Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimers disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-ε4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N = 63, Mean age = 57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N = 32) remained on their HT regimen and half (N = 31) went off HT for approximately two years (Mean  = 1.93 years). Participants included 24 APOE-ε4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR  = 6.26, 95% CI  = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-ε4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-ε4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.

Purpose

Re-examine association of fluoxetine and paroxetine with risk of testicular cancer noted in drug screening, with 4 years more follow-up and expanded study of these and other antidepressant drugs.

Methods

In the Kaiser Permanente Medical Care Program in Northern California, 906 men with testicular cancer diagnosed August 1996-December 2010 were compared with 38,253 matched controls with race/ethnicity recorded regarding receipt of antidepressant drugs at least 2 years before diagnosis or control index date. Analyses emphasized duration of use and histological subgroups.

Results

With control for race/ethnicity and use of other antidepressant drugs, odds ratios (OR) and 95 % confidence intervals (CI) for associations with testicular cancer were as follows: fluoxetine 1.22 (0.88-1.71), paroxetine 1.19 (0.78-1.83), and 1.21 (0.92-1.58) for all serotonin reuptake inhibitors. There was no statistically significant association with risk of all testicular cancers or their histological subtypes for any individual drug or for tricyclics or all antidepressants combined except for citalopram with all testicular cancers 2.55 (1.43-4.52) and those of mixed histology 4.36 (1.50-12.68) and nefazodone with embryonal cancers 9.79 (1.85-51.81). These could readily be chance findings in the context of the many analyses that were performed. Duration of use was not associated with risk of the drugs and drug groups with sufficient numbers of exposed cases for analysis.

Conclusions

We found little evidence to support a testicular carcinogenic effect of fluoxetine, paroxetine, or other antidepressant drugs, but a weakly positive association is not ruled out. The signals in prior screening may have been due to chance and/or uncontrolled confounding.

BACKGROUND: We evaluated smoking differences across nativity and race/ethnicity among women diagnosed with breast cancer. METHODS: In our Northern Californian pooled population of 5,653 [670 Asian, 690 Hispanic, and 4,300 non-Hispanic White (White)] women diagnosed with breast cancer, we evaluated smoking differences across nativity, race/ethnicity, and acculturation and effect modification of nativity by race/ethnicity and education. RESULTS: Foreign-born women currently smoked less than US-born women [odds ratio (OR) = 0.46, 95% confidence limit (CL): 0.29-0.72]. Hispanic (OR = 0.50; 95% CL: 0.32-0.78) women currently smoked less than White women. Among those who ever smoked (n = 2,557), foreign-born women smoked 5.23 fewer pack-years (PY) than US-born women (95% CL: -2.75 to -7.70). Furthermore, Asian (-4.60, 95% CL: -0.81 to -8.39) and Hispanic (-6.79, 95% CL: -4.14 to -9.43) women smoked fewer PY than White women. Associations were generally suggestive of greater smoking with greater acculturation (immigration age, US years, survey language). Finally, associations for nativity differed by education but not race/ethnicity, with a higher likelihood of smoking in US-born women only among those with less than a bachelors degree (OR = 2.84, 95% CL: 2.15-3.77; current smoking: P = 0.01, PY: P = 0.05). CONCLUSIONS: Asian and Hispanic (vs. White) and foreign-born (vs. US-born) breast cancer survivors reported fewer smoking behaviors. Smoking differences across nativity and education were driven by higher rates of smoking in US-born women with lower educational attainment. IMPACT: Smoking behavioral patterns were similar among breast cancer survivors and the general population, informing potential smoking interventions.

PURPOSE: The incidence of triple-negative breast cancer (TNBC) is higher in Black women compared to White women which is not explained by racial differences in body mass index (BMI). As BMI has limitations as an anthropometric measure, we used different anthropometric measures to examine associations with TNBC by race. METHOD: Of 161,808 postmenopausal participants in Womens Health Initiative, eligible were a subsample of 121,744 White and Black postmenopausal women enrolled from 1993 to 1998, 50-79 years of age with anthropometric measures who were followed for breast cancer incidence until March 2019. At entry, BMI, waist circumference (WC), and waist-hip ratio (WHR) were measured using standardized methods. Breast cancers were verified by central medical record review. Associations between anthropometric measures and triple-negative breast cancer risk were examined using Cox proportional hazards regression models. RESULTS: After 17.6 years (median) follow-up, there were 87 Black women and 529 White women with incident triple-negative breast cancer. Overall, there were no significant associations between anthropometric measures and risk of triple-negative breast cancer. However, compared to White women with normal BMI, White women with obesity (BMI ≥ 30) (HR 0.76, 95% CI 0.60, 0.96) were significantly associated with a lower risk of triple-negative breast cancer. And larger waist circumference (HR per centimeter 0.99, 95% CI 0.99, 1.00) was significantly associated with a lower risk of triple-negative breast cancer among White women. CONCLUSION: Overall, among postmenopausal women, anthropometric measures were not associated with risk of TNBC. The association among White women with larger waist circumference and women with obesity with a lower risk of triple-negative breast cancer needs further confirmation.

