Impact of Hormonal Therapies for Treatment of Hormone-Dependent Cancers on the Cardiovascular System

Authors, Journal, Affiliations, Type, DOI

• Okwuosa TM, Morgans A, Rhee J-W, Reding KW, Maliski S, Plana JC, Volgman AS, Moseley KF, Porter CB, Ismail-Khan R; on behalf of the AHA Cardio-Oncology Subcommittee of the Council on Clinical Cardiology and Council on Genomic and Precision Medicine
• Circulation: Genomic and Precision Medicine, June 2021; 14:e000082
• AHA Scientific Statement
• DOI: 10.1161/HCG.0000000000000082

Overview

This AHA Scientific Statement reviews the cardiovascular (CV) risks of hormonal therapies for breast cancer (endocrine therapy) and prostate cancer (androgen deprivation therapy/ADT). For breast cancer, aromatase inhibitors carry modestly higher CVD risk than tamoxifen (pooled RR 1.19), while tamoxifen significantly increases VTE; CDK4/6 inhibitor combinations add QT prolongation (ribociclib) and hypertension (palbociclib). For prostate cancer, GnRH agonists induce a metabolic syndrome-like state increasing MI/stroke risk, while GnRH antagonists have ~50% fewer major CV events; newer AR-directed agents (abiraterone/enzalutamide) carry RR 1.36 for adverse CV events. Racial/ethnic disparities are prominent and the ABCDE clinical algorithm is endorsed for multidisciplinary cardioprotection.

Keywords

Androgen deprivation therapy, breast neoplasms, cardiovascular system, endocrine therapy, hormone therapy, prevention, prostatic neoplasms

Key Takeaways

Physiology of Endocrine Therapy for Breast Cancer

• Estrogen exerts broad cardioprotective effects: reduces cardiomyocyte hypertrophy, promotes vasodilation and vascular remodeling, antiatherosclerotic; also increases coagulation factors (VII, X, antithrombin III) → increased coagulation risk
• SERMs (tamoxifen, raloxifene): Mixed estrogen agonist/antagonist; tamoxifen reduces LDL-C and Lp(a), but increases body fat, hepatic steatosis, triglycerides, and diabetes risk; net arterial CVD effect is neutral to protective but VTE risk is significantly increased
• Aromatase inhibitors (AIs — anastrozole, letrozole, exemestane): Cause systemic estradiol depletion in postmenopausal women; associated with higher CVD risk than tamoxifen (though unclear whether due to AI toxicity or tamoxifen protection)
• Ovarian function suppression (OFS): 1.35× higher dyslipidemia risk and modest ↑ arrhythmia risk (HR 1.16) vs. natural menopause
• Fulvestrant (ER downregulator): Minimal cardiotoxicity; VTE rate not significantly higher vs. anastrozole; rate of hypertension not elevated vs. anastrozole

Cardiovascular Data for Endocrine Therapy (Breast Cancer)

• AIs vs. tamoxifen — overall CVD: Meta-analysis 8 RCTs, pooled RR 1.19 (95% CI 1.07–1.34); however 3 placebo-controlled RCTs show tamoxifen itself is cardioprotective (pooled RR 0.67, 95% CI 0.45–0.98) — the AI excess may partly reflect tamoxifen protection rather than AI harm
• MI risk with AIs: 30% higher vs. tamoxifen (95% CI 1.11–1.53); Canadian cohort 2.02× higher MI risk; UK cohort RR 1.37 (NS); US Medicare cohort null association — results inconsistent across settings
• HF risk: 1.86× higher with AIs vs. tamoxifen (UK population study)
• VTE risk: AIs associated with 41% lower VTE than tamoxifen — consistent with tamoxifen's estrogen-agonistic prothrombotic effect
• Anastrozole has the strongest CVD evidence (ATAC trial; pooled RR 1.24, 95% CI 0.98–1.56)
• Duration of AI therapy: Extending beyond 5 years — meta-analysis 16,349 patients: OR 1.18 (95% CI 1.00–1.40) for CV events
• GLS monitoring: AI use independently associated with >15% decline in GLS in small echocardiographic study (n=61 left-sided breast cancer patients)

