Multidisciplinary clinical guidelines in proactive monitoring, early diagnosis, and effective management of trastuzumab deruxtecan (T-DXd)-induced interstitial lung disease (ILD) in breast cancer patients

Abstract

Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate (ADC), has altered the treatment landscape in breast cancer (BC), irrespective of the HR-receptor status. The use of the agent is increasing, despite the finding that exposure to T-DXd increases the risk of interstitial lung disease (ILD), particularly in BC patients. Although T-DXd-related ILD can be potentially severe and life-threatening, most low-grade cases can be treated safely using a multidisciplinary approach comprising early and accurate diagnosis, effective management, close monitoring, and the prompt administration of steroids. Additionally, increasing patients' education on ILD symptoms ensures close attention and enables prompt reporting, enhancing patient outcomes. It is recommended that predictive biomarkers are assessed in patients with risk factors for developing ILD. Currently, diagnostic criteria comprise newly identified pulmonary opacities, the relation of symptom onset to medication initiation, and the exclusion of other causes of ILD. The general condition of patients is weakened during the management of ILD (BC progression and corticosteroid treatment). Consequently, BC chemotherapy might be attenuated. This highlights the importance of preventing (high-grade) ILD, especially since its use is expanded. Identifying high-risk patients, diagnosing, and customizing treatment is, however, challenging and additional information on patient selection is often not fully clarified. In this paper, we provide updated multidisciplinary clinical guidance for patient selection, proactive monitoring, early diagnosis, and effectively management of T-DXd-induced ILD in HER2-positive BC patients. We describe the risk factors for developing ILD, patients' characteristics of ILD, and the histopathological and radiographic characteristics of ILD, including real-world clinical practice reports. These recommendations provide a structured step-by-step approach for managing each suspected BC-related ILD grade.

Keywords: HER2-negative breast cancer; HER2-positive breast cancer; T-DXd-induced ILD; interstitial lung disease; multidisciplinary guidance; trastuzumab deruxtecan.

Figure 1

Example of interstitial lung disease induced by trastuzumab deruxtecan therapy in a 53-year-old female patient with T4 breast cancer at the Parma Hospital. The images show patterns of interstitial lung disease evidenced in a non-contrast computed tomography (CT) scan carried out in August 2022 (A and B), radiologically worsened in a subsequent contrast enhanced CT scan carried out 1 month later in September 2022 (C and D). A cryptogenic organizing pneumonia (COP) pattern characterized by ground-glass opacities and lung consolidations (white arrowheads) can be observed in the most dependent portions of both the upper lobes (A and C) and in the posterior basal segment of the left lower lobe. In the upper lobes (A and B) it is also possible to observe the dimensional growth of the breast cancer located in the right breast, associated with skin involvement.

Figure 2

Same patient as in Figure 1, who experienced interstitial lung disease induced by trastuzumab deruxtecan therapy. (A) Lung consolidation (red square in A) seen in the right upper lobe of the non-contrast computed tomography scan carried out in August 2022. (B) Detail of the same lung consolidation, in which it is possible to observe the presence of air bronchogram within the consolidation (white arrowhead) and ground glass opacities (black arrowheads) around it.

Figure 3

Recommendations for the multidisciplinary monitoring and diagnosis of T-DXd-induced ILD based on DESTINY-Breast03 and DESTINY-Breast04 Protocols.^, Careful patient history taking, physical examination, vital sign measurement, laboratory tests, CT chest scan every 9-12 weeks or when new symptoms appear, pulmonary function testing with spirometry and diffusing lung capacity for carbon monoxide (DLCO) are all relevant. A laboratory test should include complete blood count, arterial blood gases, liver and kidney function, electrolytes, CRP, erythrocyte sedimentation rate, procalcitonin, LDH, with or without KL-6, surfactant protein A (SP-A), and SP-D. Based on clinical suspicion, blood culture, sputum, and urinary antigens should be analyzed, as well as assessing tumor markers and autoimmune antibodies. Exclude any other cause of ILD. If necessary, BAL and lung biopsy might be helpful. BAL, bronchoalveolar lavage; CT, computed tomography; ILD, interstitial lung disease; RT, radiotherapy; T-DXd, trastuzumab deruxtecan.

Figure 4

Recommended multidisciplinary management of T-DXd-associated ILD based on DESTINY-Breast03 and DESTINY-Breast04 Protocols.^, ILD, interstitial lung disease; IVIG, intravenous immunoglobulin; T-DXd, trastuzumab deruxtecan.