Background

Integrated health care delivery systems, with their comprehensive and integrated electronic medical records (EMR), are well-poised to conduct research that leverages the detailed clinical data within the EMRs. However, information regarding the representativeness of these clinical populations is limited, and thus the generalizability of research findings is uncertain.

Methods

Using data from the population-based California Cancer Registry, we compared age-adjusted distributions of patient and neighborhood characteristics for three groups of breast cancer patients: 1) those diagnosed within Kaiser Permanente Northern California (KPNC), 2) non-KPNC patients from NCI-designated cancer centers, and 3) those from all other hospitals.

Results

KPNC patients represented 32 % (N = 36,109); cancer center patients represented 7 % (N = 7805); and all other hospitals represented 61 % (N = 68,330) of the total breast cancer patients from this geographic area during 1996-2009. Compared with cases from all other hospitals, KPNC had slightly fewer non-Hispanic Whites (70.6 % versus 74.4 %) but more Blacks (8.1 % versus 5.0 %), slightly more patients in the 50-69 age range and fewer in the younger and older age groups, a slightly lower proportion of in situ but higher proportion of stage I disease (41.6 % versus 38.9 %), were slightly less likely to reside in the lowest (4.2 % versus 6.5 %) and highest (36.2 % versus 39.0 %) socioeconomic status neighborhoods, and more likely to live in suburban metropolitan areas and neighborhoods with more racial/ethnic minorities. Cancer center patients differed substantially from patients from KPNC and all other hospitals on all characteristics assessed. All differences were statistically significant (p < .001).

Conclusions

Although much of clinical research discoveries are based in academic medical centers, patients from large, integrated medical centers are likely more representative of the underlying population, providing support for the generalizability of cancer research based on electronic data from these centers.

OBJECTIVE: The use of relative and absolute effect estimates has important implications for the interpretation of study findings. Likewise, examining additive and multiplicative interaction can lead to differing conclusions about the joint effects of two exposure variables. The aim of this paper is to examine the relationship between BMI and mortality on the relative and absolute scales and investigate interaction between BMI and age. METHODS: Data from 68,132 participants in the Womens Health Initiative (WHI) study were used. The risk ratio and risk difference of BMI on mortality were estimated. A product term was also included to examine interaction between BMI and age on the multiplicative scale, and the relative excess risk of interaction was calculated to measure additive interaction. RESULTS: Results demonstrated that the mortality risk ratio decreased as women aged, but the mortality risk difference increased as women aged. Evidence of additive and multiplicative interaction between age and BMI was found. CONCLUSIONS: In postmenopausal women, the relative mortality risk associated with high BMI decreased with increasing age, but the absolute risk of high BMI increased with increasing age. This indicates the importance of considering the interaction between age and BMI to understand mortality risk in older women.

Purpose

Metabolic, hormonal, and hemostatic changes associated with pregnancy loss (stillbirth and miscarriage) may contribute to the development of cardiovascular disease (CVD) in adulthood. This study evaluated prospectively the association between a history of pregnancy loss and CVD in a cohort of postmenopausal women.

Methods

Postmenopausal women (77,701) were evaluated from 1993-1998. Information on baseline reproductive history, sociodemographic, and CVD risk factors were collected. The associations between 1 or 2 or more miscarriages and 1 or more stillbirths with occurrence of CVD were evaluated using multiple logistic regression.

Results

Among 77,701 women in the study sample, 23,538 (30.3%) reported a history of miscarriage; 1,670 (2.2%) reported a history of stillbirth; and 1,673 (2.2%) reported a history of both miscarriage and stillbirth. Multivariable-adjusted odds ratio (OR) for coronary heart disease (CHD) for 1 or more stillbirths was 1.27 (95% CI, 1.07-1.51) compared with no stillbirth; for women with a history of 1 miscarriage, the OR=1.19 (95% CI, 1.08-1.32); and for 2 or more miscarriages the OR=1.18 (95% CI, 1.04-1.34) compared with no miscarriage. For ischemic stroke, the multivariable odds ratio for stillbirths and miscarriages was not significant.

Conclusions

Pregnancy loss was associated with CHD but not ischemic stroke. Women with a history of 1 or more stillbirths or 1 or more miscarriages appear to be at increased risk of future CVD and should be considered candidates for closer surveillance and/or early intervention; research is needed into better understanding the pathophysiologic mechanisms behind the increased risk of CVD associated with pregnancy loss.