CDK4/6 Inhibitor Combinations with Endocrine Therapy

• Ribociclib + letrozole (MONALEESA-2/7): QTc >480 ms in 3.3%; risk of TdP
• Ribociclib + fulvestrant (MONALEESA-3): QTc >480 ms in 5.6%
• Tamoxifen + ribociclib (MONALEESA-7): QTc >480 ms in >5% — this combination is particularly hazardous and should be avoided; ribociclib contraindicated with tamoxifen
• Palbociclib + AI (PALOMA-1/3): New/worsening hypertension grades 1–3 in 6%
• Abemaciclib (MONARCH 1/2): No significant cardiovascular side effects
• CDK4/6 meta-analysis: overall CV toxicity RR 1.39 (P=0.01) vs. endocrine therapy alone; QT prolongation and VTE predominantly with ribociclib; hypertension predominantly with palbociclib

mTOR and PI3K Inhibitor Combinations

• Everolimus + exemestane (BOLERO-2, n=724): Metabolic syndrome in >30% — hypertriglyceridemia, dyslipidemia, hyperglycemia; class effect of mTOR inhibitors; especially high risk in type 2 diabetes
• Alpelisib + fulvestrant (SOLAR-1, n=572): Grade 3 hyperglycemia in 36.6% vs. 0.7% placebo; >40% grade 2–3 hyperglycemia

Physiology of ADT for Prostate Cancer

• ADT reduces testosterone to castrate levels (<50 ng/dL) via surgical castration (orchiectomy) or pharmacological castration
• GnRH agonists (leuprolide, goserelin, triptorelin, histrelin): Initial testosterone surge before sustained suppression; ↑ LDL-C, ↑ triglycerides, ↑ visceral fat, ↓ lean mass, ↑ insulin resistance → metabolic syndrome phenotype; endothelial dysfunction, prothrombotic state, arterial wall thickening
• GnRH antagonists (degarelix, relugolix): Immediate testosterone suppression, no surge; maintain lower FSH levels — lower FSH associated with fewer major CV events
• Androgen receptor antagonists (bicalutamide, enzalutamide, apalutamide, darolutamide) and testosterone synthesis inhibitors (abiraterone, ketoconazole): Used in combination with GnRH therapy for complete androgen blockade; additional CV toxicities specific to each drug

Cardiovascular Data for ADT (Prostate Cancer)

• GnRH agonists — population studies: Stroke HR 1.2 (95% CI 1.12–1.28); MI HR 1.20 (95% CI 1.05–1.38) vs. no ADT; meta-analysis of 8 RCTs failed to show increased CV death (RR 0.93, NS — underpowered, CV not primary endpoint)
• GnRH antagonists vs. agonists:
  • Phase 2 RCT: major CV/cerebrovascular events 3% (antagonist) vs. 20% (agonist), P=0.013
  • HERO trial (relugolix vs. leuprolide): major CV events 2.9% vs. 6.2% (HR 0.46, 95% CI 0.24–0.88) at 12 months
  • Pooled analysis of 6 phase 3 RCTs: HR 0.44 (95% CI 0.26–0.74) for CV events with antagonists vs. agonists
• Oral antiandrogen monotherapy vs. GnRH agonists: Meta-analysis — oral antiandrogen associated with 30% lower MI risk (RR 0.70, 95% CI 0.54–0.91)
• Combined androgen blockade (GnRH + antiandrogen): 10% higher stroke risk vs. oral antiandrogen alone (RR 1.10, 95% CI 1.02–1.19)
• Enzalutamide (phase 3 nonmetastatic PCa trial): CV events were leading cause of death — 2% in enzalutamide group vs. <1% in placebo
• Abiraterone: Hypertension, hypokalemia, fluid retention, arrhythmias, QT prolongation (must be given with steroid replacement)
• Newer AR-directed agents meta-analysis: RR 1.36 (95% CI 1.13–1.64) for adverse CV events; ≥3 CV comorbidities → 1.56× higher all-cause mortality on abiraterone/enzalutamide

Interactions with Traditional CV Risk Factors and Duration Effects

• Western diet, sedentary lifestyle, and smoking are shared risk factors for CVD and hormone-dependent cancers; these are further worsened by hormonal therapies
• Baseline hypertension is a risk factor for CV events in AI-treated patients (identified in 3 of 6 studies in meta-analysis)
• Pre-existing CAD increases CV event risk with both endocrine therapy and ADT
• Hormonal therapies have ≥6 cardiometabolic effects: body composition, hepatic fat accumulation, glucose metabolism, lipid metabolism, arterial wall composition, cardiovascular event rates
• Prolonged ADT increases metabolic syndrome, insulin resistance, dyslipidemia — likely responsible for increased cardiovascular mortality with longer treatment duration

