Lymphedema self-assessment among endometrial cancer survivors.

PURPOSE: Lower extremity lymphedema (LEL), which causes ankle, leg, and feet swelling, poses a significant challenge for endometrial cancer survivors, impacting physical functioning and psychological well-being. Inconsistent LEL diagnostic methods result in wide-ranging LEL incidence estimates. METHODS: We calculated the cumulative incidence of LEL based on survivor-reported Gynecologic Cancer Lymphedema Questionnaire (GCLQ) responses in addition to survivor- and nurse-reported leg circumference measurements among a pilot sample of 50 endometrial cancer survivors (27 White, 23 Black) enrolled in the ongoing population-based Carolina Endometrial Cancer Study. RESULTS: Self-leg circumference measurements were perceived to be difficult and were completed by only 17 survivors. Diagnostic accuracy testing measures (sensitivity, specificity, positive and negative predictive value) compared the standard nurse-measured ≥ 10% difference in leg circumference measurements to GCLQ responses. At a mean of ~11 months post-diagnosis, 54% of survivors met established criteria for LEL based on ≥ 4 GCLQ cutpoint while 24% had LEL based on nurse-measurement. Percent agreement, sensitivity, and specificity approximated 60% at a threshold of ≥ 5 GCLQ symptoms. However, Cohen's kappa, a measure of reliability that corrects for agreement by chance, was highest at ≥ 4 GCLQ symptoms (κ = 0.27). CONCLUSION: Our findings emphasize the need for high quality measurements of LEL that are feasible for epidemiologic study designs among endometrial cancer survivors. Future studies should use patient-reported survey measures to assess lymphedema burden and quality of life outcomes among endometrial cancer survivors.

Gastrointestinal outcomes among older women with endometrial cancer.

OBJECTIVE: Treatment for endometrial cancer may contribute to bowel dysfunction and other gastrointestinal outcomes. We investigated the risk of several gastrointestinal diagnoses among older women with endometrial cancer and matched women without a history of cancer. METHODS: Women aged 66 years and older diagnosed with endometrial cancer during 2004-2017 (N = 44,386) and matched women without a known cancer history (N = 221,219) were identified in the SEER-Medicare linked data. An index date was defined as the endometrial cancer diagnosis date in that matched set. ICD-9 and -10 diagnosis codes were used to define gastrointestinal outcomes, including constipation, abdominal pain, IBS, fecal incontinence, bowel obstruction, ileus, radiation enteritis or proctitis, colonic stricture, and vascular insufficiency of the bowel in the Medicare claims. Hazard ratios (HRs) for incident gastrointestinal diagnoses were estimated using multivariable Cox proportional hazards regression models. RESULTS: Compared to women without cancer, women with endometrial cancer had an increased risk of gastrointestinal symptoms after the index date, including constipation (HR = 2.27; 95% CI: 2.22-2.32), abdominal pain (HR = 2.94; 95% CI: 2.89-2.99), and fecal incontinence (HR = 1.96; 95% CI: 1.83-2.10). The risk of other gastrointestinal diagnoses was also higher among women with endometrial cancer (e.g., bowel obstruction: HR = 5.72; 95% CI: 5.47-5.98; ileus: HR = 7.22; 95% CI: 6.89-7.57). These associations were also apparent in sensitivity analyses limited to 1+ and 5+ years after the index date. CONCLUSIONS: Older women with endometrial cancer experience an excess risk of gastrointestinal diagnoses that may persist long after cancer diagnosis. Surveillance for these conditions may be a critical part of survivorship care.

Exome-wide assessment of isolated biliary atresia: A report from the National Birth Defects Prevention Study using child-parent trios and a case-control design to identify novel rare variants.

The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.

Patient characteristics and health system factors associated with adjuvant radiation therapy receipt in older women with early-stage endometrial cancer.

