Long-Term Complete Radiological Response in a Patient with Brain Metastases from HER2-Positive Breast Cancer Treated with Trastuzumab Deruxtecan: A Case Report and Literature Review

Abstract

Introduction

HER2-positive (HER2+) breast cancer (BC) is associated with a high incidence of brain metastases (BMs), which negatively affect prognosis and quality of life. Local therapies, such as whole-brain radiotherapy (WBRT), stereotactic radiotherapy, stereotactic radiosurgery, and neurosurgery, allow temporary control of metastatic spread. Systemic treatments are limited by the blood-brain barrier (BBB), which restricts the passage of many therapeutic molecules. Research initially focused on small molecule tyrosine kinase inhibitors due to their low molecular weight. Recent evidence suggests that tumor-induced disruption of the BBB may increase its permeability, potentially allowing larger molecules, including antibody-drug conjugates, to cross. Although trastuzumab deruxtecan (T-DXd) has demonstrated intracranial activity, evidence of durable complete responses in heavily pretreated patients with active BMs remains limited.

Case Presentation

We report a case of a HER2+ BC patient with multiple (>20) active BMs, previously treated with WBRT and trastuzumab emtansine (T-DM1), who developed intracranial progression. Third-line treatment with T-DXd resulted in a complete radiological intracranial response, which has been maintained for more than 20 months under ongoing therapy, with associated improvement in neurological symptoms and quality of life.

Conclusion

This case provides preliminary evidence that T-DXd may achieve deep and durable intracranial responses even in heavily pretreated patients with active BMs, including those previously treated with WBRT and T-DM1. The exceptional duration of response observed in this case appears to exceed historical expectations and warrants further investigation in this high-risk population.

Introduction

Breast cancer (BC) is the most common malignancy among women worldwide, with HER2-positive (HER2+) tumors accounting for 10–20% of cases. HER2+ BC is associated with aggressive behavior, high recurrence, and poor prognosis [1]. HER2-targeted therapies, including monoclonal antibodies, antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors, have substantially improved survival in metastatic breast cancer (MBC) [2–4]. Approximately one-third of HER2+ MBC patients develop central nervous system (CNS) metastases [5]. Local treatments such as whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and neurosurgery remain standard for brain metastases (BMs) [6]. Nevertheless, intracranial progression remains frequent. HER2+ patients have better survival after CNS involvement compared to other BC subtypes, likely due to more effective systemic and intracranial control [5]. Trastuzumab deruxtecan (T-DXd) is a next-generation ADC composed of a humanized anti-HER2 IgG1 antibody conjugated to deruxtecan, a potent topoisomerase I inhibitor, via a tetrapeptide linker [7]. It exerts cytotoxic effects through targeted delivery and a bystander effect. We report a case of HER2+ MBC with complete intracranial response to T-DXd after progression on WBRT and trastuzumab emtansine (T-DM1), highlighting T-DXd’s potential in active brain disease.

