Introduction

Antibody-drug conjugates (ADCs) combine the precision of targeted therapy with the cell-killing power of chemotherapy, and few have been more transformative in breast cancer than fam-trastuzumab deruxtecan (T-DXd), now approved across early-stage, metastatic, HER2-positive, HER2-low, and HER2-ultralow disease. But T-DXd carries a serious, sometimes fatal toxicity that every provider managing these patients needs to actively screen for: interstitial lung disease (ILD) and pneumonitis.

A Case That Underscores Why This Matters

70-year-old female with HER 2 + breast cancer. She received cycle ten of TDXd – 5 days ago. At office visit, for clearance for chemotherapy 5 days ago, denied shortness of breath and coughing, positive for fatigue. Labs were appropriate to proceed with treatment. Calls the office 5 days after Cycle 10 with new shortness of breath and cough. She is advised to report to the emergency room (ER) for which she refuses. Reports to clinic on Day 9 of Cycle 10 with severe shortness of breath and her oxygen saturation in the seventy’s. She is transported to the ER, where she is admitted to the Intensive Care Unit (ICU). She is later intubated and diagnosed with interstitial lung disease. Unfortunately, she passed away during her admission. She chose to delay seeing care due to treatment and disease fatigue. 

This case underscores two things worth internalizing: ILD from T-DXd can progress quickly once symptomatic, and patients may not always report symptoms promptly, whether from treatment fatigue, normalization of mild breathlessness, or simply not recognizing the significance of what they are experiencing. Confirmed ILD/pneumonitis occurs in roughly 12%–15% of patients treated with T-DXd, with median time to onset around three to six months into treatment, meaning vigilance needs to extend well past the first cycle or two.

What Monitoring Should Actually Look Like

Package labeling and guidelines recommend high-resolution CT scans every six to nine weeks for patients on T-DXd, a monitoring cadence considerably more frequent than the standard restaging CT or PET scan every three cycles (roughly every three months) that most practices, typically use for monitoring disease elsewhere in the body. This is a real gap between formal guidance and common practice, and it is one worth acknowledging directly rather than assuming routine restaging imaging is adequate to catch early ILD.

Given that gap, the most valuable tool available is a genuinely thorough respiratory symptom assessment at every visit, not just before proceeding with the next cycle. New or worsening shortness of breath or cough should not be attributed by default to anemia, deconditioning, or "just getting older," particularly in a patient on T-DXd; the threshold for pursuing imaging should be low, especially when the new or worsening shortness of breath is accompanied by a fever. Risk factors that should raise a clinician's index of suspicion further include prior chest radiation or any pre-existing lung disease.

Case Walkthrough: Grading and Response

A 69-year-old woman with metastatic, HER2-positive, hormone receptor-negative breast cancer, who had progressed on first-line therapy with liver and bone metastases, was started on second-line T-DXd (baseline ejection fraction 65%, recent echocardiogram normal, no baseline shortness of breath or cough). She presented for clearance before cycle 9 with new-onset shortness of breath on minimal exertion and a new cough; labs were otherwise unremarkable.

The next correct step is imaging, not proceeding with treatment and not simply reducing the dose. High-resolution CT confirmed grade 2 interstitial lung disease. Per grading guidelines, grade 1 ILD may allow observation or a temporary hold with close monitoring, but grade 2 or higher calls for permanent discontinuation of T-DXd. For this patient, treatment was permanently stopped and next steps for further therapy were planned given the range of other HER2-targeted and antibody-drug conjugate options now available.

Practical Questions That Come Up Often

A few recurring questions are worth addressing directly. Should pulmonary function tests be obtained at baseline, the way they might be for bleomycin? There is no formal indication for this with T-DXd; it isn't part of the labeled monitoring recommendations, and imaging or biopsy remains the primary diagnostic tool when ILD is suspected.

Is rechallenge after resolved ILD ever appropriate? This genuinely varies by physician. Some clinicians are more willing to rechallenge even after a grade 2 event, particularly if the patient was having an excellent response, despite guidelines recommending permanent discontinuation at grade 2 or higher; others will not rechallenge under any circumstances. One patient discontinued from T-DXd due to ILD has now gone several years with no evidence of disease and is off all treatment entirely, a reminder that stopping a highly effective drug for safety reasons doesn't necessarily mean losing disease control, especially if a deep response was already achieved.

For the Care Team: Building a Culture of Vigilance

Since advanced practice providers are frequently the ones clearing patients for each treatment cycle, building genuine familiarity with this toxicity, its onset window, its risk factors, and its potential severity, into every new team member's training is essential, not optional. New shortness of breath, cough or fever in a patient on T-DXd should trigger the same level of concern and workup urgency as any other potentially serious, unexplained new symptom, rather than being reflexively attributed to more common, benign explanations.

For Patients

For people being treated with trastuzumab deruxtecan (T-DXd) for HER2-positive or HER2-low breast cancer, a rare but serious lung side effect called interstitial lung disease or pneumonitis can develop, most commonly within the first three to six months of treatment, though it can happen at other times as well. Any new or worsening shortness of breath or cough, even if it seems mild or you are unsure whether it is significant, should be reported to your care team right away rather than waiting for your next scheduled visit. Catching this early, when it is mild, gives your team far more options for managing it safely than if it is allowed to progress.

Key Takeaways

  • Interstitial lung disease/pneumonitis occurs in roughly 12%-15% of patients on T-DXd, typically within 3-6 months of starting treatment, and can progress quickly and seriously if not caught early.

  • Guidelines recommend high-resolution CT scans every 6-9 weeks for T-DXd monitoring.

  • New or worsening shortness of breath, cough or a fever in a patient on T-DXd warrants prompt imaging..

  • Grade 1 ILD may allow observation or temporary hold; grade 2 or higher calls for permanent discontinuation per guidelines, though real-world rechallenge decisions vary by physician and clinical context.

References

  1. Daiichi Sankyo and AstraZeneca. Fam-trastuzumab deruxtecan-nxki (Enhertu) [package insert]. U.S. Food and Drug Administration website.

  2. National Comprehensive Cancer Network. Management of Immunotherapy-Related and ADC-Related Toxicities. Version 2.2026. Accessed June 2026.