Cardio-Oncology in Women: Protecting the Heart Through Cancer Treatment

Dr. Job Mogire, MD, FACP, FACC Board-Certified Cardiologist | Carle Foundation Hospital, Champaign, IL

As cancer survival improves, a second clinical horizon comes into view: the long-term health of the heart in women treated for cancer, particularly breast cancer. Some of the treatments that extend life can also affect the heart, and the field of cardio-oncology exists to manage that tension, so that necessary cancer treatment proceeds while cardiac harm is anticipated, monitored, and minimized.

The treatments that carry cardiac risk

Three categories account for most of the concern. 4 / Promising Anthracycline chemotherapies can cause dose-related injury to the heart muscle. HER2-targeted therapies such as trastuzumab can reduce cardiac function, often reversibly, particularly when combined with or following anthracyclines. Chest radiation can affect the heart and coronary arteries over a longer horizon. The European Society of Cardiology cardio-oncology guideline synthesizes the assessment and monitoring approach across these therapies (Lyon et al, Eur Heart J 2022).

Not every woman who receives these is affected; risk varies with the specific agent, cumulative dose, combination, and a woman’s baseline cardiovascular health.

The cardio-oncology approach

The framework is anticipatory rather than reactive. 4 / Promising It begins with baseline cardiovascular risk assessment before cardiotoxic treatment, continues with monitoring of cardiac function during and after therapy in those at risk, and manages any decline that emerges. The goal is to allow effective cancer treatment to proceed on schedule while protecting the heart, escalating cardiac care rather than interrupting cancer care wherever possible.

Survivorship and the long view

For survivors, cardiovascular attention belongs in survivorship care, especially after treatments with cardiac effects. 4 / Promising This includes appropriate monitoring of cardiac function, active management of standard cardiovascular risk factors, and alertness to symptoms such as new breathlessness or reduced exercise tolerance. The horizon for radiation-related effects in particular can be long, which makes durable follow-up, not a single post-treatment check, the right model.

Anthracyclines: how doxorubicin injures the heart muscle

Anthracyclines are among the most effective cytotoxic agents in breast cancer treatment, and doxorubicin is the prototype. The mechanism by which they cause cardiac injury is now understood at the cellular level, and that understanding matters because it explains why the damage behaves differently from nearly every other drug-related cardiac effect.

The primary pathway involves topoisomerase II beta, an enzyme present in cardiomyocytes. Doxorubicin forms a complex with topoisomerase II beta and DNA, creating double-strand DNA breaks inside the heart muscle cell. Unlike cancer cells, cardiomyocytes are largely post-mitotic: they cannot divide to replace themselves. DNA damage in a cardiomyocyte is therefore permanent in a way it is not in a rapidly dividing tumor cell. Simultaneously, doxorubicin generates reactive oxygen species through redox cycling with iron, and cardiomyocytes have comparatively limited antioxidant defenses, making them especially vulnerable to oxidative injury. The result is cardiomyocyte death, inflammation, and over time, replacement of muscle with fibrosis.

This is classified as Type I cardiotoxicity, meaning it is dose-dependent and substantially irreversible. 5 / Solid The risk rises with cumulative anthracycline dose: at a cumulative doxorubicin dose of 300 mg/m2 the incidence of clinical heart failure is estimated at approximately 1-2%, rising to 7-15% at 550 mg/m2, as reported in the landmark analysis by Swain et al (Swain et al, Cancer 2003). Most contemporary breast cancer regimens use cumulative doxorubicin doses well below 300 mg/m2, which keeps the population-level event rate low, but does not reduce it to zero, particularly in women who have other cardiac risk factors at baseline.

The word “irreversible” deserves precision. It does not mean that every woman exposed to anthracyclines will develop heart failure, or that the damage is always clinically apparent during treatment. Subclinical reductions in cardiac function may not manifest as symptoms for years. This is the reason cardio-oncology takes a long view: the injury to the myocardium occurs during treatment, but the clinical consequences may arrive a decade later, especially in the setting of additional cardiovascular stress such as hypertension or coronary disease.

Type II cardiotoxicity, by contrast, describes cardiac dysfunction that is not dose-dependent and is largely reversible on discontinuation of the offending agent. Trastuzumab is the central example, and the distinction between these two types is foundational to understanding how monitoring decisions are made.

HER2-targeted therapy: reversibility, combination risk, and the monitoring decision

Trastuzumab targets the HER2 receptor, which is overexpressed in approximately 15-20% of breast cancers and drives an aggressive tumor phenotype. Blocking HER2 with trastuzumab substantially improves outcomes in this subgroup. HER2, however, is also expressed in cardiomyocytes, where it plays a role in cell survival signaling. Blocking it in cardiac tissue impairs the heart’s ability to respond to stress, leading to a decline in systolic function that resembles, but is mechanistically distinct from, anthracycline injury.

