Pub Date: Monday, Apr 26, 2021
Author: Jeanne M. DeCara, MD
Affiliation: Professor of Medicine, Director, Cardio-Oncology, Section of Cardiology, UChicago Medicine
Cardio-oncology often focuses on early detection of toxicity or cardiovascular (CV) side effects that, if not addressed, could limit ability to continue with treatment. However, there is an equally important need to focus with a longer lens on CV risk factors that emerge as a consequence of treatment that may not be treatment-limiting but can have a significant impact on CV health in survivorship. This is particularly relevant to cancers that have good long-term survival and where the cancer treatment that modifies CV risk is expected to be of long duration. Prostate and breast cancer among the most common solid cancers in each gender, respectively. Like many other cancers, contemporary treatment for breast and prostate cancer has led to improved survival. For instance, the all-stage survival is 90% for both breast cancer and prostate cancer based on data obtained between 2010 and 2016 from the Surveillance Epidemiology and End Results (SEER) program.1,2 Hormonal therapy, defined as endocrine therapy for breast cancer and androgen deprivation therapy (ADT) for prostate cancer, often plays a key role in treating both types of hormone-dependent cancers and yet can also affect cardiovascular risk factors and in some instances alter the potential for thrombotic events. As such, these treatments can potentially have a longer-term impact on cardiovascular morbidity and mortality. With an ever-increasing number of breast and prostate cancer survivors, there is a high likelihood that not only cardio-oncologists but primary care physicians, prevention experts, and endocrinologists will encounter patients who are receiving or have been treated with hormonal therapy. For this reason, the AHA statement entitled, The Impact of Hormonal Therapies for Treatment of Hormone-Dependent Cancers (Breast and Prostate) on the Cardiovascular System: Effects and Modification, 3 is important in raising awareness of the cardiovascular effects of hormonal treatment in survivors and offers an excellent summary of the current literature. Within this statement, one learns several lessons and can foresee opportunities for future study.
Not all hormonal therapy agents are the same
A clinician who is not an oncologist might be tempted to lump the cardiovascular risks of all hormonal therapy together, but would be mistaken in taking such a simplistic viewpoint. Take for example hormone therapy for hormone receptor positive breast tumors. This can be broadly categorized into either selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). SERMs include tamoxifen and raloxifene while AIs include exemestane, anastrozole and letrozole. In their summary of the relationship between these 2 classes of hormonal therapy for breast cancer and their cardiometabolic and venous thrombotic effects, Okwuosa and colleagues highlight some important points. For one, while each of these classes of hormonal therapy exerts anti-estrogen effects, they do so through different mechanisms, potentially manifesting differing cardiovascular risk profiles. As nicely summarized by the authors of this AHA statement, tamoxifen acts directly on the estrogen receptor. Tamoxifen is known to be associated with increased venous thromboembolic risk. It’s unfavorable effects on triglyceride and glucose metabolism appear to be offset by a favorable effect on lipids, specifically low-density lipoprotein cholesterol and lipoprotein(a).4 The authors point to a recent meta-analysis of randomized clinical trials (RCTs) of hormone therapy for breast cancer in mainly post-menopausal women. Focusing on the RCTs comparing tamoxifen to placebo or no treatment, this meta-analysis revealed that tamoxifen was associated with 33% fewer cardiovascular events.5
The story for AIs may be different. Aromatase inhibitors exert their anti-estrogen effects by countering the hypothalamic-pituitary feedback loop. Patients receiving these agents might be expected to develop increased body fat composition and dyslipidemia. Clinical trials comparing AIs to placebo are unfortunately scant. More often than not, RCTs focused on demonstrating the respective oncological benefit of endocrine therapy agents compare AIs with tamoxifen alone or following tamoxifen treatment. Caution must be exercised when assessing the CV effects of AIs with or following tamoxifen given the confounding effect of the relatively more favorable cardiometabolic profile of the latter. Cardiovascular outcomes from frequently cited RCTs comparing AIs to tamoxifen have shown not shown significant increase in CV events with AIs 6–9 though as the authors of this AHA statement point out, a contemporary systematic review points toward an increased CV risk with AIs compared to tamoxifen and, in a separate meta-analysis comparing AIs to placebo or no treatment as extended adjuvant therapy, the CV event rate remained elevated with long term use.5,10 Guidelines from the American Society of Clinical Oncology acknowledge an associated increased risk of ischemic heart disease with AIs.11 The association between AIs and CV disease seems conceptually plausible based on the preliminary and limited data from small human studies evaluating the effects of AIs and tamoxifen on measures of subclinical atherosclerosis and vascular function.12
For patients with prostate cancer, hormonal therapy is geared toward reducing testosterone to castration levels. Broadly speaking, this is achieved by androgen deprivation therapy in the form of gonadotropin-releasing hormone agonists or GnRH antagonists. As the authors of this AHA statement explain, the former act on the GnRH receptor to increase GnRH which subsequently increases follicle-stimulating hormone and luteinizing hormone. LH acts on the Leydig cells in the testes to increase testosterone production that, by way of the negative feedback loop lowers LH and therefore testosterone. GnRH antagonists avoid that initial surge in testosterone by immediately preventing the pituitary release of FH and FSH, thereby reducing testosterone. Despite the end result of castration level testosterone with both types of ADT agents, pooled analyses of RCTs demonstrate a lower rate of CV events with GnRH antagonists13, a finding that is supported by trials in which CV events were pre-defined outcomes.14,15 This is another example in which agents with different mechanism of action exert hormonal effects with varying impact on anticipated CV risk. The lesson learned is that CV risk associated with hormonal therapy for breast and prostate cancer is nuanced and must be examined within the context of the specific agent prescribed. Understanding this allows health care professionals to better educate patients receiving these agents on their cardiovascular risk profiles.
