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PurposeThis study estimated associations between neighborhood socioeconomic status (NSES), walkability, green space, and incident falls among postmenopausal women and evaluated modifiers of these associations, including study arm, race and ethnicity, baseline household income, baseline walking, age at enrollment, baseline low physical functioning, baseline fall history, climate region, and urban-rural residence.MethodsThe Women's Health Initiative recruited a national sample of postmenopausal women (50-79years) across 40 U.S. clinical centers and conducted yearly assessments from 1993 to 2005 (n=161,808). Women reporting a history of hip fracture or walking limitations were excluded, yielding a final sample of 157,583 participants. Falling was reported annually. NSES (income/wealth, education, occupation), walkability (population density, diversity of land cover, nearby high-traffic roadways), and green space (exposure to vegetation) were calculated annually and categorized into tertiles (low, intermediate, high). Generalized estimating equations assessed longitudinal relationships.ResultsNSES was associated with falling before adjustment (high vs. low, odds ratio,1.01; 95% confidence interval, 1.00-1.01). Walkability was significantly associated with falls after adjustment (high vs. low, odds ratio,0.99; 95% confidence interval, 0.98-0.99). Green space was not associated with falling before or after adjustment. Study arm, race and ethnicity, household income, age, low physical functioning, fall history, and climate region modified the relationship between NSES and falling. Race and ethnicity, age, fall history, and climate region modified relationships between walkability and green space and falling.ConclusionsOur results did not show strong associations of NSES, walkability, or green space with falling. Future research should incorporate granular environmental measures that may directly relate to physical activity and outdoor engagement.

Small-scale studies offer conflicting evidence regarding the relationship/association between psoriasis and insulin resistance by HOMA-IR (homeostasis model assessment of insulin resistance). The purpose of this study was to assess the association between baseline HOMA-IR and psoriasis incidence in a large-scale longitudinal cohort of postmenopausal women. The analysis included 21,789 postmenopausal women from the Women’s Health Initiative. Psoriasis diagnosis was defined by fee-for-service Medicare ICD-9-CM codes assigned by dermatologists or rheumatologists, and a 2-year lookback period to exclude prevalent cases. Baseline HOMA-IR was calculated using the updated HOMA2 model. Hazard rates from the Cox regression models were stratified by age (10-year intervals), on WHI component (Clinical Trial or Observational Study), and on randomization status within each of the WHI clinical trials. The complete model also adjusted for ethnicity, waist–hip-ratio, and smoking and alcohol habits. Among participants free of psoriasis at entry, those with high baseline HOMA-IR (≥ 2) compared to low (P-trend: 0.011). In postmenopausal women, higher baseline HOMA-IR levels were significantly associated with higher incidence of psoriasis over 21-year cumulative follow-up. Results from this time-to-event analysis indicate that insulin resistance can precede and is associated with an increased risk of psoriasis. Study is limited by Medicare diagnostic code accuracy and cohort age.

Purpose This study examined associations between self-reported cognitive functioning and social support as well as social ties among women with breast cancer. Methods The study included 3351 women from the Women’s Health Initiative Life and Longevity After Cancer cohort who were diagnosed with breast cancer stages I–III. Social support was assessed using a modified Medical Outcomes Study (MOS) Social Support Survey, and marital status was obtained from the baseline questionnaire. We also assessed social ties (e.g., number of friends, relatives, living children) and cognitive function (Functional Assessment of Cancer Therapy-Cognitive Function [FACT-COG]) on the year-1-follow up questionnaire. Multivariable quantile regression was used to estimate the changes in median cognitive scores. Kruskal–Wallis tests were used to assess the association of cognitive function with social ties. Results The majority of participants were non-Hispanic White (93.3%), presently married (49%), with at least a 4-year college degree (53.2%), and had been diagnosed with localized breast cancer (79%). A 10-point higher social support score correlated to a 0.32 higher (better) median cognitive score (p p = 0.01). Significant associations were also present for having close relatives (p p Conclusion Women reporting higher social support and greater numbers of friends or relatives have higher cognitive functioning. Compared to divorced or separated women, married women were likely to have higher cognitive functioning. These findings suggest that social support assessments have the potential to help identify women at higher risk of cognitive decline.

Epidemiologic evidence is limited about associations between T2DM, metformin, and the risk of non-Hodgkin's lymphoma (NHL). We aimed to examine associations between T2DM, metformin, and the risk of NHL in the Women's Health Initiative (WHI) Study. Information on T2DM status (diabetes status/types of antidiabetic drug use/diabetes duration) from study enrollment and during follow-up were assessed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate associations of T2DM status with risks of overall NHL and its three major subtypes [diffuse large B-cell lymphoma (DLBCL, n = 476), follicular lymphoma (FL, n = 301) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, n = 136)] based on multivariable-adjusted Cox proportional hazards models. During a median follow-up of 18.86 years (range, 0.01-25.13; SD ± 6.55), a total of 1637 women developed NHL among 147 885 postmenopausal women. Women with T2DM and with self-reported oral medication use had 38% and 55% higher risk of DLBCL, respectively [multivariable-adjusted model HR = 1.38, 95% CI (1.06-1.81) and HR = 1.55, 95% CI (1.16-2.06)] compared to the reference group (nondiabetics/untreated diabetes). Risks of NHL and DLBCL [multivariable-adjusted model: HR = 1.28, 95% CI (1.06-1.54) and HR = 1.56, 95% CI (1.13-2.14), respectively] were significantly higher in associations with relatively short duration (≤7 years) of diabetes, compared to reference group. Additionally, an increased risk of DLBCL [HR = 1.76, 95% CI (1.13-2.75)] was found in metformin users compared to the reference group. Postmenopausal women who had T2DM, who were oral antidiabetic drug users, especially metformin, and who had a shorter diabetes duration may have higher risks of DLBCL. Further well-designed research is needed to confirm our findings.

Background: 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 carcinoma in situ (DCIS) of the breast, a putative breast cancer precursor, has not been reported. Methods: A 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 (n = 19,541) designed to reduce total fat intake to 20% of energy and to increase vegetable, fruit, and grain consumption, or to a comparison group (n = 29,294). Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the association between the intervention and DCIS risk. Results: 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. Conclusions: DM aiming to reduce fat intake was not associated with altered risk of DCIS. Impact: These results do not provide evidence of an association between dietary fat reduction and the risk of DCIS among postmenopausal women.

