Low physical function Post-Cancer diagnosis is associated with higher mortality risk in postmenopausal women.

BACKGROUND: Postmenopausal women with cancer experience an accelerated physical dysfunction beyond that expected through aging alone due to cancer and its treatments. The aim of this study is to determine whether declines in physical function after cancer diagnosis are associated with all-cause mortality and cancer-specific mortality. METHODS: This prospective cohort study included 8,068 postmenopausal women enrolled in the Women's Health Initiative (WHI) who were diagnosed with cancer and had physical function assessed within 1-year of cancer diagnosis. Self-reported physical function was measured using the 10-item physical function subscale of the RAND 36-Item Health Survey. Cause of death was determined by medical record review with central adjudication and linkage to the National Death Index. Death was adjudicated through February 2022. RESULTS: Over a median follow-up of 7.7 years from cancer diagnosis 3,316 (41.1%) women died. Our results showed that for every 10% decline in the physical function score after cancer diagnosis, all-cause mortality and cancer-specific mortality were significantly reduced by 12% (HR, 0.88; 95% CI, 0.87 to 0.89) and (HR, 0.88; 95%CI, 0.86 to 0.91), respectively. Further categorical analyses showed a significant dose-response relationship between post-diagnosis physical function categories and mortality outcomes (trend test P < .001), where the median survival time for women in the lowest physical function quartile was 9.1 (8.6, 10.6) years compared to 18.4 (15.8, 22.0) years for women in the highest physical function quartile. CONCLUSION: Postmenopausal women with low physical function after cancer diagnosis may be at higher risk of mortality from all causes and cancer-related mortality.

Physical Activity During Breast Cancer Therapy Associates With Preserved Exercise Capacity and Cardiac Function (WF97415).

Background: Cancer treatment increases cardiovascular disease risk, but physical activity (PA) may prevent cardiovascular disease. Objectives: This study examined whether greater PA was associated with better submaximal exercise capacity and cardiac function during cancer therapy. Methods: Participants included 223 women with stage I to III breast cancer (BC) before and 3 months after undergoing treatment and 126 control participants. Leisure-time PA (LTPA) was reported using the Godin-Shephard LTPA questionnaire. Cardiac function was assessed by cardiac magnetic resonance. Submaximal exercise capacity was determined by 6-minute walk distance. Results: BC participants reported similar baseline LTPA scores (24.7; 95% CI: 21.7-28.0) as control participants (29.4; 95% CI: 25.0-34.2). The BC group declined to 16.9 (95% CI: 14.4-19.6) at 3 months relative to 30.8 (95% CI: 26.2-35.8) in control participants. Among BC participants, more LTPA was related to better exercise capacity (ß ± SE: 7.1 ± 1.6; 95% CI: 4.0-10.1) and left ventricular (LV) circumferential strain (-0.16 ± 0.07; 95% CI: -0.29 to -0.02). Increased LTPA over the 3 months was associated with decreased likelihood of treatment-induced cardiac dysfunction according to LV circumferential strain classifications (OR: 0.98; 95% CI: 0.97-0.998). BC participants reporting insufficient LTPA according to PA guidelines exhibited deteriorations in exercise capacity (adjusted mean difference ± SE: -29 ± 10 m; P = 0.029), LV end-systolic volume (5.8 ± 1.3 mL; P < 0.001), LV ejection fraction (-3.2% ± 0.8%; P = 0.002), and LV circumferential strain (2.5% ± 0.5%; P < 0.001), but BC participants meeting LTPA guidelines did not exhibit these adverse changes. Conclusions: PA declined during BC therapy; however, PA participation was associated with attenuated declines in exercise capacity and cardiac function that are often observed in this population. (Understanding and Predicting Breast Cancer Events After Treatment [WF97415 UPBEAT]; NCT02791581).

Cardiovascular Imaging in Contemporary Cardio-Oncology: A Scientific Statement From the American Heart Association.