INTRODUCTION: Among women with early-stage endometrial cancer (EC), age, stage, grade, and histology are used to determine fitness for adjuvant radiation therapy (RT) administration. We examined non-cancer factors associated with adjuvant RT receipt in older women with early-stage EC. MATERIALS & METHODS: Using data from the Surveillance Epidemiology and End Results cancer registry program linked with Medicare claims, we identified 25,654 women (aged ≥66 years) diagnosed with first primary stage I-II EC during 2004-2017 who underwent a hysterectomy. Diagnosis and procedure codes were used to identify adjuvant RT claims filed for the seven-month period post-hysterectomy. Multivariable log-binomial regression was used to estimate adjuvant RT prevalence associated with patient characteristics and health system factors after adjustment for age, frailty, and endometrial factors. RESULTS: Adjuvant RT was less commonly administered to Asian American and Pacific Islander patients than non-Hispanic White patients (Prevalence ratio [PR], 0.84; 95% confidence interval [CI], 0.73 to 0.97). Compared to women treated in the Northeast region, women treated other regions of the US were less likely to undergo adjuvant RT (PR, 0.75; 95% CI, 0.71 to 0.79). Residing in rural or high neighborhood-poverty counties was associated with lower adjuvant RT administration. Higher comorbidity score was not associated with reduced prevalence of adjuvant RT receipt; however, women with high probability of predicted probability of frailty were less likely to undergo adjuvant RT (PR, 0.67; 95% CI, 0.55 to 0.81) compared to women with low probability of frailty. Women who received lymph node assessment were more likely to undergo adjuvant RT compared to women who did not (PR, 1.43; 95% CI, 1.34 to 1.51). Women treated by a gynecologic oncologist were more likely to undergo adjuvant RT compared to women treated by a non-gynecologic oncologist (PR 1.09; 95% CI, 1.04 to 1.14). Adjuvant RT was more commonly administered to women treated in larger academic hospitals. DISCUSSION: Findings suggest that various non-cancer factors affect the delivery of adjuvant RT to older women with early-stage EC in real-world oncology practice. Advancing our understanding of factors associated with adjuvant RT administration may help expand equitable access to RT.

Risk factors for head and neck cancer in more and less developed countries: Analysis from the INHANCE consortium.

OBJECTIVE: We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries. SUBJECTS AND METHODS: The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared. RESULTS: The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20 years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20 years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45 years) or female differed by country type for some HNC subsites. CONCLUSION: These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer.

Adjuvant radiation therapy and health-related quality of life among older women with early-stage endometrial cancer: an analysis using the SEER-MHOS linkage.

PURPOSE: Radiation therapy (RT) has been associated with decreased health-related quality of life (HRQOL) in clinical trials of early-stage endometrial cancer (EC), but few studies have examined the association in real-world settings. We assessed HRQOL associated with adjuvant RT for older women with early-stage EC within a large U.S. population-based registry resource. METHODS: The Surveillance Epidemiology and End Results and the Medicare Health Outcomes Survey linkage (1998-2017) was used to identify women with early-stage EC aged ≥ 65 years at survey who received surgery and were diagnosed ≥ 1-year prior (n = 1,140). HRQOL was evaluated with the 36-item Short-Form Health Survey (SF-36) until 2006 and the Veterans RAND 12-Item Health Survey (VR-12) post 2006. Ordinary least squares regression was used to estimate mean difference (MD) in T scores and 95% confidence intervals (CIs) comparing treatment groups (surgery alone, adjuvant external beam radiation therapy [EBRT], or adjuvant vaginal brachytherapy [VBT]) after accounting for confounders using propensity score weighting. RESULTS: Overall, RT was not associated with physical health (MD = 0.97; 95% CI = - 1.13, 3.07) or mental health (MD = - 0.78; 95% CI = - 2.60, 1.05) relative to surgery alone. In analyses by RT type, adjuvant VBT was associated with better general health on the SF-36/VR-12 subscale (MD = 3.59; 95% CI = 0.56, 6.62) relative to surgery alone. No statistically significant associations were observed for adjuvant VBT and physical or mental health, or for adjuvant EBRT and any HRQOL domain. CONCLUSION: Older women with early-stage EC treated with adjuvant RT did not report worse physical and mental HRQOL scores compared to those treated with surgery alone, though relevant symptoms should be evaluated further to fully understand the disease and treatment specific aspects of the HRQOL.

