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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.

Background Mechanisms underlying the adiposity–cancer relationship are incompletely understood. We quantified the mediating roles of C‐reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)‐positive breast, endometrial, and colorectal cancer risk in postmenopausal women. Methods We used a case–cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case–control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis. Results For breast cancer, the total effect RR for BMI ≥30 versus ≥18.5–

Background Higher physical activity levels are associated with lower breast cancer-specific mortality. In addition, the metabolic syndrome is associated with higher breast cancer-specific mortality. Whether the physical activity association with breast cancer mortality is modified by number of metabolic syndrome components (cardiometabolic risk factors) in postmenopausal women with early-stage breast cancer remains unknown. Methods Cardiovascular risk factors included high waist circumference, hypertension, high cholesterol, and diabetes. Breast cancers were verified by medical record review. Mortality finding were enhanced by serial National Death Index queries. Cox proportional hazards regression models were used to estimate associations between baseline physical activity and subsequent breast cancer-specific and overall mortality following breast cancer diagnosis in Women’s Health Initiative participants. These associations were examined after stratifying by cardiometabolic risk factor group. Results Among 161,308 Women’s Health Initiative (WHI) participants, 8543 breast cancers occurred after 9.5 years (median) follow-up in women, additionally with information on cardiometabolic risk factors and physical activity at entry. In multi-variable analyses, as measured from cancer diagnosis, higher physical activity levels were associated with lower all-cause mortality risk (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.78–0.95, trend P P = 0.09). The physical activity and all-cause mortality association was not significantly modified by cardiometabolic risk factor number. Conclusions Among women with early-stage breast cancer, although higher antecedent physical activity was associated with lower risk of all-cause mortality, the association did not differ by cardiometabolic risk factor number.

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.

The objective of this study was to assess the effect of menopausal hormone therapy (HT) on blood pressure control in postmenopausal women with hypertension.The Women's Health Initiative HT clinical trials were double-blinded, randomized, placebo-controlled studies of women aged 50 to 79 years testing the effects of HT (conjugated equine estrogens [CEE, 0.625 mg/d] or CEE + medroxyprogesterone acetate [MPA; 2.5 mg/d]) on risks for coronary heart disease and invasive breast cancer, the primary outcomes for efficacy and safety, respectively. This secondary analysis of the Women's Health Initiative HT trials examined a subsample of 9,332 women with hypertension (reported ever taking pills to treat hypertension or were taking antihypertensive medication) at baseline. Blood pressure was measured at baseline and up to 10 annual follow-up visits during the planned study phase. Antihypertensive medications were inventoried at baseline and years 1, 3, 6, and 9 during the study, and self-reported during extended follow-up: 2009-2010 and 2012-2013, which occurred median of 13 and 16 years after randomization, respectively. The intervention effect was estimated through year 6. Cumulative follow-up included all visits.Compared with placebo, CEE-alone had significantly ( P = 0.02) higher systolic blood pressure (SBP) by mean (95% confidene interval [CI]) = 0.9 (0.2-1.5) mm Hg during the intervention phase. For cumulative follow-up, the CEE arm was associated with increased SBP by mean (95% CI) = 0.8 (0.1-1.4) mm Hg ( P = 0.02). Furthermore, CEE + MPA relative to placebo was associated with increased SBP by mean (95% CI) = 1.8 (1.2-2.5) mm Hg during the intervention phase ( P0.001). For cumulative follow-up, the CEE + MPA arm was associated with increased SBP by mean (95% CI) = 1.6 (1.0-2.3) mm Hg ( P0.001). The mean number of antihypertensive medications taken at each follow-up visit did not differ between randomization groups during the intervention or long-term extended follow-up of 16 years.There was a small but statistically significant increase in SBP in both CEE-alone and CEE + MPA arms compared with placebo during both the intervention and cumulative follow-up phases among postmenopausal women with hypertension at baseline. However, this increase in SBP was not associated with an increased antihypertensive medication use over time among women randomized to HT compared with placebo.