Advances in cancer therapeutics have led to dramatic improvements in survival, now inclusive of nearly 20 million patients and rising. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Advances in cardiovascular imaging have solidified the critical role for robust methods for detecting, monitoring, and prognosticating cardiac risk among patients with cancer. However, decentralized evaluations have led to a lack of consensus on the optimal uses of imaging in contemporary cancer treatment (eg, immunotherapy, targeted, or biological therapy) settings. Similarly, available isolated preclinical and clinical studies have provided incomplete insights into the effectiveness of multiple modalities for cardiovascular imaging in cancer care. The aims of this scientific statement are to define the current state of evidence for cardiovascular imaging in the cancer treatment and survivorship settings and to propose novel methodological approaches to inform the optimal application of cardiovascular imaging in future clinical trials and registries. We also propose an evidence-based integrated approach to the use of cardiovascular imaging in routine clinical settings. This scientific statement summarizes and clarifies available evidence while providing guidance on the optimal uses of multimodality cardiovascular imaging in the era of emerging anticancer therapies.

Predicting All-Cause Mortality in Women With and Without Breast Cancer Using the Schonberg Index: A Women's Health Initiative Study.

BACKGROUND: When treating older women with breast cancer, life expectancy is an important consideration. ASCO recommends calculating 10-year mortality probabilities to inform treatment decisions. One useful tool is the Schonberg index, which predicts risk-based all-cause 10-year mortality. We investigated the use of this index in women aged ≥65 years with breast cancer in the Women's Health Initiative (WHI). METHODS: We calculated 10-year mortality risk scores for 2,549 WHI participants with breast cancer ("cases") and 2,549 age-matched breast cancer-free participants ("controls") using Schonberg index risk scoring. Risk scores were grouped into quintiles for comparisons. Risk-stratified observed mortality rates and 95% confidence intervals were compared across cases and controls. Observed 10-year mortality rates in cases and controls were also compared with Schonberg index-based predicted 10-year mortality rates. RESULTS: Compared with controls, cases were more often white (P=.005), had higher income and education levels (P<.001 for both), more often lived with their husband/partner (P<.001), scored higher on subjective health/happiness (P<.001), and needed less assistance in activities of daily living (P<.001). Participants with breast cancer had similar risk-stratified 10-year mortality rates compared with controls (34% vs 33%, respectively). Stratified results showed that cases had slightly higher mortality rates than controls in the lowest risk quintile and lower mortality rates in the 2 highest risk quintiles. Observed mortality rates in cases and controls were similar to Schonberg index-predicted mortality, with model c-indexes of 0.71 and 0.76, respectively. CONCLUSIONS: Among women aged ≥65 years with incident breast cancer, the Schonberg index-based risk-stratified 10-year mortality rates were similar to those in women without breast cancer, demonstrating a similar performance of the index among both populations. Along with other health measures, prognostic indexes can help predict survival among older women with breast cancer and support geriatric oncology guidelines that promote using life expectancy calculation tools for shared decision-making.

Equity in Cardio-Oncology Care and Research: A Scientific Statement From the American Heart Association.

Advances in cancer therapeutics have revolutionized survival outcomes in patients with cancer. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Recent studies have uncovered excess risks of these cardiotoxic events, especially in traditionally underrepresented populations. Despite advances in strategies to limit the risks of cardiovascular events among cancer survivors, relatively limited guidance is available to address the rapidly growing problem of disparate cardiotoxic risks among women and underrepresented patient populations. Previously decentralized and sporadic evaluations have led to a lack of consensus on the definitions, investigation, and potential optimal strategies to address disparate cardiotoxicity in contemporary cancer care (eg, with immunotherapy, biologic, or cytotoxic therapies) settings. This scientific statement aims to define the current state of evidence for disparate cardiotoxicity while proposing uniform and novel methodological approaches to inform the identification and mitigation of disparate cardio-oncology outcomes in future clinical trials, registries, and daily clinical care settings. We also propose an evidence-based integrated approach to identify and mitigate disparities in the routine clinical setting. This consensus scientific statement summarizes and clarifies available evidence while providing guidance on addressing inequities in the era of emerging anticancer therapies.