Cardiovascular disease diagnoses among older women with endometrial cancer.

BACKGROUND: Endometrial cancer (EC) shares risk factors (e.g. obesity) with cardiovascular disease (CVD), yet little research has investigated CVD diagnoses among EC survivors. We aimed to describe the burden of CVD diagnoses among older women with EC compared to women without a cancer history. METHODS: Women aged 66+ years with an EC diagnosis during 2004-2017 (N = 44,386) and matched women without cancer (N = 221,219) were identified in the SEER-Medicare linked data. An index date was defined as the cancer diagnosis date of the EC case in that matched set. ICD-9/10 diagnosis codes were used to define CVD outcomes in the Medicare claims. Prevalent CVD was identified using diagnosis codes in the year before the index date. Hazard ratios (HRs) for incident CVD diagnoses after the index date were estimated using multivariable Cox proportional hazards regression. Women with a prevalent CVD were excluded from incidence analyses for that outcome. RESULTS: Compared to women without cancer, women with EC had a higher prevalence of CVD diagnoses at the index date. In analyses beginning follow-up at 1 year post-index date, EC survivors had an increased risk of incident CVD diagnoses including ischemic heart diseases (HR = 1.73; 95% CI: 1.69-1.78), pulmonary heart disease (HR = 1.95; 95% CI: 1.88-2.02), and diseases of the veins and lymphatics (HR = 2.71; 95% CI: 95% CI: 2.64-2.78). Risk of CVD diagnoses among women with EC was also elevated within the first year post-index date. CONCLUSIONS: Management of pre-existing CVD and monitoring for incident CVD may be critical during EC treatment and throughout long-term survivorship.

Adverse Urinary System Diagnoses among Older Women with Endometrial Cancer.

BACKGROUND: Endometrial cancer and its treatment may impact urinary system function, but few large-scale studies have examined urinary diagnoses among endometrial cancer survivors. We investigated the risk of several urinary outcomes among older women with endometrial cancer compared with similar women without a cancer history. METHODS: Women aged 66+ years with an endometrial cancer diagnosis during 2004-2017 (N = 44,386) and women without a cancer history (N = 221,219) matched 1:5 on exact age, race/ethnicity, and state were identified in the Surveillance, Epidemiology, and End Results-Medicare linked data. ICD-9 and -10 diagnosis codes were used to define urinary outcomes in the Medicare claims. HRs for urinary outcomes were estimated using multivariable Cox proportional hazards regression models. RESULTS: Relative to women without cancer, endometrial cancer survivors were at an increased risk of several urinary system diagnoses, including lower urinary tract infection [HR, 2.36; 95% confidence interval (CI), 2.32-2.40], urinary calculus (HR, 2.22; 95% CI, 2.13-2.31), renal failure (HR, 2.28; 95% CI, 2.23-2.33), and chronic kidney disease (HR, 1.85; 95% CI, 1.81-1.90). Similar associations were observed in sensitivity analyses limited to 1+ and 5+ years after endometrial cancer diagnosis. Black race, higher comorbidity index, higher stage or grade cancer, non-endometrioid histology, and treatment with chemotherapy and/or radiation were often significant predictors of urinary outcomes among endometrial cancer survivors. CONCLUSIONS: Our results suggest that, among older women, the risk of urinary outcomes is elevated after endometrial cancer. IMPACT: Monitoring for urinary diseases may be a critical part of long-term survivorship care for older women with an endometrial cancer history.

The association between meat and fish intake by preparation methods and breast cancer in the Carolina Breast Cancer Study (CBCS).

