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Importance of the intersection of age and sex to understand variation in incidence and survival for primary malignant gliomas

Abstract Background Gliomas are the most common type of malignant brain and other CNS tumors, accounting for 80.8% of malignant primary brain and CNS tumors. They cause significant morbidity and mortality. This study investigates the intersection between age and sex to better understand variation of incidence and survival for glioma in the United States. Methods Incidence data from 2000 to 2017 were obtained from CBTRUS, which obtains data from the NPCR and SEER, and survival data from the CDC’s NPCR. Age-adjusted incidence rate ratios (IRR) per 100 000 were generated to compare male-to-female incidence by age group. Cox proportional hazard models were performed by age group, generating hazard ratios to assess male-to-female survival differences. Results Overall, glioma incidence was higher in males. Male-to-female incidence was lowest in ages 0-9 years (IRR: 1.04, 95% CI: 1.01-1.07, P = .003), increasing with age, peaking at 50-59 years (IRR: 1.56, 95% CI: 1.53-1.59, P < .001). Females had worse survival for ages 0-9 (HR: 0.93, 95% CI: 0.87-0.99), though male survival was worse for all other age groups, with the difference highest in those 20-29 years (HR: 1.36, 95% CI: 1.28-1.44). Incidence and survival differences by age and sex also varied by histological subtype of glioma. Conclusions To better understand the variation in glioma incidence and survival, investigating the intersection of age and sex is key. The current work shows that the combined impact of these variables is dependent on glioma subtype. These results contribute to the growing understanding of sex and age differences that impact cancer incidence and survival.


Neuro-Oncology
Gliomas are tumors that arise from glial or precursor cells and include astrocytoma, oligodendroglioma, ependymoma, and other rare histologies. 1 Gliomas are the most common type of primary malignant brain and other CNS tumor, accounting for approximately 25.1% of all primary brain and other CNS tumors and 80.8% of malignant brain and other CNS tumors, and cause significant morbidity and mortality. 1 The most commonly occurring primary malignant brain and other CNS tumor is glioblastoma multiforme (GBM), accounting for the majority of gliomas (57.7%) and comprising 14.5% of all tumors and 48.6% of malignant tumors. 1 Age is a key factor associated with incidence and survival for all cancers and therefore is also an important factor in the incidence and survival of gliomas. 2 Gliomas are more common in older adults, and peak in incidence between the ages of 45 and 65 years old. 3 Despite this, gliomas are one of the most common solid tumor types in children and account for approximately 45.5% of tumors in children and adolescents age 0-19 years. 1 Studies have shown that the median age for diagnosis of high-grade glioma is higher in females as compared to males. 4 Interest in sex differences in cancer has grown in recent years, [5][6][7][8] especially now that all National Institutes of Health (NIH) grants require an assessment of sex as a biological variable. 9 Population-based studies demonstrate that the incidence of gliomas varies significantly by sex, with males having a 30%-50% higher incidence for most glioma subtypes. 10 In addition, a recent study showed that among patients diagnosed with highgrade gliomas, there were significantly more female longterm survivors, with mean survival being 742 vs 628 days (P = .03). 4 Age or sex differences in incidence and survival for primary malignant gliomas are now well validated. 1,[5][6][7][8]11 While differences in survival and incidence based on sex and age have been studied individually, there have been no studies looking at the intersection of the 2 key variables and their interactive role on incidence and survival for gliomas. This study investigates the intersection between age and sex to better understand the variation of incidence and survival for glioma in the United States. Identifying disadvantaged sex and age groups is critical to providing individualized care for these devastating tumors.

Data Sources
Incidence data. Incidence data were obtained for the years 2000-2017 from the Central Brain Tumor Registry of the United States (CBTRUS), which receives data in collaboration with the Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries (NPCR) and the National Cancer Institute's (NCI) Survival Epidemiology and End Results Program (SEER). 12 This is the largest population-based registry focused exclusively on primary brain and other central nervous system tumors in the United States, covering the entire US population. 1 Survival data. Overall survival data from 2001 to 2016 used for analysis were obtained from the NPCR. 13 This dataset provides population-based information for 93.6% of the US population and is a subset of the data used for the incidence calculations. Overall survival information is derived from both active and passive follow-up.