In the Women's Health Initiative (WHI) randomized trial with 10,739 postmenopausal women with prior hysterectomy, conjugated equine estrogen (CEE) alone significantly reduced breast cancer incidence and breast cancer mortality. In contrast, epidemiological studies in a meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group) with 108,647 breast cancers and the Million Women's Study cohort significantly associated estrogen-alone therapy with higher breast cancer incidence and breast cancer mortality. The Collaborative Group included a meta-analysis of five smaller randomized trials and the WHI randomized trial; however, findings were restricted to the Collaborative Group appendix. Our objective is to facilitate understanding of these discordant results.Data sources supporting our review findings include the randomized WHI CEE-alone trial and the meta-analysis of five smaller randomized trials evaluating estrogen alone. We summarize the smaller randomized trials' details of breast cancer relevance and place the findings in clinical context. We review findings of the WHI randomized trial evaluating CEE alone in the context of issues raised by Collaborative Group and the Million Women Study authors. We trace the evolution of the time-from-menopause, "window of opportunity" concept and augment the Collaborative Group meta-analysis by including the most recent WHI findings.Consideration of the smaller randomized trials evaluating estrogen alone with breast cancer signals that the WHI findings of lower breast cancer incidence and lower breast cancer mortality with CEE-alone use are not a "stand-alone" outcome or due to the play of chance. The serial reports of consistent favorable breast cancer findings through 20 years of cumulative follow-up suggest CEE-alone use initiates changes that persist. After full consideration of risks and benefits, randomized trial evidence provides reassurance for postmenopausal women with prior hysterectomy who are close to menopause considering estrogen alone for climacteric symptom management.

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.

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.

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 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.

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

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.

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.

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.

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

BACKGROUND/OBJECTIVES While breast cancer and associated therapies can influence physical function (PF), findings for breast cancer's effects on PF among postmenopausal women are not consistent. This research evaluates the effect of breast cancer on change in PF. DESIGN Longitudinal cohort study analyzed using difference-in-differences (DID) method to compare the changes in PF over time between women with and without breast cancer, by invasive status, stage, and age. SETTING AND PARTICIPANTS Women's Health Initiative participants, aged 50 to 79 years at baseline, with four completed functional status assessments were eligible for inclusion (mean age = 62.1 ± 6.9 years). Women with breast cancer diagnosed between the 3rd and 11th enrollment year (n = 1636) were compared to women without breast cancer (n = 35 660). MEASUREMENTS PF was measured using the Medical Outcomes Study Short Form 36 at baseline and years 3, 11, and 12. RESULTS Compared with women without breast cancer, women with breast cancer experienced greater PF decline (P

Postoperative urinary tract infection (UTI) leads to increased patient morbidity and health care costs. A prediction model may identify patients at highest risk for UTI development. Our primary objective was to determine the rate of UTI in the first 6 weeks after benign gynecologic surgery. Our secondary objective was to identify risk factors and build a predictive model for postoperative UTI. We reviewed 310 patient records, which represent all patients who underwent clean-contaminated surgery at a tertiary center (2016–2017). UTI was defined as positive urine culture (> 100,000,000 CFU/l) in a symptomatic patient. Pre-, intra- and postoperative variables were collected. The relation between these variables and UTI was assessed through logistic regression. A clinical prediction model was built. Patients’ mean age was 58.5 years and mean body mass index was 27.5 kg/m2. Most were inpatients (65.8%) and 269 had urogynecologic procedures, with the remainder undergoing pelvic surgery for other indications. The most common operation was vaginal reconstruction for prolapse (59.7%), associated with concomitant synthetic midurethral sling in 1/3 cases. Forty patients (12.9%) developed UTI. Multivariate prediction modeling showed increasing age (OR 1.33, CI 1.01–1.75), increasing number of procedures (OR 1.42, CI 1.14–1.78) and prolonged voiding dysfunction (OR 3.78, CI 1.66–8.60) to be significant UTI predictors. Urinary tract infection in the first 6 weeks after complex pelvic surgery is common. Our prediction model identifies that patients who are older women, have prolonged voiding dysfunction and have a greater number of concomitant pelvic floor surgeries have higher risk of postoperative UTI.

Background Insulin resistance has been proposed as a mediator of the increased cancer incidence and mortality associated with obesity. However, prior studies included limited cancer deaths and had inconsistent findings. Therefore, we evaluated insulin resistance and cancer-specific and all-cause mortality in postmenopausal women participating in the Women’s Health Initiative (WHI). Methods Eligible were a subsample of 22 837 WHI participants aged 50–79 years enrolled at 40 US clinical centers from 1993 to 1998 who had baseline fasting glucose and insulin levels. Baseline insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Cancers were verified by central medical record review and deaths verified by medical record and death certificate review enhanced by National Death Index queries. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific and all-cause mortality. All statistical tests were two-sided. Results During a median of 18.9 years of follow-up, 1820 cancer deaths and 7415 total deaths occurred. Higher HOMA-IR quartile was associated with higher cancer-specific mortality (Q4 vs Q1, HR = 1.26, 95% CI = 1.09 to 1.47; Ptrend = .003) and all-cause mortality (Q4 vs Q1, HR = 1.63, 95% CI = 1.51 to 1.76; Ptrend < .001). A sensitivity analysis for diabetes status did not change findings. Among women with body mass index less than 25 kg/m2, higher HOMA-IR quartile was associated with higher cancer mortality (Fine and Gray, P = .004). Conclusions High insulin resistance, as measured by HOMA-IR, identifies postmenopausal women at higher risk for cancer-specific and all-cause mortality who could potentially benefit from early intervention.