Although adherence to the American Cancer Society (ACS) Guidelines on Nutrition and Physical Activity for Cancer Prevention associates with lower risk of obesity-related cancer (ORC) incidence and mortality, evidence in Black and Latina women is limited. This association was examined in Black and Latina participants in the Women's Health Initiative (WHI).Semi-Markov multistate model examined the association between ACS guideline adherence and ORC incidence and mortality in the presence of competing events, combined and separately, for 9301 Black and 4221 Latina postmenopausal women. Additionally, ACS guideline adherence was examined in a subset of less common ORCs and potential effect modification by neighborhood socioeconomic status and smoking.Over a median of 11.1, 12.5, and 3.7 years of follow-up for incidence, nonconditional mortality, and conditional mortality, respectively, 1191 ORCs (Black/Latina women: 841/269), 1970 all-cause deaths (Black/Latina women: 1576/394), and 341 ORC-related deaths (Black/Latina women: 259/82) were observed. Higher ACS guideline adherence was associated with lower ORC incidence for both Black (cause-specific hazard ratio [CSHR]Adherence to the ACS guidelines was associated with lower risk of ORCs and less common ORCs but was not for conditional ORC-related mortality.Evidence on the association between the American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention and cancer remains scarce for women of color. Adherence to the guidelines and risk of developing one of 13 obesity-related cancers among Black and Latina women in the Women's Health Initiative was examined. Women who followed the lifestyle guidelines had 28% to 42% lower risk of obesity-related cancer. These findings support public health interventions to reduce growing racial/ethnic disparities in obesity-related cancers.

ImportancePatients with cancer experience acute declines in physical function, hypothesized to reflect accelerated aging driven by cancer-related symptoms and effects of cancer therapies. No study has examined long-term trajectories of physical function by cancer site, stage, or treatment compared with cancer-free controls.ObjectiveExamine trajectories of physical function a decade before and after cancer diagnosis among older survivors and cancer-free controls.Design, Setting, and ParticipantsThis prospective cohort study enrolled patients from 1993 to 1998 and followed up until December 2020. The Women’s Health Initiative, a diverse cohort of postmenopausal women, included 9203 incident cancers (5989 breast, 1352 colorectal, 960 endometrial, and 902 lung) matched to up to 5 controls (n = 45 358) on age/year of enrollment and study arm.ExposuresCancer diagnosis (site, stage, and treatment) via Medicare and medical records.Main Outcomes and MeasuresTrajectories of self-reported physical function (RAND Short Form 36 [RAND-36] scale; range: 0-100, higher scores indicate superior physical function) estimated from linear mixed effects models with slope changes at diagnosis and 1-year after diagnosis.ResultsThis study included 9203 women with cancer and 45 358 matched controls. For the women with cancer, the mean (SD) age at diagnosis was 73.0 (7.6) years. Prediagnosis, physical function declines of survivors with local cancers were similar to controls; after diagnosis, survivors experienced accelerated declines relative to controls, whose scores declined 1 to 2 points per year. Short-term declines in the year following diagnosis were most severe in women with regional disease (eg, −5.3 [95% CI, −6.4 to −4.3] points per year in regional vs −2.8 [95% CI, −3.4 to −2.3] for local breast cancer) or who received systemic therapy (eg, for local endometrial cancer, −7.9 [95% CI, −12.2 to −3.6] points per year with any chemotherapy; −3.1 [95% CI, −6.0 to −0.3] with radiation therapy alone; and −2.6 [95% CI, −4.2 to −1.0] with neither, respectively). While rates of physical function decline slowed in the later postdiagnosis period (eg, women with regional colorectal cancer declined −4.3 [95% CI, −5.9 to −2.6] points per year in the year following diagnosis vs −1.4 [95% CI, −1.7 to −1.0] points per year in the decade thereafter), survivors had estimated physical function significantly below that of age-matched controls 5 years after diagnosis.Conclusions and RelevanceIn this prospective cohort study, survivors of cancer experienced accelerated declines in physical function after diagnosis, and physical function remained below that of age-matched controls even years later. Patients with cancer may benefit from supportive interventions to preserve physical functioning.

Background Cardiometabolic abnormalities are a leading cause of death among women, including women with cancer. Methods This study examined the association between prediagnosis cardiovascular health and total and cause-specific mortality among 12,076 postmenopausal women who developed local- or regional-stage invasive cancer in the Women's Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity-related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non-Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival. Results After a median follow-up of 10.0 years from the date of the cancer diagnosis, there were 3607 total deaths, with 1546 (43%) due to cancer. Most participants (62.9%) had 1 or 2 cardiometabolic risk factors, and 8.1% had 3 or 4. In adjusted models, women with 3 to 4 risk factors (vs none) had a higher risk of all-cause mortality (HR, 1.99; 95% CI, 1.73-2.30), death due to cardiovascular disease (CVD) (HR, 4.01; 95% CI, 2.88-5.57), cancer-specific mortality (HR, 1.37; 95% CI, 1.1-1.72), and other-cause mortality (HR, 2.14; 95% CI, 1.70-2.69). A higher waist circumference was associated with greater all-cause mortality (HR, 1.17; 95% CI, 1.06-1.30) and cancer-specific mortality (HR, 1.22; 95% CI, 1.04-1.42). Conclusions Among postmenopausal women diagnosed with cancer in the WHI, cardiometabolic risk factors before the cancer diagnosis were associated with greater all-cause, CVD, cancer-specific, and other-cause mortality. These results raise hypotheses regarding potential clinical intervention strategies targeting cardiometabolic abnormalities that require future prospective studies for confirmation. Lay summary This study uses information from the Women's Health Initiative (WHI) to find out whether cardiac risk factors are related to a greater risk of dying among older women with cancer. The WHI is the largest study of medical problems faced by older women in this country. The results show that women who have 3 or 4 risk factors are more likely to die of any cause, heart disease, or cancer in comparison with women with no risk factors. It is concluded that interventions to help to lower the burden of cardiac risk factors can have an important impact on survivorship among women with cancer.

Background Heart failure (HF) and breast cancer are 2 of the leading causes of death in postmenopausal women. The temporal association between HF and breast cancer in postmenopausal women has not been described. Objectives This study sought to examine the temporal association between HF and breast cancer. Methods Postmenopausal women within the WHI (Women’s Health Initiative) cohort were studied. All prevalent HF and prevalent breast cancer at enrollment were self-reported. Incident hospitalized HF and breast cancer diagnoses were adjudicated through 2017. Results Among a cohort of 44,174 women (mean age 63 ± 7 years), 2,188 developed incident invasive breast cancer and 2,416 developed incident hospitalized HF over a median follow-up of 14 and 15 years, respectively. When compared with a breast cancer- and HF-free cohort, there was no association between prevalent HF and incident invasive breast cancer and similarly, there was no association between prevalent breast cancer and incident hospitalized HF. Across the entire cohort, the median survival after incident hospitalized HF was worse compared with an incident invasive breast cancer diagnosis (5 and 19 years, respectively). In women with incident invasive breast cancer, prevalent HF was associated with an increased risk of mortality (hazard ratio: 2.28; 95% confidence interval: 1.31 to 3.95). In women with incident hospitalized HF, prevalent breast cancer was associated with an increased risk of mortality (hazard ratio: 1.66; 95% confidence interval: 1.03 to 2.68). Cause of death after incident HF was different only in women with prevalent and interim breast cancer compared with those without prevalent and interim breast cancer. Conclusions In postmenopausal women, prevalent HF was not associated with a higher incidence of breast cancer and vice versa. However, the presence of incident invasive breast cancer or incident HF in those with prevalent HF or prevalent breast cancer, respectively, was associated with increased mortality., Central Illustration

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.Of 161,808 postmenopausal participants in Women's 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.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.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.