Selection Criteria
Patients with primary brain and other CNS gliomas from individuals with no prior cancer diagnosis who were either microscopically or radiographically confirmed were included in the analysis. International Classification of Diseases for Oncology, Third Edition (ICD-O-3) codes were

Key Points
1. Male-to-female incidence increases with age in primary gliomas.
2. Female survival is worse in children 0-9 years but worse for males at all other ages in primary gliomas.

Importance of the Study
Age and sex differences in incidence and survival for primary malignant gliomas are well documented, independently. However, in order to better understand this differences, analysis of the intersection of these 2 variables are key. The current work shows that age and sex interact and influence glioma incidence and survival. Males had significantly higher incidence rates overall, and by most glioma subtypes, as compared to females for all age groups. Male-to-female incidence was lowest in children but increased into adulthood. Males with malignant gliomas also had significantly higher risk of death as compared to females, which differed by age group. These results contribute to the growing understanding and impact that both sex and age have on cancer incidence and survival. Identifying disadvantaged sex and age groups is critical in influencing further research, and in developing individual care plans for patients with these lethal tumors.

Statistical Analysis
The average annual age-adjusted incidence rates (AAIR) and 95% confidence intervals (95% CI) were estimated per 100 000 population using the methodology described in Tiwari et al. 15 All rates were age-standardized to the 2000 US population and are reported per 100 000 population. We used 10-year age interval to create age groups (0-9, 10-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, and 80 years and older) based on age at primary cancer diagnosis. Ageadjusted incidence rate ratios (IRR) for sex (male:female) with 95% CI were also generated from these standardized rates. For incidence data, counts and rates are not presented when fewer than 16 cases were reported for the specific category, or where the inclusion of the count and rate would allow for back-calculation of suppressed values. For example, if the remaining cells in a category can be used to calculate the value of a suppressed cell (n < 16), an additional cell will be suppressed. Survival differences were assessed using age-stratified Cox proportional hazards models, to generate hazard ratios (HRs) with 95% CIs of male vs female by age group. Both AAIRs/IRRs and HRs were estimated for overall gliomas, and separately for anaplastic oligodendroglioma, anaplastic oligodendroglioma, diffuse astrocytoma, GBM, and oligodendroglioma. Survival time was recorded in months and was defined from the date of diagnosis to the date of death or last known contact. The Cox proportional hazards assumption was tested for survival models, and no variables were found in violation. For survival data, counts and rates are not presented when fewer than 20 events were reported for the specific category. Additional Cox proportional hazards models were assessed on a subset of patients who had received a gross total resection (SEER Site-Specific Surgery Codes: 30, 55) to adjust for surgical treatment.
Chi-square tests were performed to assess demographic and histology differences between males and females. All analyses were performed using R (version 4.0.4) and SEER*Stat 8.3.8.
AAIRs and IRRs by sex and age are also shown for the following glioma subtypes: anaplastic oligodendroglioma, anaplastic oligodendroglioma, diffuse astrocytoma, GBM, and oligodendroglioma (Figures 1 and 2, Supplementary  Table 3). For males, the age group with the highest AAIR for anaplastic astrocytoma, diffuse astrocytoma, and GBM was 70-79 years. In males, the highest incidence for anaplastic oligodendroglioma and oligodendroglioma occurred earlier, at ages 50-59 and 30-39 years, respectively. Females showed peaks in incidence that differed from males for anaplastic oligodendroglioma and oligodendroglioma, with the highest AAIR occurring between ages 40-49 years. In addition, for anaplastic oligodendroglioma and diffuse astrocytoma, the corresponding IRRs of all age groups were significantly higher in males. For anaplastic astrocytoma and GBM, the corresponding IRRs of all age groups were significant for higher incidence in males except for age 0-9 years.

Survival
Cox proportional hazards models were used to generate HRs of male vs female sex with 95% CIs by age groups overall are shown in Figure 3 and Supplementary Subtype-specific HRs by age groups were also generated ( Figure 3, Supplementary Table 4). The HR for male was highest in age groups 30-39 and 50-59 years oligodendroglioma and anaplastic oligodendroglioma, respectively.
In order to assess the impact of extent of resection on survival differences between male and female by age  Figure 1).