A narrative review of heart failure with preserved ejection fraction in breast cancer survivors.

Advances in breast cancer (BC) treatment have contributed to improved survival, but BC survivors experience significant short-term and long-term cardiovascular mortality and morbidity, including an elevated risk of heart failure with preserved ejection fraction (HFpEF). Most research has focused on HF with reduced ejection fraction (HFrEF) after BC; however, recent studies suggest HFpEF is the more prevalent subtype after BC and is associated with substantial health burden. The increased HFpEF risk observed in BC survivors may be explained by treatment-related toxicity and by shared risk factors that heighten risk for both BC and HFpEF. Beyond risk factors with physiological impacts that drive HFpEF risk, such as hypertension and obesity, social determinants of health (SDOH) likely contribute to HFpEF risk after BC, impacting diagnosis, management and prognosis.Increasing clinical awareness of HFpEF after BC and screening for cardiovascular (CV) risk factors, in particular hypertension, may be beneficial in this high-risk population. When BC survivors develop HFpEF, treatment focuses on initiating guideline-directed medical therapy and addressing underlying comorbidities with pharmacotherapy or behavioural intervention. HFpEF in BC survivors is understudied. Future directions should focus on improving HFpEF prevention and treatment by building a deeper understanding of HFpEF aetiology and elucidating contributing risk factors and their pathogenesis in HFpEF in BC survivors, in particular the association with different BC treatment modalities, including radiation therapy, chemotherapy, biological therapy and endocrine therapy, for example, aromatase inhibitors. In addition, characterising how SDOH intersect with these therapies is of paramount importance to develop future prevention and management strategies.

Factors associated with long-term gastrointestinal symptoms in colorectal cancer survivors in the women's health initiatives (WHI study).

PURPOSE: Colorectal cancer (CRC) survivors often experience long-term symptoms after cancer treatments. But gastrointestinal (GI) symptom experiences are under-investigated in CRC survivors. We described persistent GI symptoms after cancer treatments in female CRC survivors and assessed GI symptoms' risk and life-impact factors. METHODS: A cross-sectional study utilized data from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study that recruited postmenopausal women. Correlation analyses and multivariable linear regression models were used. RESULTS: CRC survivors after cancer treatments were included (N = 413, mean age 71.2 years old, mean time since diagnosis = 8.1 years). 81% of CRC survivors experienced persistent GI symptoms. Bloating/gas was the most prevalent (54.2%± 0.88) and severe GI symptom, followed by constipation (44.1%±1.06), diarrhea (33.4%±0.76), and abdominal/pelvic pain (28.6%±0.62). Significant risk factors for GI symptoms include time since cancer diagnosis (<5 years), advanced cancer stage, high psychological distress, poor dietary habits, and low physical activity. Fatigue and sleep disturbance were the most significant risk factors for long-term GI symptoms (ß = 0.21, t = 3.557; ß = 0.20, t = 3.336, respectively, Ps < .001). High severity of GI symptoms was positively associated with poor quality of life (QOL), increased daily life interferences (social and physical functions), and low body image satisfaction (Ps < .001). CONCLUSIONS: Women CRC survivors experience a high GI symptom burden, highlighting the need to inform policy and improve the QOL of cancer survivors. Our findings will aid in identifying those more vulnerable to symptoms, and inform future survivorship care interventions (i.e., community-based cancer symptom management) by considering multiple risk factors (e.g., psychological distress).

Long-term Trajectories of Physical Function Decline in Women With and Without Cancer.

