Permissive Cardiotoxicity in HER2-Positive Metastatic Breast Cancer With Moderate Left Ventricular Dysfunction.

History of Presentation
Permissive cardiotoxicity, the continuation or reinitiation of human epidermal growth factor receptor 2 (HER2)–targeted therapy despite left ventricular (LV) dysfunction under close cardio-oncology surveillance, is increasingly recognized in metastatic breast cancer.1 Historically, HER2 therapy was typically interrupted when the LV ejection fraction (LVEF) declined below 50%, a threshold embedded in early clinical trial designs and subsequent guideline recommendations.1 However, this rigid threshold may compromise oncologic outcomes in patients with advanced disease. We present the case of a 49-year-old premenopausal woman with de novo HER2-positive metastatic breast cancer and germline breast cancer gene 2 (BRCA2) mutation who developed moderate LV dysfunction during trastuzumab and pertuzumab therapy and was managed using a permissive cardiotoxicity strategy.
Take-Home Messages
•Optimal guideline-directed medical therapy supports cardiac recovery in patients with asymptomatic left ventricular dysfunction, allowing for continued human epidermal growth factor receptor 2 therapy.

•Integrated cardio-oncology care is essential to balance cancer control with cardiovascular safety.

Past Medical History
The patient initially presented with back pain and was diagnosed with estrogen receptor+/progesterone receptor+/HER2+ breast cancer with metastatic lesions in the liver, spine, and bilateral femurs. A germline BRCA2 mutation was identified. She had no history of hypertension, diabetes mellitus, hyperlipidemia, or cardiovascular disease. Her family history was notable for breast cancer in her mother, diagnosed at age 31 and deceased at 51, and in her paternal grandmother, diagnosed at age 44. She was a lifelong nonsmoker and consumed alcohol occasionally. At the time of her cancer diagnosis, she had normal functional capacity. Baseline echocardiography showed normal LV cavity size and systolic function (LVEF 58% by 3D) and no significant valvular abnormalities. She started on paclitaxel, trastuzumab, pertuzumab, leuprolide, and letrozole.

Investigations
After 4 months of cancer therapy, echocardiography demonstrated LV dilation (left ventricular end-diastolic diameter [LVEDD] 5.6 cm, left ventricular end-diastolic volume indexed to body surface area 88 mL/m2), decline in LVEF to 35% by 2D biplane Simpson's method and 38% by 3D with diffuse hypokinesis (Figure 1A, Video 1), significantly reduced LV global longitudinal strain (GLS) at −13.4% (Figure 1B), and moderate-to-severe functional mitral regurgitation (MR) (Figure 2). She reported no cardiovascular symptoms and was clinically euvolemic on examination. Her blood pressure was 139/87 mm Hg and pulse 103 beats/min.

Differential Diagnosis
Leading the differential diagnosis was cancer therapy–related cardiac dysfunction, followed by ischemic cardiomyopathy and Takotsubo syndrome.

Management
HER2 therapy was temporarily held, and guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction was initiated: metoprolol succinate 25 mg daily, valsartan 40 mg twice daily, spironolactone 12.5 mg daily, and empagliflozin 10 mg daily. Sacubitril/valsartan was not initiated because of lack of insurance coverage and cost barriers. Medications were uptitrated over the next 4 weeks: spironolactone increased to 25 mg daily and metoprolol succinate and valsartan increased to 50 mg daily and 80 mg twice daily, respectively. Large clinical trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin and empagliflozin reduce HF hospitalizations and cardiovascular mortality across both reduced and preserved ejection fraction populations.2,3 Beyond traditional HF therapy, SGLT2 inhibitors may also confer cardioprotective and potential anticancer benefits in the cardio-oncology setting.4
The echocardiogram 3 weeks later demonstrated a decrease in MR to mild and improvement in LV size (LVEDD 5.4 cm, left ventricular end-diastolic volume indexed to body surface area 80 mL/m2) but persistent LV dysfunction with an ejection fraction of 39% by Simpson’s method and a GLS of −14%. To exclude ischemia, a Lexiscan nuclear stress test was performed, which showed a fixed apicolateral perfusion defect, consistent with apical thinning without clear evidence of ischemia. The abnormal stress test was followed by coronary angiography, which revealed normal coronary arteries. Right heart catheterization showed normal hemodynamics (right atrial pressure 4 mm Hg, pulmonary capillary wedge pressure 9 mm Hg, left ventricular end-diastolic pressure 10 mm Hg, cardiac output 8.2 L/min, and cardiac index 4.1 L/min/m2). Laboratory assessment demonstrated stable renal function and no significant electrolyte abnormalities.
The findings of improved LV size and MR, absence of clinical congestive heart failure, normal hemodynamics, metastatic disease burden, and favorable early response to HER2 therapy were considered during multidisciplinary discussions supporting the resumption of HER2 therapy under a permissive cardiotoxicity approach despite LVEF <40%. She restarted on trastuzumab and pertuzumab while continuing optimized GDMT. She was subsequently monitored with alternating cardiology and oncology visits every 2 weeks.