The benefits of adding ovarian suppression to either tamoxifen or aromatase inhibitors as adjuvant breast cancer therapy in premenopausal women are controversial. Therefore, we performed a systematic literature review and meta-analysis of relevant randomized trials.We identified and combined four qualifying trials reporting disease-free survival (DFS) and overall survival (OS) using meta-analysis.Combining ABCSG-12, SOFT, and TEXT studies, there were 65 fewer DFS events (HR 0.89, 95% CI 0.57-1.39) but 30 more deaths for ovarian suppression plus aromatase inhibitor compared to ovarian suppression plus tamoxifen (HR 1.31, 95% CI 0.93-1.84, P = 0.12, τ = 0.03, heterogeneity, P = 0.18). DFS and OS were more concordant for combined SOFT and E-3193 findings; for ovarian suppression plus tamoxifen compared to tamoxifen alone, there were 24 fewer DFS events (HR 0.83, 95% CI 0.67-1.07, P = 0.09, τGiven the discordance between DFS and OS and inconsistent estrogen suppression with ovarian suppression plus aromatase inhibitor, adding aromatase inhibitor to ovarian suppression as adjuvant therapy in premenopausal women is premature.

In early adjuvant breast cancer trial reports, aromatase inhibitors more effectively reduced breast recurrence with lower risk of thromboembolic events and endometrial cancer than tamoxifen, while aromatase inhibitors had higher fracture and cardiovascular disease risk. We used data from updated patient-level meta-analyses of adjuvant trials in analyses to summarize the benefits and risks of these agents in various clinical circumstances. Baseline incidence rates for health outcomes by age and race/ethnicity, absent aromatase inhibitor, or tamoxifen use were estimated from the Women's Health Initiative. Aromatase inhibitor and tamoxifen effects on distant recurrence were obtained from a meta-analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (Big-1-98) clinical trials. Impact on other health outcomes were obtained from meta-analyses of randomized trials comparing aromatase inhibitor to tamoxifen use and from placebo-controlled chemoprevention trials. All health outcomes were given equal weight when modeling net benefit/risk for aromatase inhibitor compared to tamoxifen use by breast cancer recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no), and by prior myocardial infarction. Over a 10-year period, the benefit/risk index was more favorable for aromatase inhibitor than for tamoxifen as adjuvant breast cancer therapy in almost all circumstances regardless of patient age, race/ethnicity, breast cancer recurrence risk, or presence or absence of a uterus. Only in older women with prior myocardial infarction and low recurrence risk was an advantage for tamoxifen seen. Using a benefit/risk index for endocrine adjuvant breast cancer therapy in postmenopausal women, benefit was higher for aromatase inhibitor use in almost all circumstances.

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

Purpose The purpose of this study was to examine the association of type II diabetes and anthropometric variables with risk of pancreatic cancer among postmenopausal women. Methods Weight, height, waist circumference, and hip circumference were measured by trained personnel, whereas history of diabetes and weight earlier in life were self-reported. Pancreatic cancer was ascertained via central review of medical records by physician adjudicators. After exclusions, 1045 cases of pancreatic cancer were diagnosed among 156,218 women over a median follow-up of approximately 18 years. Cox proportional hazards models were used to estimate the associations of study factors with pancreatic cancer risk. Results Diabetes (hazards ratio (HR): 1.30; 95% confidence intervals (95% CI): 1.01–1.66), and in particular, waist circumference, waist-to-hip ratio, and waist-to-height ratio showed positive associations with pancreatic cancer risk (HRs for highest vs. lowest level 1.38; 95% CI: 1.14–1.66, 1.40; 1.17–1.68; and 1.36; 1.13–1.64, respectively). Body mass index at the baseline showed only a borderline positive association with risk (HR: 1.21; 95% CI: 0.97–1.51). Body mass index at age 50 years, but not at ages 18 and 35 years, was also associated with increased pancreatic cancer risk. Conclusions In this study of postmenopausal women, central adiposity and, to a lesser extent, general adiposity and a history of diabetes, were associated with increased pancreatic cancer risk.