Importance: Patients 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. Objective: Examine trajectories of physical function a decade before and after cancer diagnosis among older survivors and cancer-free controls. Design, Setting, and Participants: This 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. Exposures: Cancer diagnosis (site, stage, and treatment) via Medicare and medical records. Main Outcomes and Measures: Trajectories 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. Results: This 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 Relevance: In 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.

Associations of Health-Related Quality of Life and Sleep Disturbance With Cardiovascular Disease Risk in Postmenopausal Breast Cancer Survivors.

BACKGROUND: Breast cancer (BC) survivors are at an increased risk of long-term cardiovascular disease (CVD), often attributed to cancer treatment. However, cancer treatment may also negatively impact health-related quality of life (HRQoL), a risk factor of CVD in the general population. OBJECTIVE: We examined whether sleep disturbance, and physical or mental HRQoL were associated with CVD risk in BC survivors. METHODS: We conducted a longitudinal analysis in the Women's Health Initiative of postmenopausal women given a diagnosis of invasive BC during follow-up through 2010 with no history of CVD before BC. The primary outcome was incident CVD, defined as physician-adjudicated coronary heart disease or stroke, after BC. Physical and mental HRQoL, measured by the Short-Form 36 Physical and Mental Component Summary scores, and sleep disturbance, measured by the Women's Health Initiative Insomnia Rating Scale, were recorded post BC. Time-dependent Cox proportional hazards models were used starting at BC diagnosis until 2010 or censoring and adjusted for relevant confounders. RESULTS: In 2884 BC survivors, 157 developed CVD during a median follow-up of 9.5 years. After adjustment, higher Physical Component Summary scores were significantly associated with a lower risk of CVD (hazard ratio, 0.90 [95% confidence interval, 0.81-0.99]; per 5-point increment in Physical Component Summary). No associations with CVD were found for Mental Component Summary or Insomnia Rating Scale. CONCLUSION: In BC survivors, poor physical HRQoL is a significant predictor of CVD. IMPLICATIONS FOR PRACTICE: Our findings highlight the importance for nurses to assess and promote physical HRQoL as part of a holistic approach to mitigating the risk of CVD in BC survivors.

Lifestyle and Cardiovascular Risk Factors Associated With Heart Failure Subtypes in Postmenopausal Breast Cancer Survivors.

Background: Breast cancer (BC) survivors experience an increased burden of long-term comorbidities, including heart failure (HF). However, there is limited understanding of the risk for the development of HF subtypes, such as HF with preserved ejection fraction (HFpEF), in BC survivors. Objectives: This study sought to estimate the incidence of HFpEF and HF with reduced ejection fraction (HFrEF) in postmenopausal BC survivors and to identify lifestyle and cardiovascular risk factors associated with HF subtypes. Methods: Within the Women's Health Initiative, participants with an adjudicated diagnosis of invasive BC were followed to determine the incidence of hospitalized HF, for which adjudication procedures determined left ventricular ejection fraction. We calculated cumulative incidences of HF, HFpEF, and HFrEF. We estimated HRs for risk factors in relation to HF, HFpEF, and HFrEF using Cox proportional hazards survival models. Results: In 2,272 BC survivors (28.6% Black and 64.9% White), the cumulative incidences of hospitalized HFpEF and HFrEF were 6.68% and 3.96%, respectively, over a median of 7.2 years (IQR: 3.6-12.3 years). For HFpEF, prior myocardial infarction (HR: 2.83; 95% CI: 1.28-6.28), greater waist circumference (HR: 1.99; 95% CI: 1.14-3.49), and smoking history (HR: 1.65; 95% CI: 1.01-2.67) were the strongest risk factors in multivariable models. With the exception of waist circumference, similar patterns were observed for HFrEF, although none were significant. In relation to those without HF, the risk of overall mortality in BC survivors with hospitalized HFpEF was 5.65 (95% CI: 4.11-7.76), and in those with hospitalized HFrEF, it was 3.77 (95% CI: 2.51-5.66). Conclusions: In this population of older, racially diverse BC survivors, the incidence of HFpEF, as defined by HF hospitalizations, was higher than HFrEF. HF was also associated with an increased mortality risk. Risk factors for HF were largely similar to the general population with the exception of prior myocardial infarction for HFpEF. Notably, both waist circumference and smoking represent potentially modifiable factors.