Discussion
In this study, we provide evidence to show that incidence and overall survival of primary malignant gliomas vary by sex and age. To our knowledge, this is the first analysis investigating the intersection of sex and age to better understand variation in incidence and survival for glioma. We found that the incidence of glioma was higher for males across all age groups and in general males had a higher risk of death as compared to females. Gliomas are the most common malignant brain tumor and can cause significant morbidity and mortality. For example, median survival of GBM cases diagnoses from 2001 to 2016 in the United States was only 8 months. Anaplastic ependymoma had a reported median survival of 18 months and 3 years for diffuse astrocytoma. 1 These tumors are often diagnosed through either neuroimaging techniques, such as CT or MRI scans, and pathologic confirmation from tumor tissue received at biopsy or resection. 16 The use of molecular biomarkers is also used to help differentiate between glioma types, such as between oligodendrogliomas and astrocytomas, and to identify clinically significant subgroups within certain histologies, such as glioblastoma vs anaplastic astrocytoma. 16 Molecular biomarker data are not currently available in tumor registries, such as CBTRUS, as tumor registries did not collect the 2016 WHO Classification biomarkers until 2018. 17 This information will be available in future data releases.
Age is a well-validated independent factor associated with incidence and survival for all cancers. 1 Some cancers, including brain and other CNS tumors and leukemia, are common in children while others are more common in adults. 18 Specific glioma subtypes are well documented to be quite common in childhood and very rare in adulthood and vice versa. 1 Age is one of the primary risk factors for cancer, with individuals ≥65 years of age accounting for 60% of newly diagnosed malignancies and 70% of all

Neuro-Oncology
cancer-related deaths. 19,20 Previous studies highlighted an age-adjusted cancer mortality rate for persons ≥65 at ~16 times higher than the mortality rate for those <65. 20,21 Aging is a complex process that could affect cancer risk through multiple mechanisms. Among these, are the effects of aging on nearly all aspects of the immune system, 20,22 which has been strongly implicated in cancer prevention, development, and defense. 20,23 Aging negatively impacts apoptotic cell clearance, 24 the numbers of naïve T cells, 25 and the wound healing response. 26 Neuroimmune interactions are also affected by aging in the brain, 20,27 and research has shown that aging progressively suppresses normal immunosurveillance and decreases immunotherapeutic efficacy against malignant glioma. 20 Immunosuppression increases in the brain with advanced age, and there is an inhibition of anti-glioma immunity in older adults. 28 These results suggest that cellular immunity may play an age-dependent role in the development of brain and other CNS tumors and should be integrated with emerging evidence for sex differences in immune suppression and tumor microenvironment interactions. 29,30 Studies have shown that the incidence of primary brain and other CNS tumors increases with age, and our updated study further confirms such a trend for primary brain and other CNS glioma as well as its association with sex. 1,31 An increasing incidence of primary malignant gliomas with increasing age likely suggests that malignant transformation of these cells is a chronic process with sequential changes of genetic alteration occurring with age. 1,32 Glioma incidence is at its nadir between the ages of 10-19 and peaks at 70-79 years, which suggests that both genetic and environmental factors may have a role, with genetic factors playing a relatively larger role in early life risk and the environment being the larger contributor for older age groups. 31,32 Analyzing these patterns of glioma incidence and survival with age and sex allows us to evaluate these patterns by age and generate hypotheses about their etiopathogenesis.
Sexual differentiation during development results in sex differences in cellular and systems biology, 6,33,34 including sexually dimorphic traits such as body size, metabolism, and disease risk. [35][36][37][38] Sex differences are evident in brain size, rates of myelination, and risk for neurodevelopmental disorders and psychiatric diseases. [39][40][41] In cancer, significant sex differences exist in incidence of most tumor types that arise in both sexes, suggesting fundamental biological differences between males and females impact cancer incidence. 5 Historically, sex-based differences in complex diseases have been understudied. Multiple studies have been conducted to examine the potential role of either endogenous or exogenous hormone exposures and risk of brain and other CNS tumors, with mixed results. 6 Prior research has shown that overall incidence of cancer has increased in males 42 including GBM. 8,43 Females with GBM have a significant overall survival advantage that is further enhanced after adjustment for known independent prognostic factors such as age, Karnofsky performance status (KPS), extent of resection, and receipt of standard therapy. 8 Though, this is not seen for lower grade glioma. 44 Sex differences in glioma incidence may be partially due to the genetic differences between males and females. 10 A sex-specific genome-wide association study identified 3 sex-specific glioma risk loci (7p11.2, 8q24.21, 3p21.31). 10 DNA methylation differences between males and females in 4 glioma molecular subtypes suggest an important sexspecific role for DNA methylation in epigenetic regulation of gliomagenesis. 45 In addition, research has shown that the standard treatment for GBM might be more effective for females than for males. 46 With respect to the molecular basis of this sex difference in treatment response, maleand female-specific gene expression clusters were identified that uncovered long-term survival signatures, with male long-term survivors having alterations in cell cycle genes compared to female long-term survivors that had alterations in integrin signaling genes. 7 However, our understanding of the many factors that determine sex-based differences in complex disease remains limited. Using population-based cancer registry data to better understand age/sex variation in incidence and survival is critical to moving forward our understanding of the intersection of these key variables and the role they play in tumorigenesis and treatment.
There is growing information on the role of sex and age on cancer incidence and survival. Most prior research has analyzed the impact of age and sex separately. The aim of our study was to examine the interaction between age and sex influence incidence and survival of gliomas in the United States. We found that glioma incidence is higher in males and adults, accurately aligning with the previously stated literature. Importantly, we found that this maleto-female difference in incidence was influenced by age. Male-to-female IRR of glioma was lowest in those 0-9 years old (IRR = 1.04, 95% CI: 1.01-1.07, P = .003), and increased over time, with the highest IRR present in those 50-59 years old (IRR = 1.56, 95% CI: 1.53-1.59, P < .001). Additionally, we found age and sex differences to be present in glioma survival as well, where females had overall worse survival in ages 0-9 years (HR: 0.93, 95% CI: 0.87-0.99), but better survival in all other age groups. These findings in this study imply an interaction between age and sex in glioma incidence and survival, the first study to present these findings