PURPOSE: To examine the association of a traditional Mexican diet score with risk of total, breast, and colorectal cancer among women of Mexican ethnic descent in the Womens Health Initiative (WHI). METHODS: Participants were WHI enrollees who self-identified as being of Mexican descent. Data from food frequency questionnaires self-administered at study baseline were used to calculate the MexD score, with higher scores indicating greater adherence to an a priori-defined traditional Mexican diet (high in dietary fiber, vegetables, and legumes). Incident cancers were self-reported by participants from 1993 to 2020 and adjudicated by trained physicians. We used multivariable-adjusted Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 2,343 Mexican descent women (median baseline age: 59 years), a total of 270 cancers (88 breast, 37 colorectal) occurred during a mean follow-up of 14.4 years. The highest tertile of MexD score was associated with a lower risk of all-cancer incidence (HR: 0.67; 95% CI 0.49-0.91; p-trend: 0.01) and colorectal cancer (HR: 0.38; 95% CI 0.14-0.998; p-trend < 0.05), with each unit increase in the MexD score associated with a 6% lower risk of all-cancer incidence (HR: 0.94; 95% CI 0.88-0.99). There was no statistically significant association with risk of breast cancer. CONCLUSION: Consumption of a traditional Mexican diet was associated with a significantly lower risk of all-cancer incidence and colorectal cancer. Confirmation of these findings in future studies is important, given the prevalence of colorectal cancer and a growing U.S. population of women of Mexican descent.

The association of smoking with outcomes following breast cancer prognosis is not well understood. In a cohort study called Life After Cancer Epidemiology (LACE), 2,265 women diagnosed with breast cancer were followed for a median of 12 years. We used multivariable proportional-hazards models to determine whether smoking, assessed approximately two years post-diagnosis, was associated with risk of death among these women. We also undertook a systematic review of all cohort studies to date that have examined the association between smoking and breast cancer mortality. Compared with never smokers, women who were current smokers had a twofold higher rate of dying from breast cancer [hazard ratio (HR) = 2.01, 95 % confidence interval (CI) 1.27-3.18] and an approximately fourfold higher rate of dying from competing (non-breast cancer) causes (HR = 3.84, 95 % CI 2.50-5.89). Among seven studies that met the inclusion criteria in the systematic review, three studies and our own reported significantly increased risk of breast cancer death with current smoking. We found little evidence of an association between former smoking and breast cancer mortality (HR = 1.24, 95 % CI 0.94-1.64). Consistent with findings from our prospective observational study, the systematic review of seven additional studies indicates positive association of current smoking with breast cancer mortality, but weak association with former smoking. Women who smoke following breast cancer diagnosis and treatment are at higher risk of death both from breast cancer and other causes.

Background

Women of Mexican descent are disproportionally affected by obesity, systemic inflammation, and insulin resistance (IR). Available approaches used to give scores to dietary patterns relative to dietary guidelines may not effectively capture traditional diets of Mexicans, who comprise the largest immigrant group in the United States.

Objectives

We characterized an a priori traditional Mexican diet (MexD) score high in corn tortillas, beans, soups, Mexican mixed dishes (e.g., tamales), fruits, vegetables, full-fat milk, and Mexican cheeses and low in refined grains and added sugars and evaluated the association of the MexD score with systemic inflammation and IR in 493 postmenopausal participants in the Women's Health Initiative (WHI) who are of Mexican ethnic descent.

Methods

The MexD score was developed from the baseline (1993-1998) WHI food frequency questionnaire, which included Hispanic foods and was available in Spanish. Body mass index (BMI) was computed from baseline measured weight and height, and ethnicity was self-reported. Outcome variables were high sensitivity C-reactive protein (hsCRP), glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglyceride concentrations measured at follow-up (2012-2013). Multivariable linear and logistic regression models were used to test the associations of the MexD score with systemic inflammation and IR.

Results

The mean ± SD MexD score was 5.8 ± 2.1 (12 maximum points) and was positively associated with intakes of carbohydrates, vegetable protein, and dietary fiber and inversely associated with intakes of added sugars and total fat (P < 0.01). Women with high compared with low MexD scores, consistent with a more-traditional Mexican diet, had 23% and 15% lower serum hsCRP (P < 0.05) and insulin concentrations, respectively (P < 0.05). Baseline BMI modified these associations such that lower MexD scores were associated with higher insulin and HOMA-IR in overweight/obese women (P-interaction <0.05).

Conclusion

These findings suggest that greater adherence to a traditional Mexican diet could help reduce the future risk of systemic inflammation and IR in women of Mexican descent.