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Related Perspective from Physical Activity and Survival in Postmenopausal Women with Breast Cancer: Results from the Women's Health Initiative

BackgroundTo investigate the association between walking pace and the risk of heart failure (HF) and HF sub-types.MethodsWe examined associations of self-reported walking pace with risk of incident HF and HF subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fractions, among 25,183 postmenopausal women, ages 50-79 years. At enrollment into the Women's Health Initiative cohort in 1993-1998, this subset of women was free of HF, cancer, or the inability to walk one block, with self-reported information on walking pace and walking duration. Multivariable Cox regression was used to examine associations of walking pace (casual 3 mph) with incident HF. We also examined the joint association of walking pace and duration with incident HF.ResultsThere were 1455 incident adjudicated acute decompensated HF hospitalization cases during a median of 16.9 years of follow-up. There was a strong inverse association between walking pace and overall risk of HF (HR=0.73, 95% CI [0.65, 0.83] for average vs. casual walking; HR=0.66, 95%CI [0.56, 0.78] for fast vs. casual walking). There were similar associations of walking pace with HFpEF (HR=0.73, 95%CI [0.62, 0.86] average vs. casual; HR=0.63, 95%CI [0.50, 0.80] for fast vs. casual) and with HFrEF (HR=0.72, 95%CI [0.57, 0.91] for average vs. casual; HR=0.74, 95%CI [0.54, 0.99] for fast vs. casual). The risk of HF associated with fast walking with less than 1h/week walking duration was comparable with the risk of HF among casual and average walkers with more than 2h/week walking duration.ConclusionWalking pace was inversely associated with risks of overall HF, HFpEF, and HFrEF in postmenopausal women. Whether interventions to increase the walking pace in older adults will reduce HF risk and whether fast pace will compensate for the short duration of walking warrants further study.

Introduction: Obesity-related cancer (ORC) diagnosed individuals are at an elevated risk of new-onset diabetes compared with cancer-free individuals. However, less is known about mortality among those with incident type 2 diabetes after cancer. Methods: In the Women’s Health Initiative (N=14,455 ORC cases), we measured the association of incident type 2 diabetes diagnosed 0-1 years, >1-3, >3-5, >5-7 and >7-10 years after ORC diagnosis with cancer-specific and overall mortality using stratified Cox proportional hazards regression analysis. Results: The participants were post-menopausal females with ORC and predominantly white. The number of WHI participants with ORC who developed diabetes after cancer diagnosis were: 0-1 years - 205/12992 (1.58%); 1-3 years - 326/11322 (2.88%); 3-5 years - 276/9784 (2.82%); 5-7 years - 268/8420 (3.18%); and 7-10 years - 510/6419 (7.95%). The median survival after the first year of cancer diagnosis for participants without diabetes was 16.6 years (95% CI: 16.17-17.0 years) and for those with diabetes was 10.3 years (95% CI: 7.97-14.9 years). New-onset diabetes after ORC diagnosis showed elevated overall mortality and cancer-specific mortality when compared with no diabetes diagnosis. Conclusions: Incident type 2 diabetes is associated with worse cancer-specific and overall survival, particularly in the year after diagnosis, among women with ORC. Type 2 Diabetes from time since cancer diagnosis Overall mortality HR (95% CI)a Cancer-specific mortality HR (95% CI)a 0-1 years 1.79 (1.41-2.29) 1.56 (1.04-2.34) >1-3 years 1.22 (0.99-1.51) 1.05 (0.72-1.55) >3-5 years 1.21 (0.95-1.55) 1.37 (0.89-2.12) >5-7 years 1.02 (0.78-1.33) 0.80 (0.47-1.36) >7-10 years 1.10 (0.87-1.40) 0.97 (0.59-1.60) aModel adjusted for demographics (age, education, race/ethnicity, marital status), body mass index (BMI)) and cancer characteristics (cancer type, stage, grade). CI = confidence interval; HR = Hazard ratio. Citation Format: Prasoona Karra, Maci Winn, Benjamin Haaland, Garnet Anderson, Cynthia A. Thomson, Aladdin H. Shadyab, Juhua Luo, Nazmus Saquib, Howard Strickler, Rowan Chlebowski, Rhonda Arthur, Sheetal Hardikar, Mary C. Playdon. Diabetes incidence after obesity-related cancer diagnosis and survival in the women’s health initiative [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5880.

Results of observational studies of the association between dietary fat and risk of invasive breast cancer have been inconsistent. In the Women's Health Initiative dietary modification (DM) randomized trial designed to lower fat intake, the intervention was not associated with a statistically significant reduction of overall breast cancer risk. However, the DM association with risk of ductal carcinomaA total of 48,835 postmenopausal women, ages 50-79 years at enrollment, with no breast cancer history and ≥32% of total energy intake from fat, were randomly assigned either to a dietary intervention (During 18.7 years (median) cumulative follow-up, including intervention (∼8.7 years) and post-intervention phases (∼13.0 years), 817 DCIS cases were ascertained. No evidence of an association between the DM intervention and DCIS risk was observed overall, or by trial phase (intervention and post-intervention). Similarly, no associations were found in subgroups defined by potential risk factors for DCIS.DM aiming to reduce fat intake was not associated with altered risk of DCIS.These results do not provide evidence of an association between dietary fat reduction and the risk of DCIS among postmenopausal women.

