Background

The aims of this study are to investigate the impact of pre-existing diabetes and diabetes treatments on lung cancer prognosis.

Methods

A total of 2484 women with confirmed incident lung cancer from the Women's Health Initiative were followed for an average of 2.9 years through the date of death or 29 August 2014.

Results

Compared with women with lung cancer but without diabetes, women with lung cancer and diabetes had significantly increased risk of overall mortality (HR=1.27, 95% CI: 1.07-1.50). Women with diabetes receiving insulin or metformin or women who had long duration of diabetes also had increased risk of overall mortality.

Conclusions

Our large prospective study provides evidence that pre-existing diabetes is associated with poor overall survival among women with lung cancer, but do not support the hypothesis that metformin use may have a protective effect in women with lung cancer and diabetes.

Bisphosphonates are widely prescribed to increase bone density in postmenopausal women with osteopenia or osteoporosis. Aminobisphosphonates have numerous anticancer properties and reduce bone metastases in cancer patients. Several studies, including the Women's Health Initiative (WHI), have found that use of oral bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies in women such as colorectal cancer (CRC). A few case-control and retrospective cohort studies have reported decreased risk of CRC among bisphosphonate users. In contrast, a prospective cohort study found no association. We evaluated the association between oral bisphosphonate use and CRC incidence in 156,826 postmenopausal women, ages 50 to 79 years, who participated in WHI clinical trials and observational study. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly used medications at baseline and over follow-up. A total of 1931 women were diagnosed with incident invasive CRC during a median follow-up of 12 years. Alendronate was the most commonly used bisphosphonate, accounting for >90% of the total person-years of use. The association between oral bisphosphonate use and CRC risk did not reach statistical significance (hazard ratio [HR] from multivariable-adjusted models = 0.88; 95% confidence interval [CI] 0.72-1.07; p = 0.19). Furthermore, we did not observe greater risk reductions for women with longer duration of use. Uncontrolled confounding may explain why previous studies have observed an association.

OBJECTIVES: Lung cancer is the leading cause of cancer mortality in both men and women in the United States. COPD is associated with lung cancer independently of cigarette smoking, but remains understudied in women. Utilizing data from the Womens Health Initiative Observational Study (WHI-OS), this report investigates the association between COPD and development of lung cancer, with a focus on ethnicity and cancer subtype. MATERIALS AND METHODS: The WHI-OS, part of the larger Womens Health Initiative (WHI), is comprised of postmenopausal women between ages 50 and 79 years old at enrollment. Self-administered questionnaires were utilized to gather baseline demographic, socioeconomic, and behavioral information from participants. For this analysis, COPD status was determined at study entry (baseline) and on annual survey (incident). Information on the primary outcome of interest, diagnosis of lung cancer, was also collected annually. RESULTS AND CONCLUSION: Of the 92,789 women examined, 1,536 developed lung cancer. Overall, women with COPD were 1.64 times more likely to develop lung cancer than those without COPD, after adjusting for smoking status and intensity, ethnicity, education, body mass index, and income (HR = 1.64, 95 % CI: 1.43, 1.89). The relationship between COPD and lung cancer was not found to be significantly different between ethnic groups (p-value = 0.697). The associations between COPD and lung cancer was similar across subtypes (HR range 1.31-2.16), after adjusting for smoking status and intensity. COPD increases risk of lung cancer in women, thus they may benefit from more intensive surveillance compared to similar women without COPD.

Purpose

Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood.

Methods

We used 75 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/insulin resistance (IR) traits and signaling pathways, and data from 1003 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying via obesity and lifestyle modifiers, we assessed the role of IGF-I/IR traits (fasting IGF-I, IGF-binding protein 3, insulin, glucose, and homeostatic model assessment-insulin resistance) in breast cancer risk as a mediator or influencing factor.

Results

Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E non-users and users. The mediation effects of IGF-I/IR traits on the relationship between these SNPs and cancer differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways-genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP-cancer relationship explained by traits varied 45-50% between the strata.

