Breast Cancer Survival Defined by the ER/PR/HER2 Subtypes and a Surrogate Classification according to Tumor Grade and Immunohistochemical Biomarkers

Introduction. ER, PR, and HER2 are routinely available in breast cancer specimens. The purpose of this study is to contrast breast cancer-specific survival for the eight ER/PR/HER2 subtypes with survival of an immunohistochemical surrogate for the molecular subtype based on the ER/PR/HER2 subtypes and tumor grade.Methods. We identified 123,780 cases of stages 1–3 primary female invasive breast cancer from California Cancer Registry. The surrogate classification was derived using ER/PR/HER2 and tumor grade. Kaplan-Meier survival analysis and Cox proportional hazards modeling were used to assess differences in survival and risk of mortality for the ER/PR/HER2 subtypes and surrogate classification within each stage.Results. The luminal B/HER2− surrogate classification had a higher risk of mortality than the luminal B/HER2+ for all stages of disease. There was no difference in risk of mortality between the ER+/PR+/HER2− and ER+/PR+/HER2+ in stage 3. With one exception in stage 3, the ER-negative subtypes all had an increased risk of mortality when compared with the ER-positive subtypes.Conclusions. Assessment of survival using ER/PR/HER2 illustrates the heterogeneity of HER2+ subtypes. The surrogate classification provides clear separation in survival and adjusted mortality but underestimates the wide variability within the subtypes that make up the classification.

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Molecular Subtype May Be More Associated With Prognosis and Chemotherapy Benefit Than Tumor Size in T1N0 Breast Cancer Patients: An Analysis of 2,168 Patients for Possible De-Escalation Treatment

Frontiers in Oncology ◽

10.3389/fonc.2021.636266 ◽

2021 ◽

Vol 11 ◽

Author(s):

Siji Zhu ◽

Yafen Li ◽

Weiguo Chen ◽

Xiaochun Fei ◽

Kunwei Shen ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Size ◽

Proportional Hazards ◽

Cox Regression ◽

Molecular Subtype ◽

Growth Factor Receptor ◽

Disease Free Survival ◽

Cox Proportional Hazards ◽

Breast Cancer Patients ◽

Cancer Specific Survival

PurposeBreast cancer (BC) patients with T1N0 tumors have relatively favorable clinical outcomes. However, it remains unclear whether molecular subtypes can aide in prognostic prediction for such small, nodal-negative BC cases and guide decision-making about escalating or de-escalating treatments.Patients and MethodsT1N0 BC patients diagnosed between 2009 and 2017 were included and classified into three subgroups according to receptor status: 1) hormonal receptor (HR)+/human epidermal growth factor receptor-2 (HER2)−; 2) HER2+; and 3) triple negative (TN) (HR−/HER2−). Patients’ characteristics and relapse events were reviewed. Kaplan–Meier analysis and Cox regression were used to assess the iDFS and BCSS. The effects of risk factors and adjuvant treatment benefits were evaluated by calculating hazard ratios (HRs) for invasive disease-free survival (iDFS) and breast cancer-specific survival (BCSS) with Cox proportional hazards models.ResultsIn total, 2,168 patients (1,435 HR+/HER2−, 427 HER2+, 306 TN) were enrolled. The 5-year iDFS rates were 93.6, 92.7, and 90.6% for HR+/HER2−, HER2+, and TN patients, respectively (P = 0.039). Multivariate analysis demonstrated that molecular subtype (P = 0.043), but not tumor size (P = 0.805), was independently associated with iDFS in T1N0 BC. TN patients [HRs = 1.77, 95% confidence interval (CI) = 1.11–2.84, P = 0.018] had a higher recurrence risk than HR+/HER2− patients. Adjuvant chemotherapy benefit was not demonstrated in all T1N0 patients but interacted with molecular subtype status. TN (adjusted HRs = 2.31, 95% CI = 0.68–7.54) and HER2+ (adjusted HRs = 2.26, 95% CI = 0.95–5.63) patients receiving chemotherapy had superior iDFS rates. Regarding BCSS, molecular subtype tended to be related to outcome (P = 0.053) and associated with chemotherapy benefit (P = 0.005).ConclusionMolecular subtype was more associated with disease outcome and chemotherapy benefit than tumor size in T1N0 BC patients, indicating that it may guide possible clinical de-escalating therapy in T1N0 BC.

