Abstract PS2-02-02: Safety and efficacy of trastuzumab deruxtecan and concomitant radiation therapy in breast cancer patients: an international retrospective cohort study

Abstract Background. Trastuzumab deruxtecan (T-DXd) has emerged as the standard treatment for patients with metastatic HER2-positive (HER2+) breast cancer (BC) following disease progression on first-line therapy containing taxanes and trastuzumab. Results from DESTINY-Breast04 have extended the approval of T-DXd to include metastatic BC patients with HER2-low expressing tumours. Radiation therapy (RT) is an integral component of multimodal treatment in the metastatic setting. This retrospective study aims to evaluate the safety of the concurrent use of T-DXd and RT in a consecutive, multicentre international cohort. Material/Methods. A retrospective analysis was conducted on patients with metastatic HER2+ or HER2-low BC treated at six leading European institutions. Ablative RT was defined based on a biological dose threshold of a minimum of 50Gy EQD2(10) delivered in no more than 12 fractions, as per the European Society for Radiotherapy and Oncology (ESTRO) OligoCare study. The primary objective was to assess the association between RT administration and adverse events (AEs) greater than grade 2 (G2). In all cases, RT was administered within one month prior to cycle 1 or during systemic treatment, without any interruption of T-DXd. Results. Data from 147 consecutive patients were evaluated. Sixty-seven patients received RT immediately before or during T-DXd treatment, amounting to 71 concurrent RT treatments, while 80 patients did not receive RT. The median age was 53 years old (range 28-88), and the median follow-up from T-DXd initiation was 15 months (range 1-46). Most patients received T-DXd as fourth or beyond line of systemic therapy (52.4%, N=77/147). The median total RT dose was 44Gy (range 8-48), delivered over a median of 4 fractions (range 1-20). The median EQD2 dose was 82Gy (range 12-104), and the median BED was 98Gy (range 14-125). The central nervous system was the most frequently treated site (58.2%; N=39/67), followed by bone (31.3%; N=21/67). Thirty-six patients (53.7%) received RT with ablative intent, and 31 patients (46.3%) received palliative RT. The relationship between RT and the development of G2 overall toxicity was not statistically significant (p=0.30), nor when considering acute toxicity G2 (p=0.31) and late toxicity G2 (p=0.59) separately. There was no significant association between EQD2 (50Gy or ≥50Gy) and BED (50Gy or ≥50Gy) with G2 and any grade acute and late toxicity. The only factor associated with an increased risk of acute toxicity was age ≥50 years old (p=0.035). Grade 2 interstitial lung disease (ILD) or G2-3 pneumonitis were observed in 7 cases in the RT group (10.5%) and 7 cases in the no-RT group (8.8%). Only one case of radionecrosis was reported among the 39 patients treated with intracranial RT (median follow up of 11 months). Overall, 19 patients permanently discontinued T-DXd due to toxicity, 8 in the RT group (11.9%) and 11 in the no-RT group (13.8%). Conclusion. Our preliminary findings suggest that the combination of T-DXd and concurrent RT does not increase the risk of severe acute and late toxicity. Citation Format: L. Visani, I. Ratosa, R. Bartsch, B. Linderholm, G. Griguolo, C. Becherini, M. Valzano, V. Salvestrini, A. Starzer, P. Kus, M. Lambertini, V. Guarneri, L. Livi, I. Meattini. Safety and efficacy of trastuzumab deruxtecan and concomitant radiation therapy in breast cancer patients: an international retrospective cohort study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-02-02.