Fam-trastuzumab deruxtecan in a patient with metastatic human epidermal growth factor receptor 2-positive breast cancer and pre-existing cardiac failure: a case report
Mayas Alnan1,2
, Reem Alharbi3
Contributions: (I) Conception and design: Both authors; (II) Administrative support: Both authors; (III) Provision of study materials or patients: Both authors; (IV) Collection and assembly of data: Both authors; (V) Data analysis and interpretation: M Alnan; (VI) Manuscript writing: Both authors; (VII) Final approval of manuscript: Both authors.
Background: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is aggressive with poor prognosis, and fam-trastuzumab deruxtecan-nxki (T-DXd), an antibody-drug conjugate (ADC), offers a promising treatment option for pretreated HER2-positive advanced or metastatic breast cancer. Patients treated with fam-trastuzumab deruxtecan may have an increased risk of developing left ventricular dysfunction. However, its safety in patients with pre-existing cardiac comorbidities remains unclear.
Case Description: This report presents a 72-year-old female with type-2 diabetes and metastatic HER2-positive breast cancer, who developed cardiomyopathy [ejection fraction (EF) 35–40%, New York Heart Association (NYHA) class II–III] following liposomal doxorubicin. Due to disease progression, T-DXd was initiated. After four cycles, imaging showed favorable response without worsening cardiac function. However, by the eighth cycle, mixed response was noted along with severe gastrointestinal toxicity, including gastric perforation and diarrhea, leading to dose adjustments. Ultimately, treatment was discontinued due to disease progression and toxicity, and the patient was transitioned to palliative care. Despite concerns, cardiac monitoring showed stable EF and global longitudinal strain (GLS), suggesting potential safety of T-DXd in high-risk patients.
Conclusions: This case highlights the need for further research to assess T-DXd’s safety and efficacy in patients with pre-existing cardiac dysfunction.
Keywords: Fam-trastuzumab deruxtecan-nxki (T-DXd); breast cancer; human epidermal growth factor receptor 2-positive (HER2-positive); case report
Received: 21 June 2025; Accepted: 30 December 2025; Published online: 25 February 2026.
doi: 10.21037/acr-2025-154
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Key findings
• Follow-up echocardiography demonstrated no significant changes in cardiac function (ejection fraction 35–40% and global longitudinal strain −13.6%) after treatment with fam-trastuzumab deruxtecan-nxki (T-DXd) in our patient with pre-existing cardiac dysfunction. This suggests that T-DXd may be tolerated in patients with heart failure under close cardiac monitoring.
What is known and what is new?
• Patients treated with fam-trastuzumab deruxtecan may have an increased risk of developing left ventricular dysfunction. However, its safety in patients with pre-existing cardiac comorbidities remains unclear.
• Our case suggests that fam-trastuzumab deruxtecan may be feasible in selected patients with human epidermal growth factor receptor 2-positive metastatic breast cancer and pre-existing cardiac dysfunction under close monitoring.
What is the implication, and what should change now?
• Our case suggests the potential safety for using T-DXd in a population with cardiac failure, though further studies are warranted.
Introduction
Female breast cancer is the most commonly diagnosed cancer, accounting for 1 in 4 cancer cases and 1 in 6 cancer deaths among women (1). Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in about 20% of breast cancers (2). This subtype is known for its aggressive nature and poor clinical prognosis. However, the introduction of new anti-HER2 agents has recently improved outcomes (3).
For HER2-positive breast cancer, the preferred first-line treatment regimens include pertuzumab with trastuzumab and docetaxel, or pertuzumab with trastuzumab and paclitaxel. The preferred second-line treatment is fam-trastuzumab deruxtecan-nxki (T-DXd) (4). T-DXd, an antibody-drug conjugate (ADC), offers a new treatment option for patients with heavily pretreated HER2-positive advanced or metastatic breast cancer (5). However, patients treated with fam-trastuzumab deruxtecan may have an increased risk of developing left ventricular dysfunction. Notably, this treatment has not been studied in patients with a history of significant cardiac disease or a left ventricular ejection fraction (LVEF) less than 50% prior to treatment initiation (6). This article will present a case review of a patient with a history of cardiac failure treated with T-Dxd. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-154/rc).
Case presentation
A 72-year-old female patient, with a known history of type 2 diabetes mellitus managed with medication, presented in 2015 with right breast cancer. In April 2015, she underwent a right modified radical mastectomy and axillary lymph node dissection in the USA, which revealed breast cancer classified as T2N1M0. In June 2015, she was started on endocrine treatment with Letrozole until April 2016.
In April 2016, the patient experienced a chest wall recurrence, prompting complete resection and a switch to Aromasin in May 2016. She completed radiotherapy to the chest wall by September 2016. A CT scan and positron emission tomography-computed tomography (PET-CT) scan in July 2019 in the USA revealed extensive metastatic disease involving the lungs, bones, liver, and lymph nodes. A lung biopsy confirmed invasive ductal carcinoma grade 3 with similar pathology. Consequently, she started treatment with fulvestrant 500 mg intramuscular (IM), ibrance 120 mg, and denosumab 120 mg subcutaneous (SC) in August 2019.