The key difference is reversibility. 4 / Promising Trastuzumab-related cardiac dysfunction typically improves after the drug is held or discontinued, because the mechanism is functional impairment of a signaling pathway rather than direct myocyte death. This is Type II cardiotoxicity: the cardiomyocytes are not being destroyed, they are being deprived of a survival signal. Restore or withdraw the stressor and function often recovers.

The clinical complication is sequencing. Trastuzumab is frequently given after or alongside anthracycline-based chemotherapy in HER2-positive breast cancer. The two mechanisms are additive: anthracyclines kill some myocytes and impair the heart’s reserve, and trastuzumab then removes a repair and survival signal from the cardiomyocytes that remain. The HERA trial and related adjuvant trastuzumab studies showed that the combination of prior anthracycline exposure plus trastuzumab carries a meaningfully higher rate of cardiac events than either agent alone (Suter et al, J Clin Oncol 2007).

This is why the monitoring algorithm in this population is specific: cardiac function is assessed before trastuzumab starts, periodically during the course of treatment (typically every three months), and at completion. If ejection fraction falls to a defined threshold, typically an absolute drop of 10 percentage points or more to below 50%, a decision is made about holding the drug, initiating cardioprotective therapy, or both. In many cases, the ejection fraction recovers and trastuzumab is successfully resumed. The goal is not to stop effective cancer therapy, but to detect the cardiac signal early enough that options remain open. A woman whose EF is at 35% with symptoms has far fewer options than one whose EF has dropped from 65% to 52% on surveillance echo.

Radiation and the heart: latency, mechanism, and modern mitigation

Chest radiation, used in early-stage breast cancer after lumpectomy and in some mastectomy patients at higher risk of recurrence, improves survival. It also delivers dose to cardiac structures depending on the anatomy of the tumor and the technique used. The consequences are not immediate: radiation-related cardiac injury has a latency period measured in years to decades.

The mechanisms are several. 4 / Promising Radiation can cause inflammation and fibrosis of the pericardium, leading to pericarditis or, in severe cases, constrictive pericarditis years after treatment. It accelerates atherosclerosis in coronary arteries within the radiation field, particularly the left anterior descending artery in left-sided breast cancers, leading to coronary artery disease that may present as a heart attack a decade or more after treatment. It can also damage the cardiac valves and myocardium directly.

The Darby et al study, published in the New England Journal of Medicine in 2013, quantified the coronary risk: for each gray of mean heart dose received, the rate of major coronary events increased by approximately 7.4%, with no apparent threshold below which risk was zero (Darby et al, N Engl J Med 2013). For left-sided breast cancers, mean heart doses in older techniques could be 2-6 gray or more, representing a clinically meaningful increment in lifetime cardiac risk.

Modern radiation techniques substantially reduce cardiac exposure. Deep inspiration breath hold (DIBH) takes advantage of anatomy: when a patient inhales deeply, the heart falls posteriorly away from the anterior chest wall, increasing the distance between the heart and the radiation field. Studies have shown that DIBH can reduce mean heart dose for left-sided breast irradiation by approximately 50% compared to free-breathing delivery (Bartlett et al, Radiother Oncol 2013). Proton therapy offers dose distribution advantages due to the Bragg peak, depositing radiation energy at a precise depth and minimizing exit dose to cardiac structures, though access to proton therapy remains geographically and economically limited.

For women receiving chest radiation, the implication for survivorship is straightforward: the relevant cardiovascular risk does not declare itself during the treatment course. It builds slowly over years. A woman who received left-sided breast radiation in her 40s may not face the coronary consequences until her 60s, well past the period when her oncology team is actively following her. This is one reason that radiation history must be part of the permanent cardiovascular record, not a detail that disappears from view once cancer treatment ends.

Baseline risk assessment: who is high-risk before treatment begins

Not every woman facing cardiotoxic cancer treatment carries the same cardiac risk going in, and the cardio-oncology approach stratifies based on what is present before chemotherapy or radiation begins. This matters because higher baseline risk changes the monitoring frequency and may prompt prophylactic interventions.

The ESC 2022 guideline defines a cardiovascular toxicity risk score that incorporates both patient factors and treatment factors. 4 / Promising On the patient side, relevant factors include existing heart disease (prior heart failure, cardiomyopathy, significant valve disease, or coronary artery disease), poorly controlled hypertension, diabetes, obesity, older age, prior cardiac radiation, and prior anthracycline exposure. On the treatment side, the agents themselves carry intrinsic risk levels, and combinations multiply the risk.