Inflammatory, Oxidative Stress, and Cardiac Damage Biomarkers and Radiation-Induced Fatigue in Breast Cancer Survivors.

PURPOSE: Studies examining biomarkers associated with fatigue in breast cancer survivors treated with radiation are limited. Therefore, we examined the longitudinal association between serum biomarkers and post-breast cancer fatigue in survivors treated with radiation: [oxidative stress] 8-hydroxyguanosine, myeloperoxidase; [inflammation] interleukin-6 (IL-6), c-reactive protein, growth differentiation factor-15 (GDF-15), placental growth factor, transforming growth factor-beta, [cardiac damage] cystatin-C, troponin-I. METHODS: In a secondary analysis, we included participants from the Women's Health Initiative if they had: a previous breast cancer diagnosis (stages I-III), no prior cardiovascular diseases, pre-and post-breast cancer serum samples drawn approximately 3 years apart, and fatigue measured using the Short-Form 36 vitality subscale at both serum collections. Biomarkers were measured using ELISA or RT-qPCR and modeled as the log2 post-to pre-breast cancer ratio. RESULTS: Overall, 180 women with a mean (SD) age of 67.0 (5.5) years were included. The mean (SD) vitality scores were 66.2 (17.2) and 59.7 (19.7) pre- and post-breast cancer, respectively. Using multivariable weighted linear regression, higher biomarker ratios of cystatin-C, IL-6, and GDF-15 were associated with a lower vitality score (i.e., higher fatigue). For example, for each 2-fold difference in cystatin-C biomarker ratio, the vitality score was lower by 7.31 points (95% CI: -14.2, -0.45). CONCLUSION: Inflammatory and cardiac damage biomarkers are associated with fatigue in breast cancer survivors treated with radiation; however, these findings should be replicated in a larger sample. Biomarkers could be measured in clinical practice or assessed in risk prediction models to help identify patients at high risk for fatigue.

Histamine H2 Receptor Antagonists and Heart Failure Risk in Postmenopausal Women: The Women's Health Initiative.

Background Prior studies suggested lower risk of heart failure (HF) in individuals taking H2 receptor antagonists (H2RA) compared with H2RA nonusers in relatively small studies. We evaluated the association of H2RA use and incident HF in postmenopausal women in the large-scale WHI (Women's Health Initiative) study. Methods and Results This study included postmenopausal women from the WHI without a history of HF at baseline. HF was defined as first incident hospitalization for HF and physician adjudicated. Multivariable Cox proportional hazards regression models evaluated the association of H2RA use as a time-varying exposure with HF risk, after adjustment for demographic, lifestyle, and medical history variables. Sensitivity analyses examined (1) risk of HF stratified by the ARIC (Atherosclerosis Risk in Communities) score, (2) propensity score matching on H2RA use, (3) use of proton pump inhibitors rather than H2RA nonuse as the referent, and (4) exclusion of those taking diuretics at baseline. The primary analysis included 158 854 women after exclusion criteria, of whom 9757 (6.1%) were H2RA users. During median 8.2 years of follow-up, 376 H2RA users (4.9 events/1000 person-years) and 3206 nonusers (2.7 events/1000 person-years) developed incident HF. After multivariable adjustment, there was no association between H2RA use and HF in the primary analysis (hazard ratio, 1.07; 95% CI, 0.94-1.22; P=0.31) or in any of the sensitivity analyses. Conclusions Clinical H2RA use was not associated with incident HF among postmenopausal women. Future studies are needed to evaluate potential effect modification by sex, HF severity, or patterns of use on H2RA exposure and HF risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000611.