Only recently has breast cancer survivorship earned formal recognition as a research discipline. Complicating survivorship research is the frequent overlap between aging and treatment sequelae. The ACS/ASCO 2016 Breast Cancer Survivorship Care Guideline (Guideline) reflects comprehensive literature review through April 2015, while the jointly sponsored, inaugural Cancer Survivorship Symposium in 2016 (Symposium) reflects ongoing research activity in the area. Together, these platforms provide an opportunity to examine the use of randomized trials and controlled studies in survivorship care research. All 236 citations from the Guideline and all 250 abstracts from the Symposium were reviewed independently by two authors and assigned to prospectively determined categories. Guideline citations were most frequently reviews (n = 88, 37.3%) and non-randomized, non-controlled studies (n = 51, 21.6%). Thirty-seven (15.7%) randomized trials were cited. Only 9% of Guideline recommendations were based on randomized clinical trial evidence, while 64% were based on evidence level "0" (expert opinion, clinical practice, etc.). Symposium abstracts consisted largely of non-randomized, non-controlled studies (n = 113, 45.2%), with ten completed randomized trials (4%). Few Guideline citations or Symposium abstracts incorporated matched, cancer-free controls. Based on the literature underlying the ASCO Guideline as well as a survey of the Cancer Survivorship Symposium abstracts, a significant proportion of the survivorship literature at least through 2015 consisted of non-randomized, non-controlled studies. To optimally address survivorship issues, cancer therapy sequelae need to be distinguished from normal aging in studies incorporating cancer-free controls, and randomized clinical trials are needed to inform intervention strategies.

Over the past 40 years, the prevalence of obesity has increased epidemically worldwide, which raises significant concerns regarding public health and the associated economic burden. Obesity is a major risk factor for several conditions including cardiovascular disease and type 2 diabetes, and recent evidence suggests that obesity negatively affects cancer risk and outcome. The relationship between obesity and cancer is complex and involves multiple factors both at the systemic and cellular level. Indeed, disruptions in insulin metabolism, adipokines, inflammation, and sex hormones all contribute to the adverse effects of obesity in cancer development and progression. The focus of this review will be the impact of these systemic obesity-related factors on cancer biology, incidence, and outcome. Potential therapeutic interventions and current clinical trials targeting obesity and its associated factors will also be discussed.

Since genetic and epigenetic alterations influence the development of colorectal cancer (CRC), huge potential lies in the use of DNA methylation as biomarkers to improve the current diagnosis, screening, prognosis and treatment prediction. Here we performed a systematic review on DNA methylation-based biomarkers published in CRC, and discussed the current state of findings and future challenges. Based on the findings, we then provide a perspective on future studies. Genome-wide studies on DNA methylation revealed novel biomarkers as well as distinct subgroups that exist in CRC. For diagnostic purposes, the most independently validated genes to study further are VIM, SEPT9, ITGA4, OSM4, GATA4 and NDRG4. These hypermethylated biomarkers can even be combined with LINE1 hypomethylation and the performance of markers should be examined in comparison to FIT further to find sensitive combinations. In terms of prognostic markers, myopodin, KISS1, TMEFF2, HLTF, hMLH1, APAF1, BCL2 and p53 are independently validated. Most prognostic markers published lack both a multivariate analysis in comparison to clinical risk factors and the appropriate patient group who will benefit by adjuvant chemotherapy. Methylation of IGFBP3, mir148a and PTEN are found to be predictive markers for 5-FU and EGFR therapy respectively. For therapy prediction, more studies should focus on finding markers for chemotherapeutic drugs as majority of the patients would benefit. Translation of these biomarkers into clinical utility would require large-scale prospective cohorts and randomized clinical trials in future. Based on these findings and consideration we propose an avenue to introduce methylation markers into clinical practice in near future. For future studies, multi-omics profiling on matched tissue and non-invasive cohorts along with matched cohorts of adenoma to carcinoma is indispensable to concurrently stratify CRC and find novel, robust biomarkers. Moreover, future studies should examine the timing and heterogeneity of methylation as well as the difference in methylation levels between epithelial and stromal tissues.

