Clinical Challenges and Mechanisms of Recurrent Interstitial Lung Disease after Sequential Chemo-Radiotherapy for Breast Cancer: A Case Report

Abstract

Background: Neoadjuvant chemotherapy and radiotherapy are critical for improving local tumor control and survival in breast cancer treatment. However, both modalities may cause interstitial lung injury, which can affect subsequent therapy and prognosis.

Case presentation: We report a breast cancer patient who developed drug-induced interstitial pneumonia after neoadjuvant chemotherapy with doxorubicin plus cyclophosphamide followed by paclitaxel (AC-T). Respiratory symptoms and chest computed tomography (CT) findings were consistent with interstitial pneumonia. After glucocorticoid treatment, the pulmonary condition improved, allowing successful radical mastectomy. Postoperatively, the patient continued docetaxel chemotherapy followed by radiotherapy. After radiotherapy, interstitial pneumonia recurred, and chest computed tomography findings suggested radiation-induced interstitial pneumonia.

Conclusion: This case underscores the importance of recognizing and promptly managing treatment-related interstitial pneumonia during multimodal breast cancer therapy. Early intervention is essential to reduce toxicity, ensure treatment completion, and improve patient outcomes.

Graphical abstract

Keywords

breast cancer / chemotherapy / radiotherapy / interstitial lung disease

Introduction

Breast cancer is a common malignant tumor in women with high metastasis risk. Advances in tumor screening and optimized treatment protocols have significantly improved the overall survival rates[1,2]. Neoadjuvant chemotherapy enhance survival in advanced breast cancer by inhibiting cancer cell proliferation[3]. Post-operative radiotherapy is vital for local control, eliminating residual lesions, and reducing local recurrence likelihood[4].

These treatment strategies may cause adverse effects like gastrointestinal symptoms, myelosuppression, cardiotoxicity, neurological damage, and interstitial lung disease (ILD)[5]. ILD causes alveolar and interstitial inflammation and fibrosis, leading to respiratory distress and decreased lung function[6]. Although the incidence of ILD caused by chemotherapy for breast cancer is relatively low[6–9], but with the use of various new anti-tumor drugs and sequential chemoradiotherapy for breast cancer, the incidence has significantly increased[10]. ILD’s life-threatening potential requires significant clinical attention.

Reports on breast cancer treatment-related ILD mainly highlight isolated events, recurrences after sequential treatments (chemotherapy-surgery-radiotherapy) are rare. We detail such incidences, explores pathogenesis, and discusses clinical management, offering practical guidance.

Case presentation

The patient is a 49-year-old woman with no significant medical history. She was admitted with complaints of “chest tightness and shortness of breath for over two weeks.” In July 2023, she accidentally discovered a right breast mass. A biopsy at our hospital confirmed invasive carcinoma of the right breast with right axillary lymph node metastasis. Immunohistochemistry results: cancer cells estrogen receptor (ER) (90% strong +), progesterone receptor (PR) (–), HER-2 (2 +), Ki-67 (30% +), E-cad (+), P120 (membrane +), P63 (a few cells +), CK5/6 (–), P53 (some cells +), P63 and Calponin show myoepithelial deletion around the cancer lesion, cancer cell androgen receptor (AR) (90% strong +), combined with hematoxylin and eosin (HE) staining morphology and immunohistochemical results, the lesion conforms to Invasive breast carcinoma, non-specific type (invasive ductal carcinoma); Fluorescence in situ hybridization showed no HER2 gene amplification. The final diagnosis was right breast cancer (central part) pT2N1M0, luminal B1 type, Stage IIB, axillary lymph node metastasis. She received four cycles of liposomal doxorubicin combined with cyclophosphamide chemotherapy.

After the fifth chemotherapy (docetaxel) on September 27, 2023, she developed chest tightness, dyspnea and paroxysmal cough, without fever and was admitted to our hospital on October 15, 2023. Physical exam revealed lung moist rales. Arterial blood gas analysis: pH 7.53, PaO₂ 63 mmHg, PaCO₂ 26 mmHg, SPO₂ 95.3%, P/F ratio 217 mmHg, standard bicarbonate 24.2 mmol/L, actual bicarbonate 21.2 mmol/L, base excess –0.8 mmol/L. Blood routine examination: white blood cell counts 10.24 × 10⁹/L, neutrophils 76.6%, lymphocytes 13.0%, hemoglobin 101 g/L, platelet count 335 × 10⁹/L; respiratory pathogen tests were normal. On October 16, 2023, chest computed tomography (CT) (Figure 1a) showed new bilateral interstitial changes. Suspecting drug-induced interstitial pneumonia (DIIP) chemotherapy was delayed and nasal cannula oxygen inhalation was administered. Methylprednisolone 50 mg iv drip for 5 days alleviated symptoms, followed by oral prednisone tapering off by October 31.

