Hormonal Based Therapies in the Treatment of Breast and Prostate Cancer – balancing the risks!

Modern cancer treatments have led to significant improvements in clinical outcomes and an almost overwhelming number of cancer survivors. For patients diagnosed with early-stage breast and prostate cancers, cure rates are high, and during their lifetime, cardiovascular disease may cause greater morbidity and mortality than cancer ^1,2. Those diagnosed with advanced or metastatic cancer, are living longer with their disease. Traditionally, cancer providers and individuals faced with a cancer diagnosis have focused on treatments that will provide the best chance of ‘cure’ or ‘optimal control’ in the setting of advanced disease. There has been less attention given to the potential long-term consequences of anti-cancer treatment and the potential impact on non-cancer related morbidity and mortality, including cardiovascular disease. Yet, as cancer providers we have known for decades that cancer therapies can have a negative impact on cardiovascular health. Anthracyclines – the backbone of cancer regimens for both solid and hematological malignancies – are associated with an increased risk of heart failure, often seen years after completion of treatment. Targeted agents such as trastuzumab, have revolutionized the treatment of HER2+ breast cancer, but are associated with left ventricular dysfunction, though often reversible. Tyrosine kinase inhibitors (e.g., sunitinib) are life sustaining in advanced renal cell carcinoma but are associated with an increased risk of hypertension. In the modern era of cancer care, providers must consider both the short and long-term consequences of these treatments including the impact on cardiovascular health. Indeed, the new sub-specialty of Cardio-Oncology emerged based on the recognized importance of these two fields, and the need to not only facilitate the delivery of optimal therapy for patients with cancer, but also to optimize cardiovascular care through survivorship.

Breast cancer and prostate cancer are the most common cancers in women and men, respectively, and thus affect millions of individuals world-wide. Modern cancer treatments have led to significant improvements in clinical outcomes (breast cancer 91% 5 year survival; prostate 99% 5 year survival) – but at what cost?^3,4 The American Heart Association Scientific Statement by Okwuosa et al provides a comprehensive overview and guidance to the cardiovascular consequences of hormonal therapies in the treatment of hormone-dependent breast cancer and prostate cancer. The physiology of hormonal therapy for breast and prostate cancer is carefully reviewed as is a summary of the cardiovascular toxicity of hormonal therapy in patients with breast and prostate cancer. Considerations for diagnosis and monitoring for hormone therapy-related cardiovascular toxicity as well as management strategies for prevention and treatment in this population are presented.

The authors highlight that while the use of aromatase inhibitors in breast cancer is modestly associated with an increased risk of cardiovascular events (RR 1.18; 85% CI 1.00-1.40) ⁵, the majority of studies have compared these agents to tamoxifen vs placebo. Which raises the question is the increased risk of cardiovascular events with aromatase inhibitor therapy, reflective of the protective effect of tamoxifen, or the lower estrogenic state produced with aromatase inhibitors? These findings must be viewed in the context of the clinical benefit of these agents in the treatment of hormone sensitive breast cancers. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of 31,920 post-menopausal women with hormone sensitive breast cancer demonstrated that 5 years of aromatase inhibitor therapy decreased 10-year breast cancer mortality rates by about 15% (12.1 vs 14. 2%: RR 0.85, CI 0.75 – 0.96) compared with 5 years of tamoxifen ⁶. Longer durations of aromatase inhibitor therapy (e.g., 5 vs 10 years) have been associated with higher rates of disease-free survival (95% vs 91% at 5 years) but may be associated with increased risk of cardiovascular morbidity. However, in a large international randomized control trial of women randomized after 5 years of letrozole to an additional 5 years of letrozole (total 10 years), vs placebo, there was no significant difference between groups in reported cardiovascular events (12 vs 10%)⁷. In the advanced breast cancer setting, novel therapeutic approaches targeting the mTOR/PI3K/cyclin-dependent pathway, have led to the availability of multiple lines of therapy resulting in increased life expectancy – but with an increased risk of metabolic syndrome, QT prolongation, hypertension and arrhythmias ⁸.