Conclusions

Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce breast cancer risk.

Genetic variants and traits in metabolic signaling pathways may interact with lifestyle factors such as obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal colorectal cancer (CRC) risk, but these interrelated pathways are not fully understood. In this case-cohort study, we examined 33 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/ insulin resistance (IR) traits and signaling pathways, using data from 704 postmenopausal women in Women's Health Initiative Observation ancillary studies. Stratifying by the lifestyle modifiers, we assessed the effects of IGF-I/IR traits (fasting total and free IGF-I, IGF binding protein-3, insulin, glucose, and homeostatic model assessment-insulin resistance) on CRC risk as a mediator or influencing factor. Six SNPs in the INS, IGF-I, and IGFBP3 genes were associated with CRC risk, and those associations differed between non-obese/active and obese/inactive women and between E nonusers and users. Roughly 30% of the cancer risk due to the SNP was mediated by IGF-I/IR traits. Likewise, carriers of 11 SNPs in the IRS1 and AKT1/2 genes (signaling pathway-related genetic variants) had different associations with CRC risk between strata, and the proportion of the SNP-cancer association explained by traits varied from 30% to 50%. Our findings suggest that IGF-I/IR genetic variants interact with obesity, physical activity, and exogenous E, altering postmenopausal CRC risk, through IGF-I/IR traits, but also through different pathways. Unraveling gene-phenotype-lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce CRC risk.

Purpose

Vitamin D has been implicated in lowering lung cancer risk, but serological data on the association among never-smoking women are limited. We report results examining the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with lung cancer risk among female never smokers. We also examined whether the association was modified by vitamin D supplementation and serum vitamin A concentrations.

Methods

In the Women's Health Initiative, including the calcium/vitamin D (CaD) Trial, we selected 298 incident cases [191 non-small cell lung cancer (NSCLC) including 170 adenocarcinoma] and 298 matched controls of never smokers. Baseline serum 25(OH)D was assayed by a chemiluminescent method. Logistic regression was used to estimate odds ratios (ORs) for quartiles and predefined clinical cutoffs of serum 25(OH)D concentrations.

Results

Comparing quartiles 4 versus 1 of serum 25(OH)D concentrations, ORs were 1.06 [95% confidence interval (CI) 0.61-1.84] for all lung cancer, 0.94 (95% CI 0.52-1.69) for NSCLC, and 0.91 (95% CI 0.49-1.68) for adenocarcinoma. Comparing serum 25(OH)D ≥ 75 (high) versus <30 nmol/L (deficient), ORs were 0.76 (95% CI 0.31-1.84) for all lung cancer, 0.71 (95% CI 0.27-1.86) for NSCLC, and 0.81 (95% CI 0.31-2.14) for adenocarcinoma. There is suggestive evidence that CaD supplementation (1 g calcium + 400 IU D₃/day) and a high level of circulating vitamin A may modify the associations of 25(OH)D with lung cancer overall and subtypes (p interaction <0.10).

Conclusions

In this group of never-smoking postmenopausal women, the results did not support the hypothesis of an association between serum 25(OH)D and lung cancer risk.

Background

Prior research suggests that vitamin D protects against lung cancer only among certain subgroups.

Objectives

We investigated whether vitamin D intake was associated with lung cancer and explored whether vitamin A intake modified the association.

Design

Prospective cohort data from 128,779 postmenopausal women, including 1771 incident lung cancers in the Women's Health Initiative (Clinical Trials and Observational Study) 1993-2010, were analyzed. Twelve percent of women received active intervention (1 g Ca + 400 IU vitamin D3/d) in the Calcium/Vitamin D Trial. Baseline total intake included both dietary intake (from food-frequency questionnaires) and supplement intake (from bottle labels). HRs were estimated by Cox proportional hazard models.