Case Report

In August 2021, a 44-year-old woman with a positive family history for pancreatic cancer and no significant comorbidities presented with pain in the right hypochondrium. Abdominal ultrasound revealed multiple hepatic nodular lesions of uncertain nature. She was admitted to our oncology unit for diagnostic assessment. Breast ultrasonography showed a hypoechoic irregular lesion with irregular margins and 2 centimeters microcalcifications in the upper-outer quadrant of the right breast, suspicious for malignancy. A liver biopsy confirmed infiltrating ductal carcinoma, GATA3-positive, estrogen receptor 0%, progesterone receptor 0%, androgen receptor 90%, MIB-1 40%, and HER2 3+ by immunohistochemistry. E-cadherin expression was 100%. The diagnosis was confirmed by right breast biopsy, which revealed the same immunophenotype (estrogen receptor 0%, progesterone receptor 0%, androgen receptor 90%, MIB-1 30%, HER2 immunohistochemistry 3+). A staging contrast-enhanced total-body computed tomography (CT) scan demonstrated a 27-mm spiculated lesion in the right breast and numerous confluent liver metastases up to 5 cm, with no evidence of brain or thoracic lesions. The disease was staged as cT2N0M1 (stage IV) according to the AJCC 8th edition. Baseline tumor markers were CA-125 50 U/mL (ref. <35 U/mL), CA 15-3 >4000 U/mL (ref. <32.4 U/mL), and CEA 53 ng/mL (ref. <4 ng/mL). Following a multidisciplinary evaluation and in accordance with AIOM guidelines for HER2+ MBC, the patient began first-line treatment in September 2021 with docetaxel 100 mg/m² (day 1 every 3 weeks), trastuzumab (400 mg loading dose, then 300 mg q3w), and pertuzumab (840 mg loading dose, then 420 mg q3w). Treatment-related adverse events included grade 3 alopecia, fatigue, and leukoneutropenia managed with granulocyte colony-stimulating factor. After two cycles, 18F-FDG PET/CT showed complete metabolic remission, and breast ultrasound demonstrated marked tumor reduction (15 × 7 mm). Following eight chemotherapy cycles, an April 2022 CT scan confirmed complete radiologic response, and the patient was switched to maintenance therapy with trastuzumab (300 mg q3w) and pertuzumab (420 mg q3w). Six months later, in October 2022, during the eighth maintenance cycle, tumor markers normalized, but the patient reported new-onset headaches and dizziness. A contrast-enhanced CT revealed over 20 metastatic lesions in the cerebral and cerebellar regions, with perilesional edema and a dominant 13-mm cerebellar lesion compressing the aqueduct of Sylvius, leading to supratentorial ventricular enlargement. Given the number and location of the lesions, the patient underwent WBRT (total dose 20 Gy) and corticosteroid therapy (dexamethasone), achieving partial symptom relief. In November 2022, she began second-line therapy with T-DM1 (200 mg q3w). MRI after 1 month showed partial volumetric reduction of brain lesions, and bone scintigraphy excluded skeletal involvement. Despite initial stability, the patient experienced recurrent neurological symptoms after several months. A follow-up brain MRI in June 2023 confirmed intracranial disease progression; consequently, third-line therapy with T-DXd (270 mg q3w) was initiated. T-DXd was chosen over the tucatinib-trastuzumab-capecitabine triplet due to its systemic efficacy in heavily pretreated HER2+ MBC, emerging evidence of intracranial activity, and favorable tolerability – particularly regarding hematologic toxicity, which the patient had previously experienced. The patient also had a high intracranial disease burden with minimal extracranial progression, and T-DXd was readily available at our institution. In September 2023, contrast-enhanced CT revealed a marked reduction in cerebral lesions, particularly in the cerebellum. In October 2023, brain MRI confirmed the complete disappearance of all detectable metastases according to RECIST 1.1 criteria adapted for BMs and evaluated by an experienced neuroradiologist, accompanied by resolution of neurological symptoms. By February 2024, after 11 T-DXd cycles, total-body CT and brain MRI confirmed complete response. Continued follow-up imaging – CT in February 2025, brain MRI in April 2025, and CT in June 2025 – confirmed the persistence of radiologic remission (shown in Fig. 1). Next-generation sequencing analysis for BRCA1 and BRCA2 mutations revealed no pathogenic variants. As of June 2025, the patient had completed 32 cycles of T-DXd and continues to receive therapy (shown in Fig. 2). The patient reported a significant improvement in neurological symptoms and overall quality of life during treatment with T-DXd, with good tolerability, a progressive return to daily activities, and no therapy-related adverse events except for grade 1 nausea according to CTCAE, v5.0. Cardiac function was monitored throughout anti-HER2 therapy using echocardiography every 3 months, demonstrating preserved left ventricular ejection fraction (60%) and no structural abnormalities during prolonged treatment. Serial monitoring of tumor markers was also performed during treatment, and the values are reported in Table 1.

Fig. 1.

Brain MRI images acquired prior to initiation of T-DXd therapy (June 2023), at the first on-treatment radiologic assessment (October 2023), and at the last radiologic evaluation (April 2025) are presented for comparison. a Thalamic lesions on the sagittal section. b Thalamic lesions on the coronal section. c Thalamic lesions on the axial section. d Cerebellar lesions on the axial section. e Cerebellar lesions on the coronal section.