PURPOSE: We examined the associations between intake of meat and fish by preparation methods and breast cancer in the Carolina Breast Cancer Study, a racially diverse population-based case-control study. METHODS: African American (AA) and European American (EA) women aged 20-74 years with a first diagnosis of invasive or in situ breast cancers were frequency matched by race and age group to controls identified through the North Carolina Division of Motor Vehicles and Medicare lists [AA: 548 cases, 452 controls; EA: 858 cases, 748 controls]. Participants self-reported meat preparation methods and intake frequencies. Adjusted odds ratios (OR) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression adjusted for age, race, alcohol intake, body mass index, family income, lactation, marital status, use of oral contraceptives, postmenopausal hormone use, smoking status, and offsets. RESULTS: Positive associations with breast cancer were observed for intakes of grilled/barbecued hamburger (≥ once/week, OR: 1.28; 95% CI 1.01, 1.63), and pan-fried/oven-broiled beef steak (≥ once/week, OR: 1.36; 95% CI 1.08, 1.72). Inverse associations were observed for pan-fried fish (≥ once/week, OR: 0.77; 95% CI 0.60, 0.98), and for grilled/ barbecued pork chops (> 0 time/week OR: 0.81, 95% CI 0.68, 0.97). Associations tended to be stronger among EA women than among AA women. CONCLUSION: More frequent consumption of beef prepared with high temperature methods was associated with higher odds of breast cancer while more frequent consumption of pan-fried fish or grilled/barbecued pork chops was associated with lower odds of breast cancer.

Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization.

BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.

Validity of breast cancer surgery treatment information in a state-based cancer registry.

PURPOSE: Surgery is an important part of early stage breast cancer treatment that affects overall survival. Many studies of surgical treatment of breast cancer rely on data sources that condition on continuous insurance coverage or treatment at specified facilities and thus under-sample populations especially affected by cancer care inequities including the uninsured and rural populations. Statewide cancer registries contain data on first course of cancer treatment for all patients diagnosed with cancer but the accuracy of these data are uncertain. METHODS: Patients diagnosed with stage I-III breast cancer between 2003 and 2016 were identified using the North Carolina Central Cancer Registry and linked to Medicaid, Medicare, and private insurance claims. We calculated the sensitivity, specificity, positive predictive value, negative predictive value, and Kappa statistics for receipt of surgery and type of surgery (breast conserving surgery or mastectomy) using the insurance claims as the presumed gold standard. Analyses were stratified by race, insurance type, and rurality. RESULTS: Of 26,819 patients who met eligibility criteria, 23,125 were identified as having surgery in both the claims and registry for a sensitivity of 97.9% (95% CI 97.8%, 98.1%). There was also strong agreement for surgery type between the cancer registry and the insurance claims (Kappa: 0.91). Registry treatment data validity was lower for Medicaid insured patients than for Medicare and commercially insured patients. CONCLUSIONS: Cancer registry treatment data reliably identified receipt and type of breast cancer surgery. Cancer registries are an important source of data for understanding cancer care in underrepresented populations.

Hepatocyte growth factor pathway expression in breast cancer by race and subtype.

BACKGROUND: African American women have the highest risk of breast cancer mortality compared to other racial groups. Differences in tumor characteristics have been implicated as a possible cause; however, the tumor microenvironment may also contribute to this disparity in mortality. Hepatocyte growth factor (HGF) is a stroma-derived marker of the tumor microenvironment that may affect tumor progression differentially by race. OBJECTIVE: To examine whether an HGF gene expression signature is differentially expressed by race and tumor characteristics. METHODS: Invasive breast tumors from 1957 patients were assessed for a 38-gene RNA-based HGF gene expression signature. Participants were black (n = 1033) and non-black (n = 924) women from the population-based Carolina Breast Cancer Study (1993-2013). Generalized linear models were used to estimate the relative frequency differences (RFD) in HGF status by race, clinical, and demographic factors. RESULTS: Thirty-two percent of tumors were positive for the HGF signature. Black women were more likely [42% vs. 21%; RFD = + 19.93% (95% CI 16.00, 23.87)] to have HGF-positive tumors compared to non-black women. Triple-negative patients had a higher frequency of HGF positivity [82% vs. 13% in non-triple-negative; RFD = + 65.85% (95% CI 61.71, 69.98)], and HGF positivity was a defining feature of basal-like subtype [92% vs. 8% in non-basal; RFD = + 81.84% (95% CI 78.84, 84.83)]. HGF positivity was associated with younger age, stage, higher grade, and high genomic risk of recurrence (ROR-PT) score. CONCLUSION: HGF expression is a defining feature of basal-like tumors, and its association with black race and young women suggests it may be a candidate pathway for understanding breast cancer disparities.