On November 6, 2023, a modified radical mastectomy for right breast cancer was performed. A follow-up chest CT on November 20, 2023 (Figure 1b), indicated improved resorption of interstitial changes in the lower lobes. Subsequently, three more cycles of docetaxel chemotherapy were initiated without recurrence of interstitial pneumonia. After completing chemotherapy on January 4, 2024, she began endocrine therapy with letrozole, ovarian function suppression (OFS) and Abemaciclib, and received adjuvant radiotherapy for right breast cancer at another hospital. On August 22, 2024, a routine chest CT (Figure 1c) showed new interstitial inflammation and local traction bronchiectasis in the right lung middle lobe, suspected to be radiation-induced, but she was asymptomatic with normal infection markers, so no treatment was provided. A follow-up chest CT on March 7, 2025 (Figure 1d), showed decreased interstitial inflammation.

Discussion

The current breast cancer treatment includes surgery combined with chemotherapy, radiotherapy, endocrine therapy, and targeted therapy. Neoadjuvant chemotherapy, specifically the sequential doxorubicin plus cyclophosphamide followed by paclitaxel (AC-T) regimen effectively downsizes tumors pre-surgery, increasing resectability, but may cause lung complications[2,5,11].

The pulmonary toxicity of chemotherapeutic agents is a multifactorial process involving direct drug toxicity, oxidative stress, and immune responses[6]. Doxorubicin induces lung injury by overproducing reactive oxygen species (ROS), causing oxidative stress, disrupting plasma membranes, and damaging mitochondria, leading to interstitial pneumonia[12]. Cyclophosphamide’s metabolites cause cellular injury and immune activation, releasing cytokines to promote chronic inflammation and fibrosis[13,14]. Docetaxel inhibits microtubule depolymerization in cancer cells but damages normal tissues, inducing pulmonary inflammatory and structural damage, and exacerbating ILD in patients with pre-existing lung injury[15]. Radiation-induced lung injury exhibits a distinct field-dependent effect, with its central mechanism involving deoxyribonucleic acid (DNA) double-strand breaks directly caused by ionizing radiation, sustained oxidative stress, and a complex cascade of cytokine responses. Among these, transforming growth factor-beta (TGF-β) plays a critical role in driving the progression of radiation-induced pulmonary fibrosis[16].

The worthiest mechanism in this case is the “recurrence” of ILD under the background of sequential treatment. This cannot be simply explained by the additive effect of two independent toxic events. The core mechanisms of this recurrent interstitial pneumonia may involve: Chemotherapy has caused micro-damage to alveolar epithelium and initiated chronic inflammation and repair processes (e.g., activation of the TGF-β pathway and proliferation of fibroblasts), making lung tissue extremely sensitive to subsequent radiotherapy. Low-dose radiation can trigger significant recall inflammatory responses[17,18]. The second is the immune-mediated “recall pneumonia” phenomenon. Chemotherapy drugs act as antigens to trigger immune memory, and radiotherapy, as local stimulation, can reactivate the same T cell clones and cytokine storms (such as elevated IL-6 and TNF-α), leading to the recurrence of pneumonia in the original base or new areas[19,20].

Current studies suggest that biomarkers hold potential value in predicting treatment-related pulmonary toxicity. For instance, genetic variations involved in drug metabolism (e.g., CYP3A4 and GSTP1) or DNA damage repair (e.g., TGF-β1 gene polymorphisms) may influence an individual’s susceptibility to anticancer agents or ionizing radiation, thereby modulating the risk of developing ILD[21–25]. Furthermore, changes in the levels of certain cytokines (e.g., KL-6) or markers of pulmonary epithelial injury in serum before or during early treatment have also been explored as potential indicators for predicting radiation pneumonitis or chemotherapy-associated lung injury[26–28]. In future clinical practice, for high-risk patients scheduled to undergo intensive sequential therapy—particularly those with pre-existing lung disease—prospective investigation into the role of such biomarkers could facilitate more individualized risk stratification and monitoring strategies, thereby achieving a better balance between oncologic efficacy and treatment safety. This patient had no significant documented past medical history, yet the development of ILD prompts a reexamination of underlying individual susceptibilities. First, a subclinical autoimmune tendency or undifferentiated connective tissue disease could serve as an important background factor, with chemotherapy or radiotherapy acting as a trigger for its manifestation as clinical ILD. Additionally, inadequately documented environmental exposures (e.g., occupational dust, low-dose chemicals) or passive smoking may contribute to baseline lung fragility[29]. Therefore, for patients scheduled to undergo intensive therapy, even with an unremarkable routine history, a more detailed systemic assessment—such as autoantibody screening—could help identify high-risk individuals.

