Study Links Body Composition to Trastuzumab Deruxtecan Dosing, Toxicity

Patients with metastatic breast cancer (MBC) who have larger fat tissue area, lower fat density, and higher body mass index (BMI) compared with patients who don’t have these body composition metrics are at an increased risk for dose reduction and treatment-related toxicity when being treated with trastuzumab deruxtecan (T-DXd), according to study findings published in npj Breast Cancer.

This first of its kind study evaluated how body composition affects clinical outcomes in women who received the third-generation antibody-drug conjugate.

“T-DXd dosing is calculated based on body weight. This means that a patient who weighs twice as much will receive twice the amount of the drug,” the researchers said. “High fat area, indicative of higher overall adiposity, and low-fat density, suggestive of larger adipocytes with greater lipid content, can both impact the efficacy and toxicity of oncological treatments.”

Forty-eight women who had received a diagnosis of HER2-positive or -low MBC and were treated with T-DXd at Tel Aviv Medical Center in Israel from January 2020 to March 2024 were included in the study population.

Patients were a median age of 62 years. They had a mean weight of 65.3 kilograms (kg) and a mean BMI of 29.4 ± 7.5 kg/m². More than half of the population was considered overweight or obese (62%), and about three-quarters were sarcopenic.

The researchers used computed tomography to assess skeletal muscle, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) within 60 days before initiating treatment.

Results showed that the objective response rate was lower in those who had higher SAT areas. Furthermore, high SAT and VAT areas significantly increased the chances of dose reduction compared with low SAT and VAT areas. Dose reduction was also more probable in patients with medium SAT density versus high SAT density. In addition, low and medium VAT density also increased the likelihood of dose reduction. Patients with higher BMI (25 kg/m² or above) had a significantly higher chance of dose reduction.

Half of the study population had a dose reduction and a dose delay (n=24). Of these patients, 16 experienced a single treatment adjustment because of toxicity, and the remaining eight had a second intervention in dosage or treatment timing. About 20% of patients were hospitalized because of treatment-related toxicity.

The most common toxicity was grade 2 or higher anemia, followed by neutropenia and nausea. Grade 4 neutropenia was experienced by three patients who were then hospitalized. T-DXd treatment was discontinued in seven patients because of toxicity. Moreover, patients with a higher VAT area were at a significantly increased risk for severe gastrointestinal diarrhea.

The researchers believe the study findings can assist healthcare professionals with a personalized treatment approach for patients.

“By integrating body composition assessments into clinical practice, healthcare providers can better tailor treatment plans to individual patients, potentially enhancing treatment efficacy and minimizing adverse effects,” the researchers said.

Reference:

S Yaacobi Peretz, et al. npj Breast Cancer 11, 38 (2025). https://doi.org/10.1038/s41523-025-00754-7