Cardiometabolic risk factors, physical activity, and postmenopausal breast cancer mortality: results from the Women's Health Initiative.

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 < 0.001) but not with breast cancer-specific mortality (HR 0.85, 95% CI 0.70 to 1.04, trend 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.

Statins and Left Ventricular Ejection Fraction Following Doxorubicin Treatment.

BACKGROUND: Statins taken for cardiovascular indications by patients with breast cancer and lymphoma during doxorubicin treatment may attenuate left ventricular ejection fraction (LVEF) decline, but the effect of statins on LVEF among patients with no cardiovascular indications is unknown. METHODS: A double-blind, placebo-controlled, 24-month randomized trial of 40 mg of atorvastatin per day administered to patients with breast cancer and lymphoma receiving doxorubicin was conducted within the National Cancer Institute Community Oncology Research Program across 31 sites in the United States. At pretreatment and then 6 and 24 months after initiating doxorubicin, we assessed left ventricular (LV) volumes, strain, mass, and LVEF through cardiac magnetic resonance imaging, along with cognitive function and serum markers of inflammation. The primary outcome was the difference in 24-month LVEF between placebo and treatment groups, adjusted for pretreatment LVEF. RESULTS: A total of 279 participants were enrolled in the trial. Participants had a mean (±SD) age of 49±12 years; 92% were women; and 83% were White. The mean (±SD) LVEF values were 61.7±5.5% before treatment and 57.4±6.8% at 24 months in the placebo group and 62.6±6.4% before treatment and 57.7±5.6% at 24 months in the atorvastatin group. On the basis of a multiple imputed data set for missing data and adjusted for each individual's pretreatment LVEF, 24-month declines in LVEF averaged 3.3±0.6 percentage points and 3.2±0.7 percentage points, for those randomly assigned to placebo versus statins, respectively (P=0.93). Across both treatment arms, similar percentages of individuals experienced changes of more than 10 percentage points in LVEF, LV strain, LV mass, cognition, and inflammation biomarkers, including among those with greater than 90% drug compliance. CONCLUSIONS: In patients with breast cancer and lymphoma with no existing indication for statin therapy, prospective statin administration did not affect LVEF declines 2 years after doxorubicin. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01988571.).

A review of research on the intersection between breast cancer and cardiovascular research in the Women's Health Initiative (WHI).

Both obesity and metabolic syndrome are linked to increased incidence of type 2 diabetes, cardiovascular disease (CVD), and cancers of the breast (post-menopausal), and other obesity-related cancers. Over the past 50 years, the worldwide prevalence of obesity and metabolic syndrome has increased, with a concomitant higher incidence of associated co-morbidities and mortality. The precise mechanism linking metabolic syndrome to increased cancer incidence is incompletely understood, however, individual components of metabolic syndrome have been linked to increased breast cancer incidence and worse survival. There is a bidirectional relationship between the risk of CVD and cancer due to a high burden of shared risk factors and higher rates of CVD among cancer survivors, which may be impacted by the pro-inflammatory microenvironment associated with metabolic syndrome and cancer-directed therapies. The Women's Health Initiative (WHI) is an excellent resource to study a dual relationship between cancer and CVD (cardio-oncology) with extensive information on risk factors and long-term outcomes. The purpose of this review is to provide an overview of research on cardio-oncology conducted utilizing WHI data with focus on studies evaluating both breast cancer and CVD including shared risk factors and outcomes after cancer. The review also includes results on other obesity related cancers which were included in the analyses of breast cancer, articles looking at cancer after heart disease (reverse cardio-oncology) and the role of Clonal Hematopoiesis of Indeterminate Potential (CHIP) as a shared risk factor between CVD and cancer. A summary of pertinent WHI literature helps to delineate the direction of future research evaluating the relationship between CVD and other cancer sites, and provides information on the opportunity for other novel analyses within the WHI.