Purpose Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor–positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand, to protect against aromatase inhibitor–induced bone loss. Patients and Methods Eligible women with hormone receptor–positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy (≤ 6 v > 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous denosumab 60 mg (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine bone mineral density (BMD). Results At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P < .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups. Conclusion In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.

BACKGROUND. The Gail model has been commonly used to estimate a woman's risk of breast cancer within a certain time period. High bone mineral density (BMD) is also a significant risk factor for breast cancer, but it appears to play no role in the Gail model. The objective of the current study was to investigate whether hip BMD predicts postmenopausal breast cancer risk independently of the Gail score. METHODS. In this prospective study, 9941 postmenopausal women who had a baseline hip BMD and Gail score from the Women's Health Initiative were included in the analysis. Their average age was 63.0 ± 7.4 years at baseline. RESULTS. After an average of 8.43 years of follow-up, 327 incident breast cancer cases were reported and adjudicated. In a multivariate Cox proportional hazards model, the hazards ratios (95% confidence interval [95% CI]) for incident breast cancer were 1.35 (95% CI, 1.05-1.73) for high Gail score (≥1.67%) and 1.25 (95% CI, 1.11-1.40) for each unit of increase in the total hip BMD T-score. Restricting the analysis to women with both BMD and a Gail score above the median, a sharp increase in incident breast cancer for women with the highest BMD and Gail scores was found (P < .05). CONCLUSIONS. The contribution of BMD to the prediction of incident postmenopausal breast cancer across the entire population was found to be independent of the Gail score. However, among women with both high BMD and a high Gail score, there appears to be an interaction between these 2 factors. These findings suggest that BMD and Gail score may be used together to better quantify the risk of breast cancer. Cancer 2008. © 2008 American Cancer Society.

Introduction: A growing population of older breast cancer (BC) survivors may be at risk of cardiovascular disease (CVD). Pre-existing CVD risk factors may impact on subsequent development of CVD after BC among postmenopausal women. Objectives: (1) To describe baseline CVD risk factors among postmenopausal women with and without BC prior to diagnosis of BC; and (2) To examine independent associations of BC with individual and composite CVD events (i.e., the first occurrence of coronary heart disease [CHD], angina, coronary revascularization, congestive heart failure, peripheral arterial disease, and stroke) and mortality outcomes (i.e., all-cause, CVD, and CHD death) after BC adjusting for baseline characteristics and CVD risk factors. Methods: This prospective cohort study included 101,916 women in the Women’s Health Initiative (WHI) (including 4,340 women with invasive BC) aged 50-79 years without CVD at baseline (1993-1998) through December 2010. Over a period of 10 years after BC, CVD morbidity and mortality outcomes were identified and age-adjusted rates per 1,000 person-years and hazard ratios (HRs) with 95% confidence intervals (CIs) from Cox models were determined for women who did and did not develop BC. Results: Regardless of BC status, baseline CVD risk factors prior to BC, such as smoking, hypertension, diabetes and hypercholesterolemia, were strong predictors of CVD outcomes in postmenopausal women. Multivariable Cox models revealed that women who developed BC (n = 4,340) had a similar risk of composite CVD (HR = 0.91, 95% CI, 0.82-1.02), but a higher risk of CHD (HR=1.33, 95% CI, 1.12-1.58), compared with women without BC (n = 97,576). Women aged 70-79 and on hormonal therapy at the WHI entry with localized BC during follow-up period had the highest CHD death rate. The results were similar after excluding women with baseline cancer at the WHI study entry. Conclusions: These results emphasize the great need for identification and timely management of pre-existing CVD risk factors for postmenopausal women with BC. CVD accounts for almost as many deaths as BC among women with localized disease, indicating that improved effort to prevent and treat CVD risk factors could improve survival of postmenopausal BC survivors.

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or

Loss of mental abilities represents a recognized threat to the quality of life of postmenopausal women with advancing age. Most recently, several reports have used a sensitive method (neuropsychological testing) to evaluate younger women with breast cancer after chemotherapy and hormonal modifying therapy (with tamoxifen), and found that a substantial percentage of these women had reduced mental abilities compared to women who were not treated with chemotherapy and hormonal modifying therapy. It also appears that these mental deficits are overlooked by the screening tests currently used in many large-scale breast cancer treatment and prevention studies, most likely because these simple screening tests become abnormal only when the brain is damaged to a moderate or severe degree. In the previous studies, most of the women with mental deficits obtained both chemotherapy and hormonal modifying therapy, so that it is unclear which of the two therapies caused the mental deficits. Furthermore, tens of millions of healthy women without breast cancer may soon obtain hormonal modifying therapy (with tamoxifen and possibly other drugs) to prevent future breast cancer; therefore, it is extremely important to know whether these drugs may cause injury to the brain and long-lasting problems with mental abilities. This study is designed to address these questions.