A woman with no cardiac history, well-controlled blood pressure, no diabetes, and normal baseline cardiac function who is receiving a standard adjuvant anthracycline regimen at conventional dose is at relatively low baseline risk. She warrants a baseline echo, monitoring at the end of anthracycline treatment, and surveillance during any subsequent trastuzumab. A woman with prior heart failure, hypertension, and diabetes who is receiving the same regimen is at high baseline risk: she needs closer surveillance intervals, earlier cardiology involvement, and possibly prophylactic cardioprotective therapy before chemotherapy begins.

The baseline echocardiogram serves two purposes: it establishes the actual starting point for that individual woman’s cardiac function, and it may identify previously unrecognized cardiac disease. Relying on a woman’s subjective sense of cardiac health is not sufficient. Subclinical left ventricular dysfunction is common in the general population and may be entirely asymptomatic. Without a baseline measurement, a subsequent decline cannot be interpreted: there is no reference point. Getting the baseline right is not bureaucratic; it is the foundation on which all subsequent monitoring decisions rest.

Echocardiography and global longitudinal strain: what the numbers mean

The echocardiogram is the primary tool for cardiac monitoring in cardio-oncology, but the specific measurements reported have different sensitivities and clinical meanings.

Ejection fraction is the most familiar: it represents the proportion of blood ejected from the left ventricle with each heartbeat, and a normal value is typically 55-65%. An EF below 50% represents reduced systolic function, and an EF below 40% represents significantly impaired function that typically requires treatment. The ESC 2022 guideline defines cancer therapy-related cardiac dysfunction as a drop in EF of more than 10 percentage points to below 50%, or a new drop in EF below 50%.

The limitation of EF as a monitoring tool is its relatively poor sensitivity for early injury. EF is a global, load-dependent measure: it can appear normal despite significant subclinical myocardial damage, particularly in early stages when compensatory mechanisms maintain overall pump function. By the time EF drops meaningfully, considerable myocardial injury may have already occurred.

Global longitudinal strain (GLS) addresses this limitation. 4 / Promising GLS measures the deformation of the myocardium through the cardiac cycle using speckle-tracking echocardiography, quantifying how much the heart muscle lengthens and shortens. Normal GLS values are typically more negative than -18% (by convention, greater deformation is expressed as a more negative number). A relative reduction in GLS of more than 15% from baseline suggests subclinical myocardial dysfunction even when EF remains above threshold. Studies have shown that GLS decline precedes EF decline in anthracycline-exposed patients, making it a more sensitive early warning signal (Thavendiranathan et al, J Am Coll Cardiol 2014).

In practice, both measurements are used together. A woman whose EF remains stable but whose GLS has declined by 18% is not reassuringly normal; she warrants closer follow-up and a conversation about whether cardioprotective therapy should be initiated. A woman whose EF drops from 62% to 49% during trastuzumab treatment has crossed a threshold that typically prompts holding the drug and initiating care before resuming.

Understanding these numbers allows a patient to participate meaningfully in monitoring conversations. When a cardiologist says the echo “looks fine,” it is reasonable to ask specifically about both EF and GLS, and to understand what those values are relative to the baseline.

Questions to ask before starting chemotherapy or radiation

A woman facing breast cancer treatment involving anthracyclines, HER2-targeted therapy, or chest radiation has the right to understand the cardiac implications before treatment begins. These are not questions that delay care; they are questions that set up the monitoring infrastructure that allows care to proceed safely.

Before starting anthracycline chemotherapy: What is my cumulative planned doxorubicin dose, and how does that relate to the dose thresholds associated with increased cardiac risk? Will I have a baseline echocardiogram before I start, and at what points will my cardiac function be checked during treatment? Do I have any baseline cardiac risk factors that would put me in a higher-risk category?

Before starting trastuzumab: Has my cardiac function been checked since completing anthracycline therapy, and what was the result? How often will my ejection fraction be monitored during the year or more of trastuzumab treatment? What would prompt a hold in the drug, and what would need to happen before it was resumed?

Before chest radiation for left-sided breast cancer: What is the estimated mean heart dose with the planned technique, and is deep inspiration breath hold available and appropriate for me? Will my radiation record document the cardiac dose so that my future physicians have access to it?

After treatment: Will my survivorship plan include cardiovascular follow-up, and who is responsible for that, my oncologist, my primary care physician, or a cardiologist? At what point should I have a repeat echo or other cardiac assessment? What symptoms should prompt me to seek evaluation before my next scheduled visit?

These questions are not exhaustive, but they establish the right expectation: that cardiac monitoring is part of cancer treatment, not an optional add-on, and that a woman’s long-term cardiovascular health is part of what a good treatment team is managing from the first day of therapy.

What this means

Cardio-oncology is the discipline that keeps cancer treatment from becoming a hidden cost to the heart. In women, where breast cancer treatment is a leading source of cardiotoxic exposure, the approach is baseline assessment, monitoring during and after therapy, and cardiovascular care folded into survivorship. Effective cancer treatment remains the priority, and the heart is protected alongside it rather than traded away for it.