Fig. 2.

Chronological overview of the patient’s clinical course, including the initial diagnosis, subsequent treatments prior to the initiation of T-DXd therapy, follow-up imaging evaluations, and treatment outcomes across 32 therapy cycles.

Table 1.

Tumor markers trends

Marker	Reference value	Sep 2021	Sep 2022	Oct 2022	Feb 2023	May 2023	Dec 2023	Feb 2025
CA-125	<35 U/mL	50 U/mL	–	–	–	–	–	6.58 U/mL
CA 15-3	<32.4 U/mL	>4,000 U/mL	37.9 U/mL	36.9 U/mL	28.5 U/mL	24.9 U/mL	–	34.45 U/mL
CEA	<4 ng/mL	53 ng/mL	1.45 ng/mL	1.1 ng/mL	1.26 ng/mL	0.98 ng/mL	0.4 ng/mL	1.15 ng/mL

T-DXd in HER2+ BC with BMs

T-DXd combines a monoclonal antibody with a cytotoxic payload, enabling targeted delivery and a bystander effect [8–10]. Preclinical studies, followed by clinical evidence, have shown that T-DXd penetrates BMs and induces durable responses [11]. DESTINY-Breast01 (phase 2) demonstrated efficacy in heavily pretreated HER2+ MBC, though active BMs were excluded [12]. DESTINY-Breast02 (phase 3) reported mPFS of 13.9 vs. 5.6 months for T-DXd vs. physician’s choice in patients with stable BMs [13]. DESTINY-Breast03, including patients with BMs, showed intracranial ORR 63.8% with T-DXd vs. 33.3% with T-DM1; complete intracranial responses were 27.8% vs. 2.8% [14, 15]. Data regarding the potential activity of T-DXd in patients with BC and active BM are limited. The phase 2 prospective clinical trials TUXEDO-1 and DEBBRAH demonstrated intracranial ORRs of 73.3% and 44–50% in patients with active BMs, respectively, with median PFS of 14 months in TUXEDO-1 and no cognitive decline [16, 17]. Real-world data from ROSET-BM reported 12-month PFS of 62% for active BMs and 71.4% for stable BMs [18]. Several ongoing studies are evaluating the efficacy of T-DXd in HER2+ BC patients with BMs, including those with active lesions. These include DESTINY-Breast07, DESTINY-Breast09, DESTINY-Breast12, and HER2CLIMB-04. DESTINY-Breast07, a phase 1b/2 multicenter trial, is assessing the safety, tolerability, and antitumor activity of T-DXd alone or in combination with other anticancer agents in patients with both active and stable BMs [19]. DESTINY-Breast12, a phase 3b/4 study, investigates T-DXd in real-world-like settings and demonstrates substantial and durable overall and intracranial activity in patients previously treated with HER2-targeted therapies, regardless of whether they have stable or active baseline BMs (Table 2) [20].

Table 2.

Overview of studies evaluating the efficacy of T-DXd in patients with HER2+ BC and BMs

Study	Author and published year	Therapy	Phase	Intracranial ORR	mPFS, months	mOS, months
DESTINY-Breast01 NCT03248492	Guy Jerusalem et al. [25], 2022	T-DXd	II	58.3%	18.1	NA
DESTINY-Breast02	Fabrice André et al. [13], 2023	T-DXd	III	Not reported	17.8	NA
NCT03523585
DESTINY-Breast03 trial	Javier Cortés et al. [14], 2022	T-DXd	III	63.8%	29	52.6
NCT03529110
TUXEDO-1	Rupert Bartsch et al. [16], 2024	T-DXd	II	73.3%	21	NA
NCT04752059
DEBBRAH	Vaz Batista et al. [17], 2023	T-DXd	II	46.2%	NA	NA
NCT04420598
ROSET-BM	Naoki Niikura et al. [18], 2023	T-DXd	Retrospective multicenter study	62.7%	16.1	NA
UMIN000044995
DESTINY-Breast07	Fabrice André et al. [19], 2024	T-DXd	1b/2	Not reported	NA	NA
NCT04538742
DESTINY-Breast12	Nadia Harbeck et al. [20], 2024	T-DXd	IIIb/IV	47.3%	17.3	NA
NCT04739761