Neuro-Oncology
at this scale. These data are integral in guiding future research to analyze and better understand the mechanisms between age and sex in cancer.
Cancer registry data represent the most complete dataset for characterizing patterns of cancer incidence and survival, nevertheless, some limitations are present. The data used for this analysis are limited to variables available through cancer registry datasets. Furthermore, there was no central pathology review in place for registry procedures, meaning that each case had been classified at the diagnosing institution with no central confirmation of histology at the state or national levels. Also, we currently have very limited information on molecular data. For example, it has been documented that IDH-mutant GBM is diagnosed at a younger age than IDH-wildtype GBM. 47 Future analyses with access to information would help further assess the relationships documented in our current study. Many of the predictors associated with differences in glioma survival, including extent of resection, KPS, and treatment pattern were not included in the Cox regression model for overall survival. 11 It is also possible that the treatment information available, may not be consolidated at the central registry level, and multiple reports from different facilities may not lead to the most extensive procedure being reflected. 48 However, the CBTRUS dataset, provided in collaboration with NPCR and SEER, encapsulates almost 100% of glioma cases in the United States, and the 18-year time period of the study (2000-2017) allows for this in-depth analysis of variation in incidence and survival by age and sex for this rare tumor.

Conclusion
Age and sex differences in incidence and survival or primary malignant gliomas have been independently described. However, in order to better understand this differences, analysis of the intersection of these 2 variables are key. The current work shows that age and sex interact and influence glioma incidence and survival. Males had significantly higher incidence rates overall, and by most glioma subtypes, as compared to females for all age groups. Male-to-female incidence was lowest in children but increased into adulthood. Males with malignant gliomas also had significantly higher risk of death as compared to females, which differed by age group, for both overall data and the subset of patients who had complete extent of resection data. These results contribute to the growing understanding and impact that both sex and age have on cancer incidence and survival. Identifying disadvantaged sex and age groups is critical in influencing further research, and in developing individual care plans for patients with these lethal tumors.

Supplementary Material
Supplementary material is available at Neuro-Oncology online.

Funding
The CBTRUS data were provided through an agreement with the Centers for Disease Control's (CDC) National Program of Cancer Registries. In addition, CBTRUS used data from the research data files of the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results Program, and the National Center for Health Statistics National Vital Statistics System. CBTRUS acknowledges and appreciates these contributions to this report and to cancer surveillance in general. Funding for CBTRUS was provided by the CDC under Contract No. 75D30119C06056 Amendment /Modification No: 00001, the American Brain Tumor Association, The Sontag Foundation, Novocure, the Musella Foundation, National Brain Tumor Society, the Pediatric Brain Tumor Foundation, the Uncle Kory Foundation, the Zelda Dorin Tetenbaum Memorial Fund, as well as private and in-kind donations. Contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the NCI.