While adverse medical sequelae are associated with breast cancer therapies, information on breast cancer impact on medication use is limited. Therefore, we compared medication use before and after diagnosis of early stage breast cancer to medication use in matched, cancer-free controls. Of 68,132 Women's Health Initiative participants, 3726 were diagnosed with breast cancer and, after exclusions, in 1731 breast cancer cases, medication use before and >3 years after diagnosis (mean 5.3 ± 2.1 SD) was compared to use in 1731 cancer-free matched controls on similar inventory dates. The medication category number at follow-up inventory was the primary study outcome. Medication category use (n, mean, SD) was comparable at baseline and significantly increased at follow-up in both cases (2.48 ± 1.66 vs. 4.15 ± 2.13, baseline vs follow-up, respectively, P < .0001) and controls (2.44 ± 1.67 vs. 3.95 ± 2.13, respectively, P < .0001), with clinically marginal but statistically significant additional medication category use by cases (0.20 ± 2.40, P < .0001). Tamoxifen users used somewhat more selected medication categories at follow-up assessment (mean 3.40 ± 1.89 vs. 3.21 ± 1.99, respectively, P = 0.05), while aromatase inhibitor users used more medication categories (mean 4.85 ± 2.10 vs. 4.44 ± 1.94, respectively, P = 0.02). No increase in medication category was seen in cases who were not current endocrine therapy users. Breast cancer survivors having only a clinically marginal increase in medication use compared to cancer-free controls. These findings highlight the importance of incorporation of control populations in studies of cancer survivorship.

Importance In a randomized clinical trial, a low-fat eating pattern was associated with lower risk of death after breast cancer. However, the extent to which results were driven by dietary influence on survival after breast cancer diagnosis was unknown. Objective To determine the association of a low-fat dietary pattern with breast cancer overall survival (breast cancer followed by death from any cause measured from cancer diagnosis). Design, Setting, and Participants This is a secondary analysis of the Women’s Health Initiative randomized clinical trial that was conducted at 40 US clinical centers enrolling participants from 1993 through 1998. Participants were 48 835 postmenopausal women with no previous breast cancer and dietary fat intake of greater than 32% by food frequency questionnaire. Interventions Participants were randomized to a dietary intervention group (40%; n = 19 541) with goals to reduce fat intake to 20% of energy and increase fruit, vegetable, and grain intake or a usual-diet comparison group (60%; n = 29 294). Dietary group participants with incident breast cancers continued to participate in subsequent dietary intervention activities. Main Outcomes and Measures Breast cancer overall survival for incident breast cancers diagnosed during the 8.5-year (median) dietary intervention, examined in post hoc analyses after 11.5 years (median) postdiagnosis follow-up. Results Of 1764 women diagnosed with breast cancer during the dietary intervention period, mean (SD) age at screening was 62.7 (6.7) years and age at diagnosis was 67.6 (6.9) years. With 516 total deaths, breast cancer overall survival was significantly greater for women in the dietary intervention group than in the usual-diet comparison group (10-year survival of 82% and 78%, respectively; hazard ratio [HR], 0.78; 95% CI, 0.65-0.94; P = .01). In the dietary group there were fewer deaths from breast cancer (68 vs 120; HR, 0.86; 95% CI, 0.64-1.17), other cancers (36 vs 65; HR, 0.76; 95% CI, 0.50-1.17), and cardiovascular disease (27 vs 64; HR, 0.62; 95% CI, 0.39-0.99). Conclusions and Relevance In women who received a diagnosis of breast cancer during the dietary intervention period, those in the dietary group had increased overall survival. The increase is due, in part, to better survival from several causes of death. Trial Registration ClinicalTrials.gov Identifier:NCT00000611

Although 5 years of tamoxifen has been the standard adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer for more than 2 decades, emerging results suggest that either switching to an aromatase inhibitor after 5 years of tamoxifen when postmenopausal or continuing tamoxifen for an additional 5 years can further decrease relapse risk. As a result, more premenopausal breast cancer patients will be continuing adjuvant endocrine therapy through the menopause transition. In this setting, questions arise regarding continued tamoxifen use through 10 years and/or the timing and appropriateness of switching to an aromatase inhibitor. In addition, it is now recognized that estrogen levels substantially decline for approximately 2 years after the last menstrual period and that chemotherapy and/or tamoxifen-induced amenorrhea preclude reliable ovarian function determination. Because aromatase inhibitors are only effective in a low estrogen environment without ovarian estrogen production, determination of the optimal endocrine adjuvant therapy for perimenopausal women and those recently postmenopausal represent a challenge requiring understanding of current clinical study results and the potential for interactions among therapeutic interventions, ovarian function, and clinical outcome. Available options include tamoxifen for 10 years, tamoxifen for 5 years followed by aromatase inhibitors, tamoxifen with a luteinizing hormone-releasing hormone (LHRH) agonist, aromatase inhibitor with an LHRH agonist or aromatase inhibitor with bilateral oophorectomy. Although completed (Austrian Breast Cancer Study Group [ABCSG]-12) and ongoing (SOFT [Suppression of Ovarian Function Trial], TEXT [Tamoxifen and Exemestane Trial]) clinical trials are addressing some issues, many questions will remain requiring individualized clinical judgement. Rationale supporting the available endocrine therapy options in this setting and recommendations for clinical management follow.