CV risk assessment and treatment algorithms may need to be refined in cancer patients
As clinicians, we need to be aware of the increased cardiometabolic risks of hormonal therapy and intervene early to try to mitigate long-term cardiovascular sequelae, particularly because the average duration of treatment with these agents is long; at least 5 years for breast cancer and even longer for prostate cancer. Yet, the natural question that follows is whether and how to refine the cardiovascular risk assessment when faced with a patient who is receiving hormonal therapy for cancer. Diabetes, blood pressure and lipids are incorporated into the pooled cohort cardiovascular risk equation to predict future cardiovascular events but with shared risk factors between cancer and CV disease, and with the additional potential for cancer therapies to lead to the development or worsening of CV risk factors, one wonders whether cancer and cancer treatments that modify CV risk should be considered risk enhancers. If so, is there a role for the coronary artery calcium score to further refine that risk? Also unclear is how race and ethnicity modify cardiovascular risk for patients who receive hormonal therapy and whether this interaction is adequately captured in risk assessment algorithms.
Even where we have well-delineated treatment guidelines for risk factors, the approach to a patient on hormone therapy for cancer may need to be individualized. Abiraterone is a cytochrome P450 17A1 inhibitor interferes with the production of androgen in the adrenal glands leading to mineralocorticoid excess through augmented adrenocorticotropic hormone release.16 Clinically, this is associated with hypertension. Based on the mechanism of induced hypertension, perhaps it is reasonable to start a mineralocorticoid antagonist earlier in the course of hypertension management than it would normally fall in the cascade of anti-hypertensives recommended for the general population per current guidelines.17 This is one example where our treatment algorithms may need to be individualized for a cancer patient depending on his/her cancer therapy. There are many unanswered questions in the realm of cardiovascular risk assessment and management for patients receiving cancer therapy and survivors. These provide fodder for future investigations. While awaiting more evidence, multidisciplinary tumor board-styled forums that include discussion on the development or control of CV risk factors for patients receiving hormonal therapy may lead to prompt specialty referral and individualized treatment.
Opportunities to advance knowledge through investigational collaboration and registries
Cancer treatment trials are focused on efficacy, safety and tolerability. However, cardiac risk factors and CV outcomes are not always pre-defined endpoints for data collection or analyses. As a result, much of what cardio-oncologists attempt to glean about the CV risks of cancer therapy is limited to retrospective review of enrollment criteria and reported serious adverse events. Moreover, the CV event rate in any given trial may be too small, or follow up too short, to accurately establish CV risks thereby leading us to draw conclusions from meta-analyses, which have their own limitations. In this era of fruitful cross collaboration between cardiologists and oncologists, one might argue that more routinely incorporating cardio-oncology consultants at the outset of clinical trial design for any cancer treatment anticipated to have CV effects would offer an opportunity to better define and ascertain treatment-associated changes in CV risk factors and CV outcomes. In addition, the establishment of registries that include cardiometabolic risk factors and CV events would offer insight into the real-world experience with hormone therapy outside of the constraints of RCTs.
In summary, in this AHA statement Okwuosa and colleagues have carefully summarized what is known about the cardiometabolic risks and outcomes associated with hormone therapy for breast and prostate therapy, in addition to the limitations of the data on which conclusions can be drawn. As health care professionals, we learn that not all hormone therapy agents have the same effect on cardiac risk factors or have carry similar risk for CV events. We are reminded that a “one size fits all” approach from pooled cohort CV risk equations and treatment guidelines might need to be reframed depending on the whether an individual patient has cancer and is on hormonal therapy though data supporting alternative approaches is currently lacking. Lastly, we foresee a tremendous opportunity for collaboration between cardiologists and oncologists not only in the clinical arena but also in the investigative realm through early joint collaboration in clinical trial design.