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Changes in Metabolic Syndrome Status and Breast Cancer Risk: A Nationwide Cohort Study

Cancers ◽

10.3390/cancers13051177 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1177

Author(s):

In Young Choi ◽

Sohyun Chun ◽

Dong Wook Shin ◽

Kyungdo Han ◽

Keun Hye Jeon ◽

...

Keyword(s):

Breast Cancer ◽

Metabolic Syndrome ◽

Proportional Hazards ◽

Screening Program ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Models ◽

Hazard Ratios ◽

Increased Risk ◽

Health Screening Program ◽

Design And Methods

Objective: To our knowledge, no studies have yet looked at how the risk of developing breast cancer (BC) varies with changes in metabolic syndrome (MetS) status. This study aimed to investigate the association between changes in MetS and subsequent BC occurrence. Research Design and Methods: We enrolled 930,055 postmenopausal women aged 40–74 years who participated in a biennial National Health Screening Program in 2009–2010 and 2011–2012. Participants were categorized into four groups according to change in MetS status during the two-year interval screening: sustained non-MetS, transition to MetS, transition to non-MetS, and sustained MetS. We calculated multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for BC incidence using the Cox proportional hazards models. Results: At baseline, MetS was associated with a significantly increased risk of BC (aHR 1.11, 95% CI 1.06–1.17) and so were all of its components. The risk of BC increased as the number of the components increased (aHR 1.46, 95% CI 1.26–1.61 for women with all five components). Compared to the sustained non-MetS group, the aHR (95% CI) for BC was 1.11 (1.04–1.19) in the transition to MetS group, 1.05 (0.96–1.14) in the transition to non-MetS group, and 1.18 (1.12–1.25) in the sustained MetS group. Conclusions: Significantly increased BC risk was observed in the sustained MetS and transition to MetS groups. These findings are clinically meaningful in that efforts to recover from MetS may lead to reduced risk of BC.

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Supper Timing and Cardiovascular Mortality: The Japan Collaborative Cohort Study

Nutrients ◽

10.3390/nu13103389 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3389

Author(s):

Jingyun Tang ◽

Jia-Yi Dong ◽

Ehab S. Eshak ◽

Renzhe Cui ◽

Kokoro Shirai ◽

...

Keyword(s):

Hemorrhagic Stroke ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Stroke Mortality ◽

Hazard Ratios ◽

Risk Of Mortality ◽

Increased Risk ◽

Study Participants

Evidence on the role of supper timing in the development of cardiovascular disease (CVD) is limited. In this study, we examined the associations between supper timing and risks of mortality from stroke, coronary heart disease (CHD), and total CVD. A total of 28,625 males and 43,213 females, aged 40 to 79 years, free from CVD and cancers at baseline were involved in this study. Participants were divided into three groups: the early supper group (before 8:00 p.m.), the irregular supper group (time irregular), and the late supper group (after 8:00 p.m.). Cox proportional hazards regression models were used to calculate hazard ratios (HRs) for stroke, CHD, and total CVD according to the supper time groups. During the 19-year follow-up, we identified 4706 deaths from total CVD. Compared with the early supper group, the multivariable HR of hemorrhagic stroke mortality for the irregular supper group was 1.44 (95% confidence interval [CI]: 1.05–1.97). There was no significant association between supper timing and the risk of mortality from other types of stroke, CHD, and CVD. We found that adopting an irregular supper timing compared with having dinner before 8:00 p.m. was associated with an increased risk of hemorrhagic stroke mortality.

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Abstract MP49: Sugar Sweetened and Artificially Sweetened Beverages and risk of Mortality in US adults

Circulation ◽

10.1161/circ.129.suppl_1.mp49 ◽

2014 ◽

Vol 129 (suppl_1) ◽

Author(s):

Vasanti S Malik ◽

An Pan ◽

Lawrence de Koning ◽

Eva Schernhammer ◽

Walter C Willett ◽

...