A relatively high healthy lifestyle index (HLI) score, representing a healthy diet, participation in moderate to vigorous physical exercise, no smoking, low to no alcohol intake and a normal body mass index, has been associated with a reduced risk of invasive breast cancer. However, no study has shown an association between the HLI and the risk of ductal carcinoma in situ of the breast (DCIS), which is considered to be a nonobligate precursor of invasive breast cancer. We evaluated this association in a prospective cohort of 132 230 postmenopausal women, aged 50 to 79 years, recruited between 1993 and 1998 across the United States and enrolled in the Women's Health Initiative study. The HLI score was created and categorized into quartiles. During an average follow-up of 15.4 years, 2035 DCIS cases were ascertained. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of HLI with the risk of DCIS. Women in the highest HLI quartile had a lower DCIS risk than those in the lowest quartile (HR

Background: Obesity-related cancers disproportionately affect the Black community. We assessed the relationship between diet quality, physical activity, and their combined effect on obesity-related cancer risk and mortality in Black women enrolled in the Women's Health Initiative (WHI). Methods: Data from postmenopausal (50–79 years of age) Black women enrolled in WHI clinical trials or observational studies were analyzed. Exposure variables included baseline physical activity [metabolic equivalent of tasks (MET)-hours/week of moderate-to-vigorous physical activity (MVPA)] and diet quality [Healthy Eating Index (HEI)-2015]. Outcomes included adjudicated obesity-related cancer incidence and mortality. Cox proportional hazard models were used to evaluate the association between MVPA and HEI-2015 and obesity-related cancer risk and mortality. Results: The analytical sample included 9,886 Black women, with a baseline mean body mass index (BMI) of 31.1 kg/m2 (SD = 6.8); mean HEI-2015 score of 63.2 (SD = 11.0, possible range 0 to 100); and mean MVPA of 5.0 (SD = 9.4) MET-hours/week. Over an average of 13 years of follow-up, 950 (9.6%) obesity-related cancer cases were observed, with 313 (32.9%) resulting in death. Physical activity [HR, 1.05; 95% confidence interval (CI), 0.86–1.30], diet quality (HR, 0.99; 95% CI, 0.92–1.08), and their combination (HR, 1.05; 95% CI, 0.85–1.29) were not associated with risk for any or site-specific obesity-related cancers. Similarly, these health behaviors had no association with mortality. Conclusions: Diet quality, physical activity and their combined effect, as measured, were not associated with obesity-related cancer risk and mortality in Black women enrolled in WHI. Impact: Other social, behavioral, and biological factors may contribute to racial disparities observed in obesity-related cancer rates.

Cross-sectional studies suggest that falls are prevalent among older breast cancer survivors. However, fall risk in this population has not been comprehensively examined. Therefore, we compared fall risk in older women post-breast cancer diagnosis to fall risk before cancer diagnosis and to risk in cancer-free matched controls. Among 2019 women in the Women’s Health Initiative with localized breast cancer diagnosed at age ≥ 60 years with fall assessment data for 3 years pre-diagnosis and 3 years post-diagnosis, recurrent fall risk post-diagnosis was compared to risk in 2019 cancer-free controls matched by age, year of WHI entry, and baseline fall frequency. Generalized estimating equations under a logistic regression model were used to compare fall recurrence in breast cancer survivors and controls. Multi-variable models were adjusted for the matching factors, race/ethnicity, body mass index, and multiple chronic conditions. In breast cancer survivors aged 70.8 years (mean) at diagnosis, over the 3-year pre-diagnosis interval, recurrent falls were reported by 18.5%. Over the 3-year post-diagnosis interval, recurrent falls were reported by 21.8% of breast cancer survivors and 20.0% of controls over the same time period (P = 0.27). Recurrent fall risk did not differ between breast cancer survivors and control women (OR 1.07, 95% CI 0.92–1.25), even after multi-variable adjustment. In contrast to prior reports, older breast cancer survivors were not more likely to experience recurrent falls than age-matched counterparts. These findings underscore the need for incorporation of cancer-free control populations in survivorship studies to distinguish cancer sequelae from processes related to aging.

PURPOSE: Delays in adjuvant breast cancer (BC) therapy have been shown to worsen outcomes. However, thus far studies have only evaluated delays to initial treatment, or a particular modality, such as chemotherapy, leaving uncertainty about the role of delay to subsequent therapy and the effects of cumulative delay, on outcomes. We investigated the associations of delays across treatment modalities with survival. METHODS: We included 3368 women with incident stage I-III BC in the Women’s Health Initiative (WHI) enrolled in fee-for-service Medicare who underwent definitive surgery. This prospective analysis characterized treatment delays by linking WHI study records to Medicare claims. Delays were defined as >8 weeks to surgery, chemotherapy, and radiation from diagnosis or prior treatment. We used Cox proportional hazards models to estimate BC-specific mortality (BCSM) and all-cause mortality (ACM) in relation to treatment delays. RESULTS: We found 21.8% of women experienced delay to at least one therapy modality. In adjusted analysis, delay to chemotherapy was associated with a higher risk of BCSM (HR=1.71; 95% CI: 1.07–2.75) and ACM (HR=1.39; 95% CI: 1.02–1.90); delay in radiation increased BCSM risk (HR=1.49; 95% CI: 1.00–2.21) but not ACM risk (HR=1.19; 95% CI: 0.99–1.42). Delays across multiple treatment modalities increased BCSM risk 3-fold (95% CI: 1.51–6.12) and ACM risk 2.3-fold (95% CI: 1.50–3.50). CONCLUSIONS: A delay to a single treatment modality, and to a greater extent an accumulation of delays were associated with higher BCSM and ACM after BC. Timely care throughout the continuum of breast cancer treatment is important for optimal outcomes.