Discussion

BMs occur in 25–50% of advanced HER2+ BC patients and are associated with high morbidity and mortality [6]. Improved systemic therapies have increased OS, but median OS after CNS involvement remains 2–16 months [21]. A baseline prognostic assessment using the Breast-GPA score helps contextualize the outcome observed in this case. At the time of CNS progression, the patient (44 years old, HER2+ disease, multiple BMs, and KPS ≥70) had an estimated Breast-GPA of approximately 2.5, corresponding to a median overall survival of about 13–18 months. In this context, the durable complete intracranial response achieved with T-DXd, persisting beyond 18 months with preserved quality of life, appears to exceed expected prognostic outcomes. Historically, BMs were managed with local approaches such as neurosurgery, SRS, or WBRT with negative impact on long-term neurocognitive function [22–24]. Systemic treatment has emerged as an attractive alternative to WBRT when stereotactic radiotherapy or SRS is not feasible, with the aim of preventing WBRT-associated neurocognitive decline. The limited ability of certain systemic treatments to cross the blood-brain barrier (BBB), together with the unique brain tumor microenvironment, may contribute to poor lesion control [25]. Initial research in this field focused primarily on small molecule tyrosine kinase inhibitors, due to their low molecular weight, as larger molecules are generally unable to penetrate the intact BBB [26]. Preclinical studies have suggested that disruption of the BBB by tumor cells may increase its permeability, potentially allowing larger molecules such as ADCs to reach intracranial lesions [27]. From a clinical perspective, T-DXd has demonstrated potent extracranial activity in heavily pretreated HER2+ MBC patients, likely due to its unique pharmacologic properties, including signaling-independent cytotoxicity and a bystander effect. More recently, clinical studies have also reported intracranial activity of T-DXd; however, available data are still limited, particularly in patients with active and heavily pretreated BMs. What distinguishes the present case is the treatment sequence: the patient received WBRT followed by T-DM1, and subsequently T-DXd. Notably, this approach resulted in a durable complete intracranial response lasting over 20 months in a patient with more than 20 active BMs. This represents a particularly challenging clinical scenario in which prognosis is generally poor and such outcomes remain uncommon. While this observation is consistent with emerging clinical evidence, it is based on a single case and should be interpreted with caution. The depth and duration of response observed in this case appear to exceed historical expectations, thereby reinforcing the clinical relevance of this finding.

Conclusions

Few studies have specifically investigated the effectiveness of third-generation ADCs in patients with active BM or leptomeningeal disease. The limited data available so far suggest that ADCs may have promising activity in this population. Considering the negative prognosis associated with CNS involvement, these preliminary findings warrant further investigation in well-designed clinical trials to address this unmet need.

Statement of Ethics

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. According to national guidelines and institutional policies, ethical approval is not required for single-patient case reports. Therefore, no approval from the Ethical Review Board was needed. This case report has been prepared following the CARE guidelines. The completed CARE checklist is provided as supplementary material (for all online suppl. material, see https://doi.org/10.1159/000552141).

Conflict of Interest Statement

The authors declare no conflicts of interest.

Funding Sources

This research received no external funding.

Author Contributions

Conceptualization: Martina Musarra, Mariapia Marafioti, Giordana Di Mauro, Dalila Incognito, and Giuliana Ciappina; methodology, validation, formal analysis, investigation, data curation, writing – original draft preparation, writing – review and editing, visualization, supervision, and project administration: Martina Musarra and Mariapia Marafioti; software: Martina Musarra, Mariapia Marafioti, Tindara Franchina, Mariacarmela Santarpia, and Marco Donato; and resources: Martina Musarra, Mariapia Marafioti, Jessica Alejandra Portillo Funes, Maria Concetta Ingemi, and Maria Fernanda Danzè. All authors have read and agreed to the published version of the manuscript.

Funding Statement

This research received no external funding.

Data Availability Statement

The original data presented in this study are included in the article. Further inquiries can be directed to the corresponding author.