Outcome and Follow-Up
On follow-up, the patient remained asymptomatic and physically active. Repeat echocardiography was performed 8 weeks after HER2 therapy reinitiation, demonstrating normalization of LV size (LVEDD 4.9 cm) and improvement in LVEF to 52% by 3D (Figure 3A) and GLS to −17.5% (Figure 3B). In addition, only mild MR was present (Video 2). Six months after GDMT initiation, the echocardiogram showed similar findings. Positron emission tomography/computed tomography scans showed stable metastatic disease with declining tumor markers, and HER2 therapy was continued without additional cardiac events.
This reflects the principle of permissive cardiotoxicity, which emphasizes proactive continuation of lifesaving therapy with mitigation strategies rather than reactive discontinuation.1 In patients with metastatic HER2-positive breast cancer, permissive cardiotoxicity represents a critical shift from rigid adherence to LVEF thresholds toward an individualized, risk-benefit approach. For patients whose prognosis depends on uninterrupted HER2 blockade, brief or permanent discontinuation of therapy may significantly compromise survival outcomes. Maintaining treatment continuity under close cardio-oncology supervision allows for optimization of GDMT, prevention of symptomatic HF, and preservation of oncologic control.1,5
Emerging evidence suggests that permissive cardiotoxicity is most effective in a subset of patients who are asymptomatic, maintain preserved functional capacity, and exhibit early improvement or stability on GDMT. Those with nonischemic cardiomyopathy, minimal comorbidity burden, normal hemodynamics, and robust recovery of GLS or LVEF are more likely to tolerate continued HER2-directed therapy without major cardiac events. In contrast, patients with symptomatic HF, elevated biomarkers, or poor tolerance to GDMT may warrant a more conservative approach. The patient described here exemplifies this favorable phenotype, as she remained asymptomatic, tolerated GDMT well, and achieved rapid echocardiographic recovery, consistent with outcomes observed in the SAFE-HEaRT study and recent longitudinal data by Zhou et al.6,7

Discussion
Although permissive cardiotoxicity is increasingly supported by emerging guidelines, a gap remains in the literature regarding the safety of HER2 therapy continuation in patients with moderate or worse cardiac dysfunction (LVEF <40%), especially in the setting of a germline BRCA2 mutation. This case contributes to the evolving evidence supporting permissive cardiotoxicity. The SAFE-HEaRT study prospectively demonstrated that patients with baseline LVEF 40% to 49% could safely complete HER2 therapy on GDMT, with over 90% avoiding major cardiac events.6 Retrospective cohorts have also reported the feasibility of continuing trastuzumab despite asymptomatic LVEF declines <50%, though careful patient selection and surveillance are required.8,9 HER2-targeted therapies, particularly trastuzumab and pertuzumab, have transformed outcomes for patients with HER2-positive metastatic breast cancer, and their discontinuation, especially early in the treatment course, can significantly compromise oncologic control. Furthermore, the cardiotoxic risk of these agents may be overstated in nonanthracycline regimens, and with the emergence of newer HER2-targeted agents, the therapeutic window for blockade is expanding.6 More recent data indicate that although most patients tolerate permissive cardiotoxicity, up to 14% may have persistent LV dysfunction at 3-year follow-up.7 Collectively, these studies reinforce that permissive cardiotoxicity is feasible in selected patients when supported by a cardio-oncology team, optimized GDMT, and advanced imaging.
In this case, a multidisciplinary team carefully balanced the risk of cardiomyopathy progression against the oncologic imperative to continue HER2 therapy. Her disease had demonstrated early biochemical and imaging response, and discontinuation of HER2 blockade posed a significant risk of disease progression. Based on the absence of cardiac symptoms and a favorable clinical trajectory on GDMT, HER2 therapy was resumed under a permissive cardiotoxicity approach despite an LVEF of <40%. She remained on an optimal HF regimen with frequent clinical and echocardiographic follow-up. Over the ensuing months, her LVEF improved to 52% while continuing concomitant cardiac and cancer therapies.
GLS and 3D echocardiographic quantification served as sensitive markers of dysfunction and recovery in this patient, consistent with guideline recommendations for contemporary imaging.2 The American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines endorse the routine use of GLS in cardio-oncology care, alongside 3D LVEF quantification, which minimizes interobserver variability and better captures myocardial impairment.10 The observed recovery of both LVEF and GLS highlights the potential reversibility of HER2-related cardiotoxicity when managed with timely GDMT and multidisciplinary oversight. Her clinical course demonstrates how modern GDMT, including SGLT2 inhibitors validated in DAPA-HF and EMPEROR-Preserved,4,5 may contribute to stabilization and recovery, complementing traditional neurohormonal blockade. The integration of cardioprotective therapies with ongoing oncologic treatment exemplifies the collaborative, multidisciplinary decision-making central to cardio-oncology.
Baseline and serial measurements of cardiac biomarkers such as high-sensitivity cardiac troponin and N-terminal pro–B-type natriuretic peptide are recommended for patients receiving HER2-targeted therapy to identify subclinical myocardial injury or stress. Although biomarkers were not obtained in this case, they can complement echocardiographic measures to refine risk assessment and guide therapy decisions in permissive cardiotoxicity. Incorporating biomarkers alongside imaging supports individualized monitoring and aligns with the multidisciplinary care principles emphasized in the European Society of Cardiology guidelines.7

Conclusions
This case contributes to the growing recognition that HER2-targeted therapy can be safely continued or resumed in select patients with LVEF <50% when guided by advanced imaging, expert input, and proactive GDMT. To our knowledge, this represents one of the first reported cases of HER2 therapy reinitiation below guideline thresholds in a patient with BRCA2-mutated, HER2-positive metastatic breast cancer. This case illustrates that HER2-directed therapy can be safely resumed in patients with moderate LV dysfunction when guided by permissive cardiotoxicity principles. Such a strategy relies on vigilant imaging, comprehensive GDMT, and close collaboration between disciplines to balance oncologic efficacy with cardiovascular safety.

Funding Support and Author Disclosures
The paper processing charge was provided by the Letts O'Brien Fund for Breast Cancer Research, Farmington, CT. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.