Background: In postmenopausal women, use of hormone therapy is associated with a lower incidence of diabetes (DM). The association of adjuvant endocrine therapy (AET) with DM has not been well studied among women treated for early stage breast cancer. The objective of this study was to examine the association of AET with risk of developing DM among postmenopausal women who developed breast cancer. Methods: 5,013 postmenopausal women from the Women’s Health Initiative diagnosed with non-metastatic breast cancer who were diabetes-free at cancer diagnosis and who had information on use of AET were included. AET use was gathered using 2 methods: 1) review of medication inventories for use of tamoxifen or aromatase inhibitors (AI) and 2) review of the Life and Longevity after Cancer (LILAC), a supplemental questionnaire used from 2009-2010 to gather treatment information from women who developed cancer. Results from these 2 collection methods were analyzed separately due to the timing of the surveys as well as data granularity (i.e. LILAC queried use of AET, not type). The primary outcome of interest for this study was diabetes-free survival, which was calculated from the date of breast cancer diagnosis to first diagnosis of DM. Participants who did not develop DM after breast cancer were censored at their last follow-up visit or date of death. Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI). Results: After 10.4 median year’s follow-up post breast cancer diagnosis, 13% (632/5,013) of participants developed DM. Of the 2,646 who had medication inventory data, 1,352 (51%) reported AI use and 1,449 (55%) reported tamoxifen use. Participants who reported use of AIs were 13% more likely to develop DM than participants who did not use AIs (HR=1.13, CI=0.91-1.39). Participants who reported use of tamoxifen were 11% less likely to develop DM than those who did not use tamoxifen (HR=0.89, CI=0.72-1.11). Of the 3,769 participants with LILAC data from the supplemental questionnaire, 2,543 (67%) reported use of AET; these participants were 25% more likely to develop DM than those who did not use AET (HR=1.25, CI=1.02-1.53). When plotted over time, the risk of diabetes in AET users versus non-users was identical at 5 years (5% v 5%, respectively), was 35% higher at 10 years (12% v 9%, respectively), and 30% higher at 15 years (18% v 14%, respectively) (log-rank p=0.029). Conclusion: DM has not been reported as an adverse event in women on AET. Our data suggest an association of AET with DM among postmenopausal women with early stage breast cancer. When looking at specific types of AETs, the risk was marginally increased for AIs but marginally decreased for tamoxifen, with risk more apparent in subsequent years. These data have significance for survivorship care. Citation Format: Joanne E Mortimer, Rebecca A Nelson, Laura Kruper, Kathy Pan, Christina M Dieli Conwright, Aladdin H Shadyab, Lewis Kuller, Barbara Howard, Rowan T Chlebowski. Association of adjuvant endocrine therapy with diabetes among women with postmenopausal breast cancer in the Women’s Health Initiative (WHI) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-04.

Background Most studies demonstrating an association between excess adiposity and postmenopausal breast cancer have used anthropometric measures, particularly body mass index (BMI). However, more direct body fat measures may more accurately determine the relationship between body fat distribution and breast cancer risk. Methods Cox proportional hazards regression models were created to examine the associations of dual‐energy x‐ray absorptiometry (DXA) body fat measures (at baseline and during follow‐up) with breast cancer risk among 10 931 postmenopausal women from the Women's Health Initiative cohort. A total of 639 incident invasive breast cancer cases (including 484 estrogen receptor positive (ER+) cases) were ascertained after a median follow‐up of 15.0 years. Results Excess whole body fat mass and trunk fat mass were positively associated with risk invasive breast cancer risk. These associations persisted even after additional adjustment for standard anthropometric measures. In time‐dependent analyses, we observed that both whole body fat mass and trunk fat mass, in the highest versus lowest category, were associated with a doubling of risk of invasive breast cancer overall (HR: 2.17; 95% CI: 1.54‐3.05 and 2.20; 1.55‐3.14, respectively) and of ER+ breast cancer (2.05; 1.37‐3.05 and 2.03; 1.34‐3.07, respectively). The remaining DXA measures were also positively associated with breast cancer risk in baseline and time‐dependent analyses. Conclusion These findings suggest that DXA‐derived body fat measures are positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors., Our study demonstrated that DXA‐derived body fat measures were positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors. These findings suggest that DXA‐derived measures of overall and central adiposity may explain invasive breast cancer risk beyond that of BMI and other risk factors.

In the Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, dietary intervention significantly reduced breast cancer mortality (P = 0.02). In observational studies, physical activity is associated with lower breast cancer incidence. Currently, dietary intervention influence on other health-related behaviors is unknown. Therefore, we evaluated whether the WHI dietary intervention influenced self-directed physical activity.Of 48,835 postmenopausal women, 19,541 were randomized to dietary intervention (18 nutritionist-led group sessions first year, then quarterly sessions throughout 8.5 years [median] intervention) and 29,294 to a usual diet comparison (written health-related materials only). Neither randomization group received specific or ongoing instructions to increase physical activity. Episodes per week of moderate or vigorous recreational physical activity (MVPA) were serially reported. Marginal longitudinal logistic regression models were used to assess physically inactive (MVPA = 0) or physically active (MVPA 0) participants by randomization group. Marginal Poisson regression models estimated mean weekly MVPA.At entry, 45.6% of all participants reported physical inactivity (MVPA = 0). In 43,760 women with MVPA information, throughout 15.9 years (median) cumulative follow-up, dietary intervention group participation was associated with 7% lower physical inactivity rate (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.91, 0.95, P 0.001) and a 4% higher mean MVPA (ratio of means [RM] 1.04 95% CI 1.02, 1.06, P 0.001), relative to the comparison group.In a randomized trial setting, a low-fat dietary pattern intervention was associated with a long-term, favorable influence on self-directed recreational physical activity.NCT00000611.

Importance The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. Objective To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women’s Health Initiative clinical trials. Design, Setting, and Participants Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017. Interventions In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years’ median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years’ median intervention duration. Main Outcomes and Measures The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer. Results Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93;P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97;P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45;P Conclusions and Relevance In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

Agency breast cancer prevention guidelines for other than hereditary cancers have not materially changed in 20 years; endocrine-targeted agents (then, tamoxifen; now, adding raloxifene and aromatase inhibitors) reduce good prognosis estrogen receptor (ER)–positive, progesterone receptor (PR)–positive cancers without reducing deaths from breast cancer. Across three tamoxifen placebo-controlled prevention trials (N = 23,360) begun almost 30 years ago, although there were 226 fewer breast cancer cases, there were nine more deaths from breast cancer in the tamoxifen groups. Following clinical advances, currently more than half of breast cancer cases are solved problems with extremely low risk of death. As endocrine-targeted agents commonly prevent these cancers, widespread implementation of current prevention strategies may not reduce deaths from breast cancer. Compared with other breast cancers, ER-positive, PR-negative cancers and triple-negative cancers have inferior survival (90.6% v 83.8% v 78.1%, respectively; P < .001). Against this background, in the Women's Health Initiative Dietary Modification randomized trial (N = 48,835), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.77; 95% CI, 0.64 to 0.94) and deaths from breast cancer were reduced 21% ( P = .02). In the Women's Health Initiative randomized, placebo-controlled trial evaluating conjugated equine estrogen (N = 10,739), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.44; 95% CI, 0.27 to 0.74) and deaths from breast cancer were reduced 40% ( P = .04). These findings suggest that reexamination of breast cancer risk reduction strategies and clinical practice is needed.