Prognostic impact of socioeconomic status compared to overall stage for HPV-negative head and neck squamous cell carcinoma.

OBJECTIVE: To estimate the relative prognostic ability of socioeconomic status (SES) compared to overall stage for HPV-negative head and neck squamous cell carcinoma (HNSCC) MATERIALS AND METHODS: Data were obtained from the Carolina Head and Neck Cancer Epidemiology Study (CHANCE). An empirical 4-category SES classification system was created. Cox proportional hazards models, survival gradients, Bayesian information criterion (BIC), and Harrell's C index were used to estimate the prognostic ability of SES compared to stage on overall survival (OS). RESULTS: The sample consisted of 1229 patients with HPV-negative HNSCC. Patients with low SES had significantly increased risk of mortality at 5 years compared to patients with high SES (HR 3.11, 95% CI 2.07-4.67; p < 0.001), and the magnitude of effect was similar to overall stage (HR 3.01, 95% CI 2.35-3.86; p < 0.001 for stage IV versus I). Compared to overall stage, the SES classification system had a larger total survival gradient (35.8% vs. 29.1%), similar model fit (BIC statistic of 7412 and 7388, respectively), and similar model discriminatory ability (Harrell's C index of 0.61 and 0.64, respectively). The association between low SES and OS persisted after adjusting for age, sex, race, alcohol, smoking, overall stage, tumor site, and treatment in a multivariable model (HR 2.96, 95% CI 1.92-4.56; p < 0.001). CONCLUSION: SES may have a similar prognostic ability to overall stage for patients with HPV-negative HNSCC. Future research is warranted to validate these findings and identify evidence-based interventions for addressing barriers to care for patients with HNSCC.

Long-term Patterns of Excess Mortality among Endometrial Cancer Survivors.

BACKGROUND: We investigated excess mortality after endometrial cancer using conditional relative survival estimates and standardized mortality ratios (SMR). METHODS: Women diagnosed with endometrial cancer during 2000-2017 (N = 183,153) were identified in the Surveillance Epidemiology and End Results database. SMRs were calculated as observed deaths among endometrial cancer survivors over expected deaths among demographically similar women in the general U.S. POPULATION: Five-year relative survival was estimated at diagnosis and each additional year survived up to 12 years post-diagnosis, conditional on survival up to that year. RESULTS: For the full cohort, 5-year relative survival was 87.7%, 96.2%, and 97.1% at 1, 5, and 10 years post-diagnosis, respectively. Conditional 5-year relative survival first exceeded 95%, reflecting minimal excess mortality compared with the general population, at 4 years post-diagnosis overall. However, in subgroup analyses, conditional relative survival remained lower for Black women (vs. White) and for those with regional/distant stage disease (vs. localized) throughout the study period. The overall SMR for all-cause mortality decreased from 5.90 [95% confidence interval (CI), 5.81-5.99] in the first year after diagnosis to 1.16 (95% CI, 1.13-1.19) at 10+ years; SMRs were consistently higher for non-White women and for those with higher stage or grade disease. CONCLUSIONS: Overall, endometrial cancer survivors had only a small survival deficit beyond 4 years post-diagnosis. However, excess mortality was greater in magnitude and persisted longer into survivorship for Black women and for those with more advanced disease. IMPACT: Strategies to mitigate disparities in mortality after endometrial cancer will be needed as the number of survivors continues to increase.