Results

No significant association was observed overall. Among never smokers, a total vitamin D intake ≥400 IU/d was significantly associated with lower risks of lung cancer (HR: 0.37; 95% CI: 0.18, 0.77 for ≥800 compared with <100 IU/d; P-trend = 0.01). No significant effect modification of total vitamin A intake on the association between total vitamin D intake and lung cancer was found. However, the Calcium/Vitamin D Trial active intervention was significantly associated with a lower lung cancer risk only among women with a vitamin A intake <1000 μg/d retinol activity equivalents (HR: 0.69; 95% CI: 0.50, 0.96; P-interaction = 0.09).

Conclusions

Vitamin D intake was associated with a lower lung cancer risk in never-smoking, postmenopausal women. Lower vitamin A intake may be important for a beneficial association of 1 g Ca + 400 IU vitamin D3 supplementation with lung cancer. This trial was registered at clinicaltrials.gov as NCT00000611.

Introduction

Women Veterans may have higher rates of both active and passive tobacco exposure than their civilian counterparts, thereby increasing their risk for lung cancer.

Purpose of the study

To compare differences in active and passive smoking exposure and lung cancer incidence among women Veterans and non-Veterans using prospective data from the Women's Health Initiative (WHI).

Design and methods

We used data from the WHI, which collected longitudinal demographic, clinical, and laboratory data on 161,808 postmenopausal women. We employed linear and multinomial regression and generalized linear models to compare active and passive smoking exposure between Veterans and non-Veterans and Cox proportional hazards models to estimate differences in lung cancer incidence rates.

Results

After adjustment, Veterans had 2.54 additional pack years of smoking compared with non-Veterans (95% confidence interval [CI] 1.68, 3.40). Veterans also had a 1% increase in risk of any passive smoking exposure (95% CI 1.00, 1.02) and a 9% increase in risk of any workplace exposure (95% CI 1.07, 1.11) compared with non-Veterans. After adjustment for age and smoking exposures, Veterans did not have a higher risk of lung cancer compared with non-Veterans (relative risk = 1.06 95% CI 0.86, 1.30).

Implications

Women Veterans had higher rates of tobacco use and exposure to passive smoking, which were associated with a higher risk for lung cancer compared with non-Veterans. Clinicians who care for Veterans need to be aware that older women Veterans have more exposures to risk factors for lung cancer.

Objective

Nearly, a third of obese individuals, termed metabolically benign obese, have a low burden of adiposity-related cardiometabolic abnormalities, whereas a substantial proportion of normal-weight individuals possess risk factors.

Methods

In cross-sectional analyses of 699 normal weight and 1,294 overweight/obese postmenopausal women enrolled in a nested case-control stroke study ancillary to the Women's Health Initiative Observational Study, we compared levels of adiponectin, leptin, and resistin among metabolically benign normal weight, at-risk normal weight, metabolically benign obese, and at-risk obese women using components of the ATP III definition of the metabolic syndrome (metabolically benign: ≤1 of the four components; at-risk phenotype: ≥2 components or diabetes).

Results

Overall, 382/699 normal-weight women (54.6%) and 328/1,194 overweight/obese women (27.5%) were metabolically benign. Among normal-weight women, at-risk women had higher leptin and lower adiponectin levels compared to metabolically benign women; multivariate-adjusted odds ratios were significant for having leptin (OR: 2.51; 95% CI: 1.28-5.01) and resistin (1.46; 1.03-2.07) in the top tertile and adiponectin in the bottom tertile (2.64; 1.81-3.84). Compared to metabolically benign overweight/obese women, at-risk obese women had higher odds of having leptin in the top tertile (1.62; 1.24-2.12) and adiponectin in the bottom tertile (2.78; 2.04-3.77).

Conclusions

Overall, metabolically benign overweight/obese women had an intermediate adipokine profile (between at-risk obese and metabolically benign normal-weight women), whereas at-risk normal-weight women had a less favorable profile compared to metabolically benign normal-weight women. As adiponectin was the only adipokine independent of BMI, it may be most likely to have a role in the etiological pathway of these phenotypes.

Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes and homeostasis model-insulin resistance (HOMA-IR-a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-<25.0, 25.0-<30.0 and ≥30.0 kg/m² ) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis.