes; and studies of the effects of IAP exposure via dermal and/or oral routes. CONCLUSIONS: IAP from indoor coal use increases the risk of lung cancer. Installing chimneys can reduce risk, and some genotypes, including GSTM1-null, can increase risk. Additional research is needed regarding the effects of IAP on other cancers and the effects of different types of solid fuels, oral and dermal routes of IAP exposure, genetic and epigenetic mechanisms, and genetic susceptibility.

Cancer and environment: definitions and misconceptions.

BACKGROUND: Scientific evidence supports an association between environmental exposures and cancer. However, a reliable estimate for the proportion of cancers attributable to environmental factors is currently unavailable. This may be related to the varying definitions of the term "environment." The current review aims to determine how the reporting of the definition of the environment and of the estimates of environmentally attributable risks have changed over the past 50 years. METHODS: A systematic literature search was performed to retrieve all relevant publications relating to the environment and cancer from January 1960 to December 2010 using PubMed, EMBASE, Scopus, and Web of Science. Definitions of the environment and environmentally attributable risks for cancer were extracted from each relevant publication. RESULTS: The search resulted in 261 relevant publications. We found vast discrepancies in the definition of the environment, ranging from broad (including lifestyle factors, occupational exposures, pollutants, and other non-genetic factors) to narrow (including air, water, and soil pollutants). Reported environmentally attributable risk estimates ranged from 1% to 100%. CONCLUSIONS: Our findings emphasize the discrepancies in reporting environmental causation of cancer and the limits of inference in interpreting environmentally attributable risk estimates. Rather than achieving consensus on a single definition for the environment, we suggest the focus be on achieving transparency for any environmentally attributable risks.