Racial/Ethnic Disparities

• Black women with breast cancer: 25% greater CVD RR vs. White women; SEER data: 3× higher all-cause death risk; 6× higher HF/CVD death risk
• Black men with prostate cancer: 13% greater CVD RR vs. White men
• Black patients initiating AI therapy have higher median ASCVD risk scores and more CV risk factors than White patients at baseline
• Black patients with prostate cancer: higher rates of hypertension, diabetes, and obesity; White patients: higher rates of low HDL-C and high triglycerides
• Health inequities and structural racism are likely root causes — must be addressed at multilevel interventions

Diagnosis and Monitoring

• No definitive guidelines exist for monitoring and managing hormonal therapy–related cardiotoxicity
• Endocrine therapy monitoring intensity should be informed by prior cardiotoxic therapy (anthracyclines, trastuzumab, RT) which have direct cardiotoxic effects
• Baseline ECG recommended (inexpensive, useful for QT assessment before CDK4/6 inhibitor combinations)
• Annual ECG + biomarkers (BNP, troponin) + cardiovascular imaging (echo/CMR/stress testing) as appropriate
• SERM patients: monitor for hypertension, DVT/PE, and long-term pulmonary hypertension
• ADT patients: monitor lipid profile, BMI, waist-to-hip ratio, HbA1c, and blood pressure; baseline CV history including tobacco, obesity, metabolic syndrome, diabetes, hypertension, dyslipidemia

Management Strategies

• ABCDE algorithm: A — Awareness of heart disease risks + Aspirin (individualized, high-risk patients only); B — Blood pressure; C — Cholesterol + Cigarette/tobacco cessation; D — Diet/weight management + Dose of chemo/RT + Diabetes prevention/treatment; E — Exercise + ECG + Echocardiogram
• Pooled Cohort Equations / PREVENT equations to calculate 10-year ASCVD risk and identify statin candidates
• Prevention follows general CVD prevention guidelines — no dedicated RCTs for hormonal therapy–specific cardioprotection
• Multidisciplinary approach: oncologist + cardiologist/cardio-oncologist ± endocrinologist ± social work/mental health
• Patient education and engagement as cornerstone of the care model

Limitations of the document

• Predominantly observational data and cancer RCT subgroup analyses — dedicated cardio-oncology RCTs with primary CV endpoints are lacking
• Observational studies confounded by indication — patients prescribed different drugs have different baseline risk profiles
• Cancer outcome trials not powered for CV endpoints; CV events reported only as adverse events
• Limited racial/ethnic data, particularly for Hispanic, Asian, and Indigenous populations
• Duration-specific CV effects not well characterized
• No validated cancer population-specific CV risk prediction models

Key Concepts Mentioned

• concepts/Hormonal-Therapy-CV-Risk — dedicated CV risk framework for hormonal therapies in breast and prostate cancer
• concepts/Cancer-Therapy-Related-CV-Toxicity — broader CTR-CVT framework; hormonal therapy is one component
• concepts/Cardio-Oncology — multidisciplinary care model
• concepts/Torsades-de-Pointes — CDK4/6 inhibitor (ribociclib) + tamoxifen combination causes significant QTc prolongation

Key Entities Mentioned

• entities/Atrial-Fibrillation — AF risk with CDK4/6 inhibitor combinations
• entities/Heart-Failure — increased risk with AIs and ADT
• entities/Pulmonary-Hypertension — long-term risk with SERM-induced VTE/PE

Wiki Pages Updated

• wiki/sources/Hormonal-Rx-AHA-2021.md — created
• wiki/concepts/Hormonal-Therapy-CV-Risk.md — created
• wiki/concepts/Cancer-Therapy-Related-CV-Toxicity.md — updated ADT and endocrine therapy sections
• wiki/concepts/Torsades-de-Pointes.md — updated with CDK4/6 inhibitor QT data
• wiki/concepts/Cardio-Oncology.md — updated connections
• wiki/wikiindex.md — updated
• wiki/sourceindex.md — updated
• log.md — appended