Keyword(s):

Proportional Hazards ◽

Total Mortality ◽

Cox Proportional Hazards ◽

Health Study ◽

Sweetened Beverages ◽

Risk Of Mortality ◽

Regular Consumption ◽

Increased Risk ◽

Artificially Sweetened Beverages ◽

Cvd Mortality

Background: Sugar sweetened beverages (SSBs) are the single largest source of calories and added sugars in the US diet and regular consumption has been associated with weight gain and risk of chronic diseases. Artificially sweetened beverages (ASBs) are often suggested as alternatives to SSB but little is known about their long-term health effects. Whether consumption of SSBs or ASBs is associated with risk of mortality is unknown. Methods: We prospectively followed 38,602 men from the Health Professional’s Follow-up study (1986-2010) and 82,592 women from the Nurses’ Health study (1980-2010) who were free from cardiovascular disease (CVD) and cancer at baseline. Diet was assessed using validated food frequency questionnaires every 4 years and Cox Proportional Hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Results: We documented 27,691 deaths (6,631 CVD and 10,447 cancer deaths) during 3.14 million person-years. After adjusting for major dietary and lifestyle risk factors, and BMI, baseline diabetes, hypertension and hypercholesterolemia, consumption of SSBs was associated with an increased risk of total mortality, which was mainly driven by CVD mortality among individuals consuming at least 2 servings per day; pooled HRs (95% CIs) across categories (<1/month, 1-4/month, 2-6/week, 1-<2/day and ≥2/day) were 1.00, 0.95 (0.91, 0.98), 0.96 (0.93, 0.99), 1.02 (0.96, 1.08), and 1.18 (1.04, 1.33), respectively (P-trend= 0.0001) for total mortality, and 1.00, 0.97 (0.90, 1.02), 0.96 (0.90, 1.02), 1.04 (0.93, 1.16) and 1.28 (1.09, 1.51), respectively (P-trend=0.007) for CVD mortality. In contrast, ASBs were not associated with mortality; pooled HR’s (95% CIs) across categories (<1/month, 1-4/month, 2-6/week, 1-<2/day and ≥2/day) were 1.00, 0.92 (0.89, 0.95), 0.91 (0.86, 0.97), 0.91 (0.86, 0.95) and 0.99 (0.85, 1.15), respectively (P-trend=0.50) for total mortality and 1.00, 0.86 (0.80, 0.92), 0.87 (0.81, 0.94), 0.96 (0.88, 1.06) and 0.96 (0.74, 1.25), respectively (P-trend=0.99) for CVD mortality. No associations were observed with cancer mortality for either SSBs or ASBs in multi-variable adjusted models. Conclusion: Regular consumption of SSBs is associated with an increased risk of total and CVD mortality, providing additional support for recommendations and policies to limit intake of these beverages.

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Osteoarthritis and risk of mortality in the USA: a population-based cohort study

International Journal of Epidemiology ◽

10.1093/ije/dyy187 ◽

2018 ◽

Vol 47 (6) ◽

pp. 1821-1829 ◽

Cited By ~ 15

Author(s):

Angelico Mendy ◽

JuYoung Park ◽

Edgar Ramos Vieira

Keyword(s):