The management of interstitial pneumonia following oncologic chemoradiotherapy should adopt a multidisciplinary and integrated strategy based on severity grading. Diagnosis is foundational, requiring the integration of treatment history (specific agents or prior thoracic radiation), new-onset respiratory symptoms, and characteristic high-resolution CT findings, alongside systematic exclusion of infections, tumor progression, heart failure, or other etiologies. Severity is graded per the Common Terminology Criteria for Adverse Events (CTCAE) to guide therapeutic decisions. Core management principles include: (1) For drug-induced ILD[19]: immediate discontinuation of the suspected agent; intervention according to CTCAE grade—Grade 1 (asymptomatic) may warrant observation or drug suspension; Grade 2 (symptomatic) requires drug cessation and initiation of glucocorticoids (e.g., prednisone 1−2 mg/kg per day); Grades 3−4 (severe/life-threatening) necessitate hospitalization, intravenous methylprednisolone, and oxygen/respiratory support. Steroids should be tapered gradually to prevent recurrence. (2) For radiation pneumonitis[20]: symptomatic patients (≥ Grade 2) are similarly treated first-line with glucocorticoids (e.g., prednisone 1 mg/kg per day) alongside supportive care; effective pharmacotherapy for established radiation-induced pulmonary fibrosis is currently lacking, with management focusing on symptomatic oxygen therapy and support, while antifibrotic agents (e.g., nintedanib) remain under investigation.

The monitoring and prevention of chemoradiotherapy-associated interstitial pneumonia require a comprehensive strategy. Based on current guideline consensus[20,30], preventive measures involve a thorough pre-treatment assessment of patient risk factors (e.g., advanced age, smoking history, pre-existing lung disease, and prior thoracic radiation), completion of baseline chest high-resolution CT and pulmonary function tests; careful drug selection, avoiding known high-risk combinations for pulmonary toxicity (e.g., immune checkpoint inhibitors with specific targeted agents), and exercising heightened vigilance, particularly with concurrent radiotherapy. For monitoring, patient education should be enhanced during treatment to encourage prompt reporting of new or worsening symptoms such as cough and dyspnea; any suspicious symptoms should trigger immediate chest high-resolution CT to detect interstitial changes early. For asymptomatic patients, routine oncologic follow-up imaging frequency is suggested, but the interval should be shortened if any respiratory symptoms arise. Multidisciplinary collaboration is emphasized throughout to enable risk-stratified management and early intervention.

Despite recurrent interstitial pneumonia, severe outcomes were absent.  Unavailable detailed radiotherapy data obscures etiology, potentially linked to precision radiotherapy and localized injury, necessitating further clinical analysis. Therefore, combined therapy demands thorough risk assessment, monitoring, and pulmonary function testing. Immediate discontinuation of causative drugs is critical for DIIP. In this case, chest CT confirmed interstitial pneumonia. Initial glucocorticoid therapy achieved favorable clinical resolution, demonstrating its efficacy in symptom alleviation and pulmonary recovery[6]. Imaging confirmed radiation-induced interstitial pneumonia (RIIP) recurrence, but lacking significant symptoms suggests the chemo-radiotherapy strategy’s lung impact was manageable.

Conclusion

This case highlights the importance of maintaining a vigilant awareness of pulmonary adverse reaction symptoms during the comprehensive treatment of breast cancer patients. For patients who have previously experienced interstitial pneumonia, clinical decision-making should be more cautious, potentially requiring adjustments to chemotherapy dosages or the selection of drug regimens with lower pulmonary toxicity risks. Furthermore, it is particularly critical to enhance the combination of treatment monitoring and early intervention.

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The Author(s) 2026. This article is published by Higher Education Press at journal.hep.com.cn.