Okwuosa TM, Morgans A, Rhee J-W, MD; Reding KW, Maliski S, Plana J-C, Volgman AS, Moseley KF, Porter CB, Ismail-Khan R; on behalf of the American Heart Association Cardio-Oncology Subcommittee of the Council on Clinical Cardiology and the Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular Radiology and Intervention. Impact of hormonal therapies for treatment of hormone-dependent cancers (breast and prostate) on the cardiovascular system: effects and modifications: a scientific statement from the American Heart Association [published online ahead of print April 26, 2021]. Circ Genom Precis Med. 2021;14:e000082. doi: 10.1161/HCG.0000000000000082
- Available from: https://seer.cancer.gov/statfacts/html/breast.html
- Available from: https://seer.cancer.gov/statfacts/html/prost.html
- Okwuosa TM, Morgan A, Rhee JW, Reding KW, Malisky S, Plana JC, Volgman AS, Moseley KF, Porter CB, Ismail-Khan R; , On behalf of the American Heart Association Cardio-Oncology Committee of the Council on Clinical Cardiology and Council on Genomic and Precision Medicine, Council on Arteriosclerosis, Thrombosis and Vascular Biology and Council on Cardiovascular Radiology and Intervention. The impact of hormonal therapies for treatment of hormone-dependent cancers (breast and prostate) on the cardiovascular system: Effects and modifications. A scientific statement from the American Heart Association. Circulation. 2021.
- Morales M, Santana N, Soria A, Mosquera A, Ordovás J, Nóvoa J, Betancor P, Valerón PF, Díaz-Chico B, Chirino R. Effects of tamoxifen on serum lipid and apolipoprotein levels in postmenopausal patients with breast cancer. Breast Cancer Res Tr [Internet]. 1996;40:265–270. Available from: https://doi.org/10.1007/BF01806815
- Khosrow-Khavar F, Filion KB, Al-Qurashi S, Torabi N, Bouganim N, Suissa S, Azoulay L. Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol. 2017;28:487–496.
- A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer. New Engl J Medicine. 2006;354:2200–2200.
- Group B 1-98 C, Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thürlimann B, Paridaens R, Smith I, Mauriac L, Forbes JF, Price KN, Regan MM, Gelber RD, Coates AS. Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer. New Engl J Medicine. 2009;361:766–776.
- Group TA Tamoxifen, Alone or in Combination (ATAC) Trialists’. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol. 2006;7:633–643.
- Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Mastro LD, Smith I, Chirgwin J, Nogaret J-M, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five Years of Letrozole Compared With Tamoxifen As Initial Adjuvant Therapy for Postmenopausal Women With Endocrine-Responsive Early Breast Cancer: Update of Study BIG 1-98. J Clin Oncol. 2007;25:486–492.
- Goldvaser H, Barnes TA, Šeruga B, Cescon DW, Ocaña A, Ribnikar D, Amir E. Toxicity of Extended Adjuvant Therapy With Aromatase Inhibitors in Early Breast Cancer: A Systematic Review and Meta-analysis. Jnci J National Cancer Inst. 2017;110:31–39.
- Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Rowden D, Solky AJ, Stearns V, Winer EP, Griggs JJ. Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol. 2014;32:2255–2269.
- Blaes A, Beckwith H, Florea N, Hebbel R, Solovey A, Potter D, Yee D, Vogel R, Luepker R, Duprez D. Vascular function in breast cancer survivors on aromatase inhibitors: a pilot study. Breast Cancer Res Tr [Internet]. 2017;166:541–547. Available from: https://doi.org/10.1007/s10549-017-4447-6
- Albertsen PC. Re: Androgen deprivation therapy and cardiovascular risk: No meaningful difference between GnRH antagonist and agonists. European journal of cancer (Oxford, England : 1990). 2017;87:203.
- David M, Avivit P, Yaara B, Liat S-G, Tzlil T, Sivan S, Guy W, Jack B, Daniel K, M. DWC, Eli R, H. PJ. Cardiovascular Morbidity in a Randomized Trial Comparing GnRH Agonist and GnRH Antagonist among Patients with Advanced Prostate Cancer and Preexisting Cardiovascular Disease. J Urology [Internet]. 2019;202:1199–1208. Available from: https://doi.org/10.1097/JU.0000000000000384
- Shore ND, Saad F, Cookson MS, George DJ, Saltzstein DR, Tutrone R, Akaza H, Bossi A, Veenhuyzen DF van, Selby B, Fan X, Kang V, Walling J, Tombal B, Investigators HS. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. New Engl J Med. 2020;382:2187–2196.
- Hu J-R, Duncan MS, Morgans AK, Brown JD, Meijers WC, Freiberg MS, Salem J-E, Beckman JA, Moslehi JJ. Cardiovascular Effects of Androgen Deprivation Therapy in Prostate Cancer: Contemporary Meta-Analyses. Arteriosclerosis Thrombosis Vasc Biology. 2020;40:e55–e64.
- Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Himmelfarb CD, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson JD, Wright JT. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127–e248.
Science News Commentaries
Commentary: A Sleeping Giant: The Powerful Link Between Sleep Disordered Breathing and Cardiac Arrhythmias 08/01/2022 | Author: Bige Ozkan MD, Chiadi E. Ndumele MD, PhD, FAHA | The incidence and prevalence of cardiac ...