Androgen deprivation therapy is the backbone of systemic therapy for men with high-risk localized, recurrent and metastatic prostate cancer, but at the cost of increased risk of cardiovascular complications such as myocardial infarctions, strokes and arrhythmias. The authors highlight the strength of evidence supporting a higher risk of cardiovascular complications with the use of GnRH agonists vs GnRH antagonists. Androgen-receptor directed therapies (oral agents) are now commonly used in combination with GnRH agonists or antagonists further reducing testosterone signaling resulting in a higher risk of experiencing a cardiovascular event compared to no reduction in testosterone signaling. Less data is available on the risk of cardiovascular toxicity with the newer generation androgen receptor-directed therapies (e.g., enzalutamide and abiraterone acetate); however, early data suggests these drugs are associated with an increased risk of experiencing a cardiovascular event compared to no exposure (RR=1.36; 95% CI 1.13-1.64) ⁹. This raises the question - how do providers deal with the increased efficacy of newer generation androgen deprivation therapies in the context of increased risk of cardiovascular toxicities?

In addition to considering the direct impact of anti-cancer therapies on the risk of cardiovascular toxicity, health care professionals must take into consideration the presence of co-morbidities including pre-existing cardiovascular risk factors and disease, as well as sociodemographic and lifestyle factors. Not only are comorbid diagnoses, including CVD, common in patients with cancer, but underlying risk factors overlap. Low cardiorespiratory fitness, for instance, is associated with an increased incidence and mortality from both cardiovascular disease and cancer ¹⁰. Risk factors for CVD are prevalent in breast and prostate cancer survivors ¹¹, and, in fact, may be more common in cancer survivors than in the general population ¹². Cancer survivors are more likely than those without cancer to have higher body mass index (BMI), be hypertensive, have diabetes, and have a history of tobacco use ¹³. Yet, one in three cancer survivors with risk factors for CVD may not receive advice from their medical provider about healthy behavior change ¹³. The authors highlight that for men with prostate cancer, risk factors such as dyslipidemia, insulin insensitivity and obesity are adversely impacted by androgen deprivation therapy. There are differences in cardiovascular outcomes in different racial/ethnic groups treated with hormonal therapy – a 25% greater risk of cardiovascular disease among black women compared with white women with breast cancer; and a 13% greater relative risk among black men compared with white men with prostate cancer ¹⁴. Increasing age, an established risk factor for both cancer and cardiovascular disease, may adversely impact cardiovascular outcomes in the setting of longer durations of hormonal therapy. Among breast cancer survivors age >50 years, deaths due to cardiovascular disease account for 35% of non-cancer related deaths ¹⁵. The complicated associations between cancer and CVD require special attention during and after treatment ¹⁶.

There are no specific guidelines for cardiovascular monitoring of patients with breast or prostate cancer prescribed hormonal therapy, thus this AHA statement is opportune. With the exception of anthracyclines and trastuzumab, guidelines and position papers published by cardiology and oncology societies, have been based, in large part, on expert opinion. The American Society of Clinical Oncology (ASCO) guideline on prevention and monitoring of cardiac dysfunction in survivors of adult cancers focuses on the impact of anthracyclines, HER-2 targeted therapies (trastuzumab), and radiation on cardiovascular risk in patients with cancer ¹³. In 2020 the European Society of Medical Oncology (ESMO) published consensus recommendations on the Management of Cancer Patients throughout Oncological Treatment – there are no specific recommendations for cardiovascular surveillance in patients with cancer prescribed hormonal therapy ¹⁴. Similar to the clinical considerations published in this AHA statement, ESMO recommends that all patients treated with potentially cardiotoxic anti-cancer therapy undergo the following: careful cardiac exam, ECG, baseline left ventricular ejection fraction assessment and cardiac biomarkers (troponin, natriuretic peptides). The frequency of these assessments is dependent, in part, on the type of anticancer therapy prescribed and on the presence or absence of cardiovascular symptoms ¹⁴.

The AHA scientific statement by Okwuosa et al provides health care professionals with a comprehensive framework of best strategies for cardiovascular risk assessment, monitoring and prevention/management in patients with breast or prostate cancer prescribed hormonal therapy and should be considered a platform on which to build as more data emerges to support evidence-based recommendations. The implementation of these recommendations into clinical practice will be challenging and will require a multidisciplinary approach including involvement of: oncologists, cardiologists, cardio-oncologists, nurses, pharmacists, exercise physiologists, primary care providers and allied health care providers. Health care systems will need to acknowledge the necessity to provide comprehensive cardiovascular care for cancer survivors, including the resources necessary to implement these strategies. In turn, more evidence is needed to prove that the adoption of this strategy will result in improved clinical outcomes (e.g., reduction in cardiac events) for cancer survivors. Society has invested heavily in finding a ‘cure’ for cancer – as a medical profession it is our responsibility to ensure that unrecognized cardiovascular disease does not offset the gains made in cancer detection, treatment, and survivorship.