In 2021, a PET-CT scan showed disease progression in the lungs and liver. She began single-agent Paclitaxel in June 2021. Due to a significant increase in CA15-3 levels to over 700, gemcitabine was added on day 1 of the third cycle in August 2021. After completing six cycles in October 2021, she was seen by an oncologist at Memorial Sloan Kettering Cancer Center (MSKCC) in New York. Further PET-CT scans indicated disease progression, leading to the initiation of liposomal doxorubicin (40 mg/m2).
The patient completed 10 cycles of liposomal doxorubicin by December 2022, but this was complicated by cardiomyopathy, with poor ejection fraction (EF) and low global longitudinal strain (GLS). She started anti-failure medication, and a repeated echocardiogram showed an EF of 35–40% with New York Heart Association (NYHA) class II–III.
The patient was admitted for palliative support. Her overall condition had deteriorated following the recent discovery of worsening and recurrent tumors with metastasis, causing progressive shortness of breath, lower limb edema, and abdominal distention over the last few months. She experienced frequent abdominal pain but no chest pain, palpitations, presyncope, or syncopal attacks. The patient was taking Entresto 50 mg twice daily (BID), eplerenone 25 mg once daily (OD), metoprolol 50 mg extended release (XL), and empagliflozin 10 mg.
Given the recent data from the DESTINY 04 study presented at American Society of Clinical Oncology (ASCO) and her last biopsy showing estrogen receptor (ER)++ HER2+1, the decision was made to proceed with Trastuzumab Deruxtecan, despite the risk of cardiac failure in light of her known cardiomyopathy. She received the first dose on August 2, 2022.
After four cycles, a CT scan showed a favorable response, with no major complications. Cardiac follow-up by echocardiogram showed no significant change compared to prior studies, with an EF of 35–40% and GLS (Avg) of −13.6%. However, the treatment with Trastuzumab Deruxtecan was complicated by gastric perforation and several admissions for severe diarrhea despite dose reductions. After eight cycles, a CT scan showed a mixed response, and therapy was continued. Following the ninth cycle, she was admitted with grade 3–4 diarrhea, leading to a reduced dose for the tenth cycle. A CT scan after cycle ten showed progressive disease.
In 2023, the patient discontinued fam-trastuzumab and went to Germany to continue treatment. She received two doses of nab-paclitaxel and Avastin, followed by a switch to sacituzumab. She completed five cycles (day 1 and 8), with the last dose on December 18, 2023, complicated by significant gastrointestinal toxicity, including diarrhea, abdominal pain, and cramps. The patient was eventually shifted to palliative care and passed away on December 28, 2023. Figure 1 summarizes the disease course and treatments of our patient chronologically.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report was not obtained from the patient or the relatives after all possible attempts.
Discussion
T-DXd is an ADC composed of a humanized anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody with the same amino acid sequence as trastuzumab, covalently linked to a topoisomerase inhibitor via a tetrapeptide-based cleavable linker (5). Unlike several other approved HER2-targeted treatments, trastuzumab deruxtecan is capable of effectively targeting tumor cells with low HER2 expression, as seen in this case. Therapy with trastuzumab deruxtecan has been associated with markedly longer progression-free and overall survival (7).
Despite these promising results, the safety profile and adverse effects of T-DXd are not completely known yet due to the relatively new approval of T-DXd. Severe adverse reactions and complications, such as interstitial lung disease (ILD) and neutropenia, have been observed. Other common reported adverse effects (≥20%) include fatigue, nausea, vomiting, diarrhea, hair loss, constipation, decreased appetite, cough, anemia, leukopenia, and thrombocytopenia (5).
Patients treated with fam-trastuzumab deruxtecan may be at increased risk of developing left ventricular dysfunction. However, this treatment has not been studied in patients with a history of significant cardiac disease. The DESTINY-03 randomized phase III clinical trial excluded all patients with an LVEF less than 50% prior to treatment initiation (6,8).
Conclusions
In the presented case, the patient was diagnosed with cardiac failure, with an EF of 35–40% and classified as NYHA class II–III, prior to treatment with T-DXd. To our knowledge, this is not well-studied yet. Fortunately, cardiac follow-up via echocardiogram showed no significant changes compared to prior studies, with an EF of 35–40% and a GLS average of −13.6% after treatment with T-DXd. This suggests potential safety for using T-DXd in a population with cardiac failure, though further studies are warranted.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-154/rc
Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-154/prf
Funding: None.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-154/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report was not obtained from the patient or the relatives after all possible attempts.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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Cite this article as: Alnan M, Alharbi R. Fam-trastuzumab deruxtecan in a patient with metastatic human epidermal growth factor receptor 2-positive breast cancer and pre-existing cardiac failure: a case report. AME Case Rep 2026;10:65.