Proportional Hazards ◽

Population Based ◽

Cox Proportional Hazards ◽

Self Report ◽

Joint Disease ◽

Renal Diseases ◽

X Rays ◽

Risk Of Mortality ◽

Increased Risk ◽

Risk Of Cancer

Abstract Background Osteoarthritis (OA) is the most common joint disease, but its association with mortality is unclear. Methods We analysed data on adult participants in the 1988–94 and 1999–2010 National Health and Nutrition Examination Surveys, followed for mortality through 2011. OA was defined by self-report, and in a subset of participants 60 years or older with knee X-rays, radiographic knee OA (RKOA) was defined as Kellgren–Lawrence score ≥2. Cox proportional hazards were used to determine the mortality hazard ratio (HR) associated with self-reported OA and RKOA, adjusting for covariates. Results The sample included 51 938 participants followed for a median 8.9 years; 2589 of them had knee X-rays and were followed for a median of 13.6 years. Self-reported OA and RKOA prevalences were 6.6% and 40.6%, respectively. Self-reported OA was not associated with mortality. RKOA was associated with an increased risk of mortality from cardiovascular diseases (CVD) {HR 1.43 [95% confidence interval (CI): 1.32, 1.64]}, diabetes [HR 2.04 (1.87, 2.23)] and renal diseases [HR 1.14 (1.04, 1.25)], but with a reduced risk of cancer mortality [HR 0.88 (0.80, 0.96)]. Participants with early RKOA onset (diagnosed before age 40) had a higher risk of mortality from all causes [HR 1.53 (1.43, 1.65)] and from diabetes [HR 7.18 (5.45, 9.45)]. Obese participants with RKOA were at increased risk of mortality from CVD [HR 1.89 (1.56, 2.29)] and from diabetes [HR: 3.42 (3.01, 3.88)]. Conclusions Self-reported OA was not associated with mortality. RKOA was associated with higher CVD, diabetes and renal mortality, especially in people with early onset of the disease or with obesity.

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Brain metastases in breast cancer: Different survival by biological subtype and Ki67 expression

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.1069 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 1069-1069

Author(s):

D. Sartori ◽

M. Bari ◽

G. L. Pappagallo ◽

F. Rosetti ◽

S. Olsen ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Proportional Hazards ◽

Fold Increase ◽

Cox Proportional Hazards ◽

Her2 Overexpression ◽

Cns Metastases ◽

Risk Of Death ◽

Pathologic Features ◽

Increased Risk

1069 Background: Ten to 15% of patients (pts) with breast cancer will be diagnosed with central nervous system (CNS) metastases, and autopsy series suggest that up to 30% of pts have evidence of CNS disease at the time of death. The idenfication of factors that may predispose to CNS metastasis may help lead to earlier detection and possibly to improvement in disease management. Methods: Breast cancer pts with CNS metastases were identified within a database of 1300 breast cancer diganoses from 1995 to 2007 at the Department of Oncology, Azienda ULSS 13 VE. Pathologic features of tumor samples were examined using standard immunohistochemical assays. Results: Fifty-one pts with CNS metastases were identified. Median age at primary breast cancer diagnosis was 49 years (range, 28–78); median time to CNS metastases was 45 months (range, 3–244). HER2 overexpression was found in tumors from 25 pts (49.0%); 23 pts had tumors lacking overexpression of HER2, estrogen receptors (ER), and progesterone receptors (PgR) (ie, “triple negative” disease). Overexpression of p53 (at least 20% tumor cells positive), Ki67 (at least 20%), and BCL2 (at least 30%) were detected in tumors from 16 pts (31.4%), 32 pts (62.7%), and 14 pts (27.5%), respectively. Median survival from CNS involvement was 3.67 months (95% CI 2.05–5.28), with 24.4% and 15.3% of patients estimated to be alive at 12 and 24 months, respectively (Kaplan-Meier product limit method). A Cox proportional hazards analysis found that Ki67 overexpression was the only factor independently associated with a significantly increased risk of death (2.7-fold increase, p=0.028), while triple negative status was associated with a 1.8-fold increase in the risk of death (P=0.08) (Table). Conclusions: In our series of breast cancer pts with CNS metastases, nearly all had either HER2 overexpression or triple-negative disease. Pts whose tumors had higher proliferative indices, assessed by Ki67, had the poorest prognosis. [Table: see text] [Table: see text]

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Chemotherapy and Cardiotoxicity in Older Breast Cancer Patients: A Population-Based Study

Journal of Clinical Oncology ◽

10.1200/jco.2005.02.5841 ◽

2005 ◽

Vol 23 (34) ◽

pp. 8597-8605 ◽

Cited By ~ 226

Author(s):