BACKGROUND: Breast cancer mortality is substantially higher in Black compared to White women due in part to higher rates of poor prognosis triple-negative breast cancer (TNBC) in Black women. The influence of African ancestry on this disparity has not been adequately examined. METHODS: Using the Women’s Health Initiative cohort of 161,808 postmenopausal women, we examined risk of TNBC in 6,166 Black participants with information on African ancestry, of whom 374 had incident localized breast cancers. African ancestry was based on genetic information from 656,852 single nucleotide polymorphisms with ancestry groups stratified by

INTRODUCTION: Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer associated with poor clinical outcome. Patients diagnosed with TNBC may experience many treatment-associated changes, including weight gain, reduced physical activity levels, and worsening metabolic profiles. We sought to identify the association between baseline metabolic syndrome (MetS) components with survival outcomes in WHI participants diagnosed with TNBC. METHODS: The WHI comprises 161,308 post-menopausal women aged 50-79 who were enrolled from 1993-1998 and were at low risk of 3-year mortality at study screening. After excluding women with a history of cancer and those randomized to the dietary modification treatment arm, we identified 615 participants diagnosed with non-metastatic TNBC while on study. MetS status at baseline was assessed at study entry (prior to subsequent breast cancer diagnosis) using the following risk factors: 1) high waist circumference (≥88 cm), 2) high blood pressure (>135 mg Hg systolic and/or > 85 diastolic, or anti-hypertension medication use), 3) history of high cholesterol, and 4) history of diabetes. Groups were stratified into: 1) no MetS components (none), 2) 1-2 MetS components, and 3) 3-4 MetS components. All breast cancers were verified by medical record review. Survival status was augmented by serial National Death Index queries. Outcomes of interest included breast cancer specific survival, as well as all-cause survival after breast cancer, with survival time calculated from date of TNBC diagnosis to date of death or off-study. Baseline demographic, clinicopathologic, and treatment differences were assessed across MetS groups using chi-squared analyses. Kaplan-Meier curves were plotted across MetS groups and survival rates were compared using the log-rank statistic. RESULTS: Of 615 participants diagnosed with TNBC, the distribution of MetS was as follows: 29% had no MetS components (n=178), 53% had 1-2 components (n=323), and 7% had 3-4 components (n=43). The median time from enrollment to TNBC diagnosis was 8.6 years (median), with those in the highest MetS group having a significantly shorter time to diagnosis than those without any MetS (7.0 years vs. 9.8 years, respectively, p CONCLUSION: Although TNBC is associated with poor clinical outcome, differences in all-cause mortality in women with TNBC remain significantly influenced by MetS. TNBC patients with 3-4 MetS components have 10-year all-cause survival rates over 35% lower than TNBC survivors with no MetS components. This finding highlights the importance of women’s overall health status and medical condition, even after the diagnosis of an aggressive breast cancer. Table 1. Breast cancer and all-cause survival rates by MetS group.MetSNBreast Cancer Survival (%)All-Cause Survival (%)3-year5-year10-yearp-value3-year5-year10-yearp-value01789087840.098782710.0081-23238983798777653-443877363836445 Citation Format: Yuan Yuan, Rebecca Nelson, Kathy Pan, Jessica Yan, Susan E Yost, Rami Nassir, Rowan Chlebowski. Metabolic syndrome impacts survival in postmenopausal women with triple negative breast cancer: Results from the women’s health initiative [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-03.

Developments in systemic therapies beyond traditional cytotoxic chemotherapy have resulted in an unparalleled number of US Food and Drug Administration approvals in the past 5 years for ovarian, endometrial, and cervical cancer. In this review, we highlight registration trials leading to recent Food and Drug Administration approvals for targeted systemic therapies in advanced gynecologic malignancies, encompassing three classes of agents: the antiangiogenic anti-vascular endothelial growth factor antibody bevacizumab in ovarian and cervical cancer, poly (ADP-ribose) polymerase inhibitors in ovarian cancer, and the immune checkpoint inhibitor pembrolizumab in cervical and endometrial cancer. The addition of bevacizumab to chemotherapy has been approved in frontline and relapsed advanced ovarian cancer, in both platinum-resistant and platinum-sensitive settings. Three poly (ADP-ribose) polymerase inhibitors are approved for women with ovarian cancer. Olaparib and rucaparib are utilized in recurrent germline or somatic BRCA mutated ovarian cancer. Along with a third poly (ADP-ribose) polymerase inhibitor, niraparib, they are also Food and Drug Administration approved as maintenance therapy regardless of BRCA mutation status for patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. More recently, olaparib was approved as maintenance therapy for BRCA mutated ovarian cancer following first-line platinum-based chemotherapy. Pembrolizumab has been approved for relapsed cervical cancer with programmed death ligand 1 positivity and relapsed solid tumors with mismatch repair deficiency, which applies to 30% of endometrial cancers. Together, these therapies represent the advent of personalized medicine in gynecologic malignancies. Additional information is required to determine cost-effective strategies for incorporating these therapies and rational means of sequencing these agents.

Two complementary studies in separate components of the Women’s Health Initiative (WHI) examined relationships among weight loss, diet composition and breast cancer incidence and outcome in postmenopausal women. In the WHI Observational Study, 61,335 postmenopaus al women had their weight change determined over a 3-year period with subsequent follow-up. Women with weight loss greater than or equal to 5% had significantly lower breast cancer incidence compared to women with stable weight. In the WHI Dietary Modification randomized clinical trial involving 48,835 postmenopausal women, implementation of a low-fat eating pattern significantly reduced deaths after breast cancer. Thus, moderation regarding dietary composition and body weight maintenance can reduce a postmenopausal woman’s risk of being diagnosed with breast cancer and of dying after breast cancer.

Background:Obese postmenopausal women are at higher breast cancer risk potentially driven by hyperinsulinemia. However, reports of insulin level associations with breast cancer incidence and survival are inconsistent. Therefore, we examined associations among insulin resistance by homeostasis model assessment-insulin resistance (HOMA-IR) index and incident breast cancer, deaths from breast cancer, and deaths after breast cancer in postmenopausal women participating in the Women's Health Initiative (WHI). Patients and Methods:From the 161,808 postmenopausal women, aged 50-79 years, enrolled at 40 US clinical centers from 1993 through1998 in WHI clinical trials or the observational study, 22,837 with available fasting serum insulin and glucose by the same methodology and no prior breast cancer represent the current study population. The exposure was insulin resistance (HOMA-IR index) as [fasting insulin (qIU/ml) times fasting glucose (mg/dL) / 22.5. Survival by cause was determined by central medical record or death certificate review, enhanced by National Death Index queries. Breast cancers, initially ascertained by serial survey, were confirmed by medical record review. Associations between HOMA-IR quartiles and breast cancer outcomes were examined using Cox multi- variate proportional hazards models with results reported as hazard ratios (HR) and 95% confidence intervals. Results: At entry, women in the highest HOMA-IR quartile were more likely to be Black, have lower education level, have higher body mass index (BMI), higher waist circumference ≥ 88 cm and lower physical activity levels, but have lower calculated five-year breast cancer risk. After 18.1 years median follow-up from randomization with 1,148 incident breast cancers, breast cancer incidence was higher in women in the highest, compared to the lowest, HOMA-IR index quartile (HR 1.39 95% CI 1.14 -1.69, P = 0.0012). Of the women with incident breast cancer, 353 (31%) have died, with cause of death available on 334 (95% of cases) where breast cancer was the most common cause of death (33%); followed by cardiovascular disease (24%); and other cancers (13%). With median post-breast cancer diagnosis follow-up of 10.5 years, breast cancer mortality was examined from breast cancer diagnosis. No association was found between death from breast cancer and HOMA-IR. However, women with breast cancer in the highest HOMA-IR quartile, compared to women in the lowest, were significantly more likely to experience death after breast cancer from any cause (HR 1.45 95% CI 1.00 - 2.09, P = 0.0488) and were at somewhat higher risk of death from cardiovascular disease (HR 1.51 95% CI 0.67 - 3.41) and other causes (HR 1.93 95% CI 0.87-4.27). Conclusion:In postmenopausal women, higher insulin resistance is associated with higher breast cancer incidence and more deaths after breast cancer, likely due to insulin influence on several causes of death. However, deaths from breast cancer, even in this older postmenopausal population, remains a major factor limiting survival which needs to be addressed. The findings suggest insulin resistance represented a potential intervention target for postmenopausal women with early stage breast cancer. Citation Format: Chlebowski RT, Pan K, Mortimer J, Cespedes Feliciano EM, Gunter MJ, Hurria A, Rohan T, Vitolins MZ, Adams-Campbell L, Ho G, Cheng T-YD, Nelson R. Insulin resistance and breast cancer incidence and mortality in postmenopausal women [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-10.