Socioeconomic Status Drives Racial Disparities in HPV-negative Head and Neck Cancer Outcomes.

OBJECTIVES/HYPOTHESIS: To determine drivers of the racial disparity in stage at diagnosis and overall survival (OS) between black and white patients with HPV-negative head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Retrospective cohort study. METHODS: Data were examined from of a population-based HNSCC study in North Carolina. Multivariable logistic regression and Cox proportional hazards models were used to assess racial disparities in stage at diagnosis and OS with sequential adjustment sets. RESULTS: A total of 340 black patients and 864 white patients diagnosed with HPV-negative HNSCC were included. In the unadjusted model, black patients had increased odds of advanced T stage at diagnosis (OR 2.0; 95% CI [1.5-2.5]) and worse OS (HR 1.3, 95% CI 1.1-1.6) compared to white patients. After adjusting for age, sex, tumor site, tobacco use, and alcohol use, the racial disparity persisted for advanced T-stage at diagnosis (OR 1.7; 95% CI [1.3-2.3]) and showed a non-significant trend for worse OS (HR 1.1, 95% CI 0.9-1.3). After adding SES to the adjustment set, the association between race and stage at diagnosis was lost (OR: 1.0; 95% CI [0.8-1.5]). Further, black patients had slightly favorable OS compared to white patients (HR 0.8, 95% CI [0.6-1.0]; P = .024). CONCLUSIONS: SES has an important contribution to the racial disparity in stage at diagnosis and OS for HPV-negative HNSCC. Low SES can serve as a target for interventions aimed at mitigating the racial disparities in head and neck cancer. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1301-1309, 2021.

Integrating access to care and tumor patterns by race and age in the Carolina Breast Cancer Study, 2008-2013.

PURPOSE: Understanding breast cancer mortality disparities by race and age is complex due to disease heterogeneity, comorbid disease, and the range of factors influencing access to care. It is important to understand how these factors group together within patients. METHODS: We compared socioeconomic status (SES) and comorbidity factors in the Carolina Breast Cancer Study Phase 3 (CBCS3, 2008-2013) to those for North Carolina using the 2010 Behavioral Risk Factor Surveillance Study. In addition, we used latent class analysis of CBCS3 data to identify covariate patterns by SES/comorbidities, barriers to care, and tumor characteristics and examined their associations with race and age using multinomial logistic regression. RESULTS: Major SES and comorbidity patterns in CBCS3 participants were generally similar to patterns in the state. Latent classes were identified for SES/comorbidities, barriers to care, and tumor characteristics that varied by race and age. Compared to white women, black women had lower SES (odds ratio (OR) 6.3, 95% confidence interval (CI) 5.2, 7.8), more barriers to care (OR 5.6, 95% CI 3.9, 8.1) and several aggregated tumor aggressiveness features. Compared to older women, younger women had higher SES (OR 0.5, 95% CI 0.4, 0.6), more barriers to care (OR 2.1, 95% CI 1.6, 2.9) and aggregated tumor aggressiveness features. CONCLUSIONS: CBCS3 is representative of North Carolina on comparable factors. Patterns of access to care and tumor characteristics are intertwined with race and age, suggesting that interventions to address disparities will need to target both access and biology.

Employment Changes Following Breast Cancer Diagnosis: The Effects of Race and Place.

The financial implications of breast cancer diagnosis may be greater among rural and black women. Women with incident breast cancer were recruited as part of the Carolina Breast Cancer Study. We compared unadjusted and adjusted prevalence of cancer-related job or income loss, and a composite measure of either outcome, by rural residence and stratified by race. We included 2435 women: 11.7% were rural; 48.5% were black; and 38.0% reported employment changes after diagnosis. Rural women more often reported employment effects, including reduced household income (43.6% vs 35.4%, two-sided χ2 test P = .04). Rural white, rural black, and urban black women each more often reported income reduction (statistically significant vs. urban white women), although these groups did not meaningfully differ from each other. In multivariable regression, rural differences were mediated by socioeconomic factors, but racial differences remained. Programs and policies to reduce financial toxicity in vulnerable patients should address indirect costs of cancer, including lost wages and employment.