John J. Doyle ◽

Alfred I. Neugut ◽

Judith S. Jacobson ◽

Victor R. Grann ◽

Dawn L. Hershman

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Proportional Hazards ◽

Population Based ◽

Cox Proportional Hazards ◽

Stage I ◽

Breast Cancer Patients ◽

Primary Tumors ◽

Increased Risk

Purpose Adjuvant chemotherapy, especially with anthracyclines, is known to cause acute and chronic cardiotoxicity in breast cancer patients. We studied the cardiac effects of chemotherapy in a population-based sample of breast cancer patients aged ≥ 65 years with long-term follow-up. Patients and Methods In the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we analyzed treatments and outcomes among women ≥ 65 years of age who were diagnosed with stage I to III breast cancer from January 1, 1992 to December 31, 1999. Propensity scores were used to control for baseline heart disease (HD) and other known predictors of chemotherapy, and Cox proportional hazards models were used to estimate the risk of cardiomyopathy (CM), congestive heart failure (CHF), and HD after chemotherapy. Results Of 31,748 women with stage I to III breast cancer, 5,575 (18%) received chemotherapy. Chemotherapy was associated with younger age, fewer comorbidities, hormone receptor negativity, multiple primary tumors, and advanced disease. Patients who received chemotherapy were less likely than other patients to have pre-existing HD (45% v 55%, respectively; P < .001). The hazard ratios for CM, CHF, and HD for patients treated with doxorubicin (DOX) compared with patients who received no chemotherapy were 2.48 (95% CI, 2.10 to 2.93), 1.38 (95% CI, 1.25 to 1.52), and 1.35 (95% CI, 1.26 to 1.44), respectively. The relative risk of cardiotoxicity among patients who received DOX compared with untreated patients remained elevated 5 years after diagnosis. Conclusion When baseline HD was taken into account, chemotherapy, especially with anthracyclines, was associated with a substantially increased risk of CM. As the number of long-term survivors grows, identifying and minimizing the late effects of treatment will become increasingly important.

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Association between Serum Interleukin-6 Concentration and Mortality in Patients with Coronary Artery Disease

Mediators of Inflammation ◽

10.1155/2013/726178 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 32

Author(s):

Dongfang Su ◽

Zhongxia Li ◽

Xinrui Li ◽

Yuming Chen ◽

Yuan Zhang ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Cardiovascular Mortality ◽

Interleukin 6 ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratios ◽

Risk Of Mortality ◽

Increased Risk ◽

Artery Disease

Objectives. To evaluate whether serum interleukin-6 (IL-6) is associated with increased risk of mortality in coronary artery disease (CAD) patients.Methods. We performed a prospective cohort study of 718 CAD patients from the Guangzhou Cardiovascular Disease Cohort (GCDC) study. Multivariable-adjusted Cox proportional hazards regression analyses were used to examine the association between serum IL-6 with all-cause and cardiovascular mortality.Results. During the 1663 person-years of followup, the cumulative all-cause mortality and cardiovascular mortality were 6.5% (n=47) and 3.3% (n=24), respectively. The mean length of followup was2.32±0.81years. In the multivariable analyses, a one-SD increment in log-transformed serum IL-6 was positively associated with an increased risk of all-cause and cardiovascular mortality, with hazard ratios (HR) of 2.93 (95% CI, 2.11–4.08) and 2.04 (95% CI, 1.34–3.68) within the patients combined and 2.98 (95% CI, 2.12–4.18) and 3.10 (95% CI, 1.98–4.85) within males, respectively. Patients in the highest serum IL-6 tertile versus the lowest tertile were at higher risk of all-cause and cardiovascular mortality, with HR of 17.12 (95% CI 3.11–71.76) and 8.68 (95% CI, 1.88–37.51), respectively.Conclusions. In hospitalized patients with CAD, serum IL-6 is significantly associated with all-cause and cardiovascular mortality.

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Associations Between Anemia, Cognitive Impairment, and All-Cause Mortality in Oldest-Old Adults: A Prospective Population-Based Cohort Study

Frontiers in Medicine ◽

10.3389/fmed.2021.613426 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jia Wangping ◽

Han Ke ◽

Wang Shengshu ◽

Song Yang ◽

Yang Shanshan ◽

...