10552 Background: In the WHI DM randomized trial, randomization to the dietary intervention group was associated with a 21% lower breast cancer mortality (P = 0.02) (JCO 2020), and while not an intervention target, with higher physical activity as well. Therefore, we examined whether these lifestyle changes attenuate age-related physical functioning decline. Methods: From 1993-1998, 48,835 postmenopausal women, aged 50-79 years, were randomized to dietary intervention or usual diet comparison groups through 8 years intervention and 19 years cumulative follow-up. Breast cancer findings, as primary outcome, have been reported. Physical functioning was assessed using the RAND 36-Item Short Form Health Survey (SF-36), which assessed limitations of 10 hierarchical physical activities, scored from 0 to 100, with a higher score indicating less limited physical function. The trajectory of longitudinal physical functioning was the primary study outcome, assessed by comparing findings in the two randomization groups, overall, and by baseline physical activity and age decade. Additionally, findings were reported against a disability threshold (when assistance in daily activities is required). Results: Physical functioning was assessed nearly half a million times during the study (n = 495,317) with 11.0 (median) assessments per participant. Physical functioning score was significantly better in the intervention versus comparison groups during the 8-year intervention and extended follow-up through 12 years (median) (P = 0.001), representing a reduction in age-related functional decline. The intervention effect subsequently lost significance at 19 years and both randomization groups crossed the disability threshold at similar times. Differences between randomization groups in physical functioning emerged after stratification by physical activity and age decade (P-interaction = 0.007). Among all participants physically active at entry, the intervention initially had a statistically significant, favorable influence on physical functioning which attenuated post-intervention. In contrast, among younger, physically inactive women 50-59 years of age, the intervention had a persistent, statistically significant, favorable influence on physical functioning with associated delay in crossing the disability threshold. Conclusions: In the primary prevention setting of the WHI DM randomized trial, with long-term follow-up, a dietary intervention which has been shown to reduce breast cancer mortality also significantly reduced age-related functional decline through 12 years. Among all participants, the intervention effect was attenuated with longer follow-up. However, reduction in age-related functional decline was sustained in younger women in the intervention group who were inactive at entry, a potential target population for future behavior interventions. Clinical trial information: NCT00000611.

ImportanceAbout 25% of all triple-negative breast cancers (TNBCs) and 10% to 20% of high-grade serous ovarian cancers (HGSOCs) harbor BRCA1 promoter methylation. While constitutional BRCA1 promoter methylation has been observed in normal tissues of some individuals, the potential role of normal tissue methylation as a risk factor for incident TNBC or HGSOC is unknown.ObjectiveTo assess the potential association between white blood cell BRCA1 promoter methylation and subsequent risk of incident TNBC and HGSOC.Design, Setting, and ParticipantsThis case-control study included women who were participating in the Women’s Health Initiative study who had not received a diagnosis of either breast or ovarian cancer before study entrance. A total of 637 women developing incident TNBC and 511 women developing incident HGSOC were matched with cancer-free controls (1841 and 2982, respectively) in a nested case-control design. Cancers were confirmed after central medical record review. Blood samples, which were collected at entry, were analyzed for BRCA1 promoter methylation by massive parallel sequencing. The study was performed in the Mohn Cancer Research Laboratory (Bergen, Norway) between 2019 and 2022.Main Outcomes and MeasuresAssociations between BRCA1 methylation and incident TNBC and incident HGSOC were analyzed by Cox proportional hazards regression.ResultsOf 2478 cases and controls in the TNBC group and 3493 cases and controls in the HGSOC group, respectively, 7 (0.3%) and 3 (0.1%) were American Indian or Alaska Native, 46 (1.9%) and 30 (0.9%) were Asian, 1 (0.04%) and 1 (0.03%) was Native Hawaiian or Pacific Islander, 326 (13.2%) and 125 (3.6%) were Black or African, 56 (2.3%) and 116 (3.3%) were Hispanic, 2046 (82.6%) and 3257 (93.2%) were White, and 35 (1.4%) and 35 (1.0%) were multiracial. Median (range) age at entry was 62 (50-79) years, with a median interval to diagnosis of 9 (TNBC) and 10 (HGSOC) years. Methylated BRCA1 alleles were present in 194 controls (5.5%). Methylation was associated with risk of incident TNBC (12.4% methylated; HR, 2.35; 95% CI, 1.70-3.23; P P P P = .003). Across individuals, methylation was not haplotype-specific, arguing against an underlying cis-acting factor. Within individuals, BRCA1 methylation was observed on the same allele, indicating clonal expansion from a single methylation event. There was no association found between BRCA1 methylation and germline pathogenic variant status.Conclusions and RelevanceThe results of this case-control suggest that constitutional normal tissue BRCA1 promoter methylation is significantly associated with risk of incident TNBC and HGSOC, with potential implications for prediction of these cancers. These findings warrant further research to determine if constitutional methylation of tumor suppressor genes are pancancer risk factors.

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.

Background Triple-negative breast cancer (TNBC) has a high recurrence risk and poor clinical outcomes. Associations between metabolic syndrome (MetS) risk components and mortality in postmenopausal women with TNBC were examined in the Women's Health Initiative. Methods Five hundred forty-four postmenopausal women were diagnosed with nonmetastatic TNBC. Baseline risk components included a high waist circumference (≥88 cm), high blood pressure, hypercholesterolemia, and diabetes. Groups were categorized by the number of MetS risk components: none, 1 or 2, or 3 or 4. Hazard ratios (HRs) and 95% confidence intervals (CIs) across groups were computed with multivariable adjusted Cox models. Outcomes included breast cancer-specific mortality and breast cancer overall mortality (breast cancer followed by death from any cause). Variables in the multivariable model included age at TNBC diagnosis; race/ethnicity; income; education; clinical/observational trial status; history of oral contraceptive, hormone, and/or statin use; cancer stage; and chemotherapy and/or radiation treatment status. Results Of the 544 participants with TNBC, 33% had no MetS risk components (n = 178), 59% had 1 or 2 risk components (n = 323), and 8% had 3 or 4 risk components (n = 43). After a median follow-up from diagnosis of 8.3 years, multivariable results showed that women with 3 or 4 risk components had a nonsignificantly higher risk of breast cancer mortality (HR, 2.05; 95% CI, 0.94-4.47 trend P = .114) and a significantly higher risk of overall mortality (HR, 2.13; 95% CI, 1.22-3.71; trend P = .006) versus women with 0 risk components. Conclusions Postmenopausal women with TNBC and 3 or 4 MetS risk components have a nonsignificantly higher breast cancer mortality risk and a significantly higher overall mortality risk, likely because of negative influences of metabolic risk factors on several causes of death.