Epidemiology: Back to the Future.

In 2018, the Society for Epidemiologic Research and its partner journal, the American Journal of Epidemiology, assembled a working group to develop a set of papers devoted to the "future of epidemiology." These 14 papers covered a wide range of topic areas and perspectives, from thoughts on our profession, teaching, and methods to critical areas of substantive research. The authors of those papers considered current challenges and future opportunities for research and education. In light of past commentaries, 4 papers also include reflections on the discipline at present and in the future.

High Cancer Burden Among Antiretroviral Therapy Users in Malawi: A Record Linkage Study of Observational Human Immunodeficiency Virus Cohorts and Cancer Registry Data.

BACKGROUND: With antiretroviral therapy (ART), AIDS-defining cancer incidence has declined and non-AIDS-defining cancers (NADCs) are now more frequent among human immunodeficiency virus (HIV)-infected populations in high-income countries. In sub-Saharan Africa, limited epidemiological data describe cancer burden among ART users. METHODS: We used probabilistic algorithms to link cases from the population-based cancer registry with electronic medical records supporting ART delivery in Malawi's 2 largest HIV cohorts from 2000-2010. Age-adjusted cancer incidence rates (IRs) and 95% confidence intervals were estimated by cancer site, early vs late incidence periods (4-24 and >24 months after ART start), and World Health Organization (WHO) stage among naive ART initiators enrolled for at least 90 days. RESULTS: We identified 4346 cancers among 28 576 persons. Most people initiated ART at advanced WHO stages 3 or 4 (60%); 12% of patients had prevalent malignancies at ART initiation, which were predominantly AIDS-defining eligibility criteria for initiating ART. Kaposi sarcoma (KS) had the highest IR (634.7 per 100 000 person-years) followed by cervical cancer (36.6). KS incidence was highest during the early period 4-24 months after ART initiation. NADCs accounted for 6% of new cancers. CONCLUSIONS: Under historical ART guidelines, NADCs were observed at low rates and were eclipsed by high KS and cervical cancer burden. Cancer burden among Malawian ART users does not yet mirror that in high-income countries. Integrated cancer screening and management in HIV clinics, especially for KS and cervical cancer, remain important priorities in the current Malawi context.

Genetic ancestry and population differences in levels of inflammatory cytokines in women: Role for evolutionary selection and environmental factors.

Selection pressure due to exposure to infectious pathogens endemic to Africa may explain distinct genetic variations in immune response genes. However, the impact of those genetic variations on human immunity remains understudied, especially within the context of modern lifestyles and living environments, which are drastically different from early humans in sub Saharan Africa. There are few data on population differences in constitutional immune environment, where genetic ancestry and environment are likely two primary sources of variation. In a study integrating genetic, molecular and epidemiologic data, we examined population differences in plasma levels of 14 cytokines involved in innate and adaptive immunity, including those implicated in chronic inflammation, and possible contributing factors to such differences, in 914 AA and 855 EA women. We observed significant differences in 7 cytokines, including higher plasma levels of CCL2, CCL11, IL4 and IL10 in EAs and higher levels of IL1RA and IFNα2 in AAs. Analyses of a wide range of demographic and lifestyle factors showed significant impact, with age, education level, obesity, smoking, and alcohol intake, accounting for some, but not all, observed population differences for the cytokines examined. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with percent of African ancestry among AAs. Through admixture mapping, the signal was pinpointed to local ancestry at 1q23, with fine-mapping analysis refined to the Duffy-null allele of rs2814778. In AA women, this variant was a major determinant of systemic levels of CCL2 (p = 1.1e-58) and CCL11 (p = 2.2e-110), accounting for 19% and 40% of the phenotypic variance, respectively. Our data reveal strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. The substantial immune differences by ancestry may have broad implications to health disparities between AA and EA populations.