Keyword(s):

Cohort Study ◽

Cognitive Impairment ◽

Mortality Risk ◽

Proportional Hazards ◽

Oldest Old ◽

Population Based ◽

Cox Proportional Hazards ◽

Risk Of Mortality ◽

Increased Risk ◽

All Cause Mortality

Objective: To evaluate the combined effects of anemia and cognitive function on the risk of all-cause mortality in oldest-old individuals.Design: Prospective population-based cohort study.Setting and Participants: We included 1,212 oldest-old individuals (men, 416; mean age, 93.3 years).Methods: Blood tests, physical examinations, and health questionnaire surveys were conducted in 2012 were used for baseline data. Mortality was assessed in the subsequent 2014 and 2018 survey waves. Cox proportional hazards models were used to evaluate anemia, cognitive impairment, and mortality risk. We used restricted cubic splines to analyze and visualize the association between hemoglobin (Hb) levels and mortality risk.Results: A total of 801 (66.1%) deaths were identified during the 6-year follow-up. We noted a significant association between anemia and mortality (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.14–1.54) after adjusting for confounding variables. We also observed a dose-response relationship between the severity of anemia and mortality (P < 0.001). In the restricted cubic spline models, Hb levels had a reverse J-shaped association with mortality risk (HR 0.88, 95% CI 0.84–0.93 per 10 g/L-increase in Hb levels below 130 g/L). The reverse J-shaped association persisted in individuals without cognitive impairment (HR 0.88, 95% CI 0.79–0.98 per 10 g/L-increase in Hb levels below 110 g/L). For people with cognitive impairment, Hb levels were inversely associated with mortality risk (HR 0.83, 95% CI 0.78–0.89 per 10 g/L-increase in Hb levels below 150 g/L). People with anemia and cognitive impairment had the highest risk of mortality (HR 2.60, 95% CI 2.06–3.27).Conclusion: Our results indicate that anemia is associated with an increased risk of mortality in oldest-old people. Cognitive impairment modifies the association between Hb levels and mortality.

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Prediabetes, Diabetes, and the Risk of All-Cause and Cause-Specific Mortality in a Japanese Working Population: Japan Epidemiology Collaboration on Occupational Health Study

10.2337/figshare.13483515 ◽

2021 ◽

Author(s):

Zobida Islam ◽

Shamima Akter ◽

Yosuke Inoue ◽

Huan Hu ◽

Keisuke Kuwahara ◽

...

Keyword(s):

Proportional Hazards ◽

Cox Proportional Hazards ◽

World Health ◽

Health Study ◽

Expert Committee ◽

Risk Of Mortality ◽

Japanese Workers ◽

Increased Risk ◽

Health Organization

Objective: Prediabetes has been suggested to increase mortality risk; however, the definitions of prediabetes that can predict mortality remain elusive. We prospectively investigated the association of multiple definitions of prediabetes with the risk of mortality from all-causes, cardiovascular disease (CVD), and cancer in Japanese workers. Research design and methods: The study included 62,785 workers who underwent a health checkup in 2010 or 2011 and were followed up for mortality from 2012 to March 2019. <a>Prediabetes was defined according to fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c) level or a combination of both using the American Diabetes Association (ADA) or World Health Organization (WHO)/International Expert Committee (IEC) criteria. </a>The Cox proportional hazards regression model was used to investigate the associations. Results: Over a 7-year follow-up, 229 deaths were documented. <a>Compared with normoglycemia, prediabetes defined according to ADA criteria was associated with a higher risk of all-cause (hazard ratio [HR] 1.53; 95% confidence interval [CI] 1.12–2.09) and cancer (HR 2.37; 95% CI 1.45–3.89) mortality but not with CVD mortality. </a>The results were materially unchanged when prediabetes was defined according to ADA FPG, ADA HbA1c, WHO FPG, or combined WHO/IEC criteria. Diabetes was associated with the risk of all-cause, CVD, and cancer mortality. Conclusion: In a cohort of Japanese workers, FPG- and HbA1c-defined prediabetes according to ADA or WHO/IEC was each associated with a significantly increased risk of mortality from all-causes and cancer but not CVD.

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