BackgroundPrior studies of dietary protein intake and breast cancer have been mixed and were limited by dietary self-report measurement error.MethodsBiomarker-calibrated total protein intake and estimated vegetable protein and animal protein intake were determined from baseline food frequency questionnaires in 100 024 Women’s Health Initiative participants. Associations between total, animal, and vegetable protein intake and breast cancer incidence, deaths from breast cancer, and deaths after breast cancer were estimated using Cox proportional hazards regression. Breast cancers were verified by medical record review and survival outcomes enhanced by National Death Index queries. All statistical tests were 2-sided.ResultsAfter 14 years of follow-up, there were 6340 incident breast cancers, 764 deaths from breast cancer, and 2059 deaths after breast cancer. In multivariable analyses, higher calibrated total protein intake was not associated with breast cancer incidence or deaths from or after breast cancer. Vegetable protein intake was associated with statistically significantly lower breast cancer incidence (hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.96 to 0.99, Ptrend = .006) and statistically significantly lower risk of death after breast cancer (HR = 0.93, 95% CI = 0.91 to 0.97, Ptrend < .001) but not with deaths from breast cancer. In contrast, higher animal protein intake was associated with statistically significantly higher breast cancer incidence (HR = 1.03, 95% CI = 1.01 to 1.06, Ptrend = .02) but not with deaths from or after breast cancer.ConclusionsCalibrated total protein intake was not associated with breast cancer incidence or mortality. Higher vegetable protein intake was associated with lower breast cancer incidence and lower risk of death after breast cancer. Higher animal protein intake was associated with higher breast cancer incidence.

Background In the Women's Health Initiative (WHI) dietary modification (DM) randomised trial, the low-fat dietary intervention reduced deaths from breast cancer (P = 0.02). Extending these findings, secondary analysis examined dietary intervention influence on breast cancer mortality by metabolic syndrome (MS) components. Methods In total, 48,835 postmenopausal women with no prior breast cancer were randomised to a low-fat dietary intervention or comparison groups. Four MS components were determined at entry in 45,833 participants: (1) high waist circumference, (2) high blood pressure, (3) high cholesterol and (4) diabetes history. Forest plots of hazard ratios (HRs) were generated with P-values for interaction between randomisation groups and MS component score. Primary outcome was death from breast cancer by metabolic syndrome score. Results HRs and 95% confidence intervals (CI) for dietary intervention influence on death from breast cancer were with no MS components (n = 10,639), HR 1.09, 95% CI 0.63-1.87; with 1-2 MS components (n = 30,948), HR 0.80, 95% CI 0.62-1.02; with 3-4 MS components (n = 4,246), HR 0.31, 95% CI 0.14-0.69 (interaction P = 0.01). Conclusions While postmenopausal women with 3-4 MS components were at higher risk of death from breast cancer, those randomised to a low-fat dietary intervention more likely had reduction in this risk. Registry ClinicalTrials.gov (NCT00000611).

INTRODUCTION:Evidence on the association between diabetes and risk of bladder cancer has been controversial. In addition, findings on the associations between duration of diabetes, diabetes treatment, and risk of bladder cancer have been inconsistent. METHODS:A total of 148,208 participants in Women's Health Initiative study were included. Information on diabetes status, diabetes duration, and treatment was collected both at baseline and during follow-up. Information on potential confounders including age, race/ethnicity, education, occupation, family history of cancer, smoking status, alcohol consumption, total physical activity, body mass index, and daily dietary intake were collected at baseline. Bladder cancer cases were collected and confirmed by a centralized review of pathology reports. Cox proportional hazard models with time-varying covariates were used to examine associations of diabetes status, duration of diabetes, and diabetes treatment with bladder cancer risk. RESULTS:During a median follow-up of 18.5years, 865 bladder cancer cases were identified. There were no significant associations of diabetes, duration of diabetes, or diabetes treatment with risk of bladder cancer. Participants with prevalent diabetes did not have significantly higher risk of bladder cancer compared with those without diabetes. CONCLUSION:Diabetes was not significantly associated with risk of bladder cancer among postmenopausal women.

PURPOSE Observational studies of dietary fat intake and breast cancer have reported inconsistent findings. This topic was addressed in additional analyses of the Women’s Health Initiative (WHI) Dietary Modification (DM) clinical trial that evaluated a low-fat dietary pattern influence on breast cancer incidence. METHODS In the WHI DM trial, 48,835 postmenopausal women, ages 50-79 years, with no prior breast cancer, and a dietary fat intake of ≥ 32% of energy were randomly assigned at 40 US centers to a usual diet comparison group (60%) or dietary intervention group (40%). The goals were to reduce fat intake to 20% of energy and increase vegetable, fruit, and grain intake. Breast cancers were confirmed after central medical record review and serial National Death Index linkages to enhance mortality findings. RESULTS During 8.5 years of dietary intervention, breast cancer incidence and deaths as a result of breast cancer were nonsignificantly lower in the intervention group, while deaths after breast cancer were statistically significantly lower both during intervention and through a 16.1-year (median) follow-up. Now, after a long-term, cumulative 19.6-year (median) follow-up, the significant reduction in deaths after breast cancer persists (359 [0.12%] v 652 [0.14%] deaths; hazard ratio [HR], 0.85; 95% CI, 0.74 to 0.96; P = .01), and a statistically significant reduction in deaths as a result of breast cancer (breast cancer followed by death attributed to the breast cancer) emerged (132 [0.037%, annualized risk] v 251 [0.047%] deaths, respectively; HR, 0.79; 95% CI, 0.64 to 0.97; P = .02). CONCLUSION Adoption of a low-fat dietary pattern associated with increased vegetable, fruit, and grain intake, demonstrably achievable by many, may reduce the risk of death as a result of breast cancer in postmenopausal women.

Purpose Inspired by the American Society of Clinical Oncology's recommendations to strengthen the evidence base for older adults with cancer, the purpose of this systematic review is to identify the reporting of treatment efficacy and adverse events specific to older adults with cancer in Phase III chemo-therapeutic clinical trials. This review also investigates the frequency with which these data points were reported in the literature to identify gaps in reporting and opportunities to expand the knowledge base on clinical outcomes for older adults with cancer. Methods Chemo-therapeutic clinical trial data published from July 1, 2016 to June 30, 2017 was reviewed. Manuscripts (n = 929) were identified based on keyword searches of EMBASE and PubMed. After removal of duplicates (n = 116) and articles that did not meet this study's inclusion criteria (n = 654), 159 articles were identified for review. Results Reviewed papers were published in 36 different scientific journals and included twenty-five different cancer types. Of the 159 articles, 117 (73.6%) reported age-specific medians and 75 (47.2%) included stratifications of data by age. Treatment efficacy was reported in 96.2% of the articles with 39.9% reporting effectiveness of treatment by age. Reporting of adverse events was included in 84.9% of the articles with only 8.9% reporting these events stratified by age. Conclusion Results suggest inadequate reporting of treatment efficacy and adverse events as well as basic descriptive statistics about the age distribution of study subjects. Conscious efforts are needed to address these deficiencies at every level of planning and conducting clinical trials as wells as reporting outcomes stratified by age. Ultimately, standardized reporting could lead to improved treatment decisions and outcomes for older adults with cancer.

Ovarian cancer is a heterogeneous disease that encompasses a number of different histologic subtypes, including high-grade serous carcinomas (the most frequent), endometrioid, and clear cell, mucinous, and low-grade serous carcinomas. Mutations in the tumor suppressor gene TP53, BRCA mutations, and abnormalities of DNA repair genes are found primarily in high-grade serous carcinomas, while mutations in other key molecular pathways such as Ras/Raf/MEK/ERK, PI3K/AKT/mTOR, and the ErbB family are present in the less common ovarian histologies. Three PARP inhibitors have been FDA approved for the treatment of recurrent OC or for use as maintenance therapy after platinum-based chemotherapy.

BACKGROUND Insulin resistance is associated with higher all-cause and cancer-specific mortality in postmenopausal women. However, to the authors' knowledge, information regarding insulin resistance and breast cancer mortality risk is limited. Therefore, the authors examined associations between insulin resistance and breast cancer incidence and mortality in a subsample of Women's Health Initiative participants. METHODS A total of 22,837 postmenopausal women with fasting baseline glucose and insulin levels were followed for incident breast cancer and breast cancer mortality. Breast cancers were verified by medical record review and serial National Death Index linkage-enhanced mortality findings. Insulin resistance was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR). Multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) with 95% confidence intervals (95% CIs) for quartile comparisons. Outcomes included breast cancer incidence, deaths from breast cancer, and deaths after breast cancer (breast cancer followed by death from any cause). RESULTS During a median of 19.8 years of follow-up of 1328 breast cancer cases, there were 512 deaths reported, 151 of which were from breast cancer. Breast cancer incidence was higher in women in the highest HOMA-IR quartile (HR, 1.34; 95% CI, 1.12-1.61 [P for trend = .003]). Although HOMA-IR was not found to be associated with risk of death from breast cancer (HR, 1.04; 95% CI, 0.60-1.79), women in the highest versus those in the lowest HOMA-IR quartile were at a higher risk of death after breast cancer (HR, 1.78; 95% CI, 1.32-2.39 [P for trend

Breast cancer survivors frequently report sleep problems, but little research has studied sleep patterns longitudinally. We examined trends in sleep quality and duration up to 15 years before and 20 years after a diagnosis of breast cancer, over time among postmenopausal women participating in the Women’s Health Initiative (WHI). We included 12,098 participants who developed invasive breast cancer after study enrollment. A linear mixed-effects model was used to determine whether the time trend in sleep quality, as measured by the WHI Insomnia Rating Scale (WHIIRS), a measure of perceived insomnia symptoms from the past 4 weeks, changed following a cancer diagnosis. To examine sleep duration, we fit a logistic regression model with random effects for both short (, Epidemiology: Long-term sleep patterns unaffected by breast cancer diagnosis Despite frequent reports of poor sleep among survivors of breast cancer, a large epidemiological study has found no evidence that diagnosis of invasive breast cancer long-term sleep problems. Chloe Beverly of The Ohio State University in Columbus, USA, and colleagues examined long-term patterns in sleep quality, sleep duration and symptoms of depression among more than 12,000 participants of the Women’s Health Initiative who were diagnosed with breast cancer. On the whole, they found that women developed insomnia at a slightly slower rate after their diagnosis and the prevalence of depression went down, with little change in sleep duration. Although some women may experience cancer-related sleep disturbances shortly after their diagnosis and treatment, the findings suggest that, over the long term, most sleep issues remain consistent compared to before diagnosis.

BACKGROUND: Sleep is a crucial factor for optimal health, but breast cancer survivors often report poor sleep quality. It is estimated 20-70% of survivors have at least one sleep problem, which contribute to quality of life and health differences among survivors. Minority groups tend to have poorer sleep quality and shorter sleep duration than Non-Hispanic Whites (NHW). African-Americans (AA) with breast cancer have a poorer prognosis than NHW for each stage-specific diagnosis and are twice as likely as NHW to report short sleep duration, yet survivor studies are still lacking in AA participants. The purpose of this study was to examine sleep quality and duration patterns before and after cancer diagnosis by race/ethnicity among WHI breast cancer survivors. METHODS: There were 12,098 postmenopausal women diagnosed with invasive breast cancer after WHI enrollment who were eligible for this secondary analysis. Baseline demographic and clinical characteristics were described. The WHI Insomnia Rating Scale (WHIIRS) was measured at multiple time points pre- and post-diagnosis. A higher WHIIRS scores (0-20 points) indicates greater sleep disturbance and ≥9 points identifies clinical insomnia. A linear mixed model was fit to the WHIIRS sleep quality data to examine if the trend in sleep quality with time changed following a cancer diagnosis. For short ( RESULTS: The majority of participants were NHW (87.4%), mean age at diagnosis was 70.3 years, and 75% had localized breast cancer at diagnosis. At baseline, 30% of women had insomnia. The lowest average WHIIRS score was 5.6 among Asians, and the highest was 6.6 among American-Indians and NHWs (p=0.02). AAs had the most women sleeping ≤5 hrs/night and NHW had the least (19.6% vs 5.7%, p DISCUSSION: Sleep is an appealing area to target for improvement due to the multiple ways it can be treated. With increasing survival rates, there is an emphasis on improving quality of life in survivors. Our results span 20 years pre-diagnosis to 15 years post-diagnosis and are similar to shorter follow-up studies which found most women's sleep problems resolve within a few years of treatment completion. The lack of difference by race was an unexpected finding in another similar longitudinal study, which suggested most differences are seen in cross-sectional sleep studies. This study adds to the literature on longitudinal sleep data, especially to the little data on sleep trajectories in minority breast cancer survivors. Citation Format: Beverly CM, Naughton M, Foraker R, Pennell M, Young G, Hale L, Crane T, Pan K, Danhauer S, Feliciano E, Paskett E. Racial/ethnic differences in sleep quality and duration among breast cancer survivors: Results from the women's health initiative (WHI) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-02.