PS5-06-02: Cdk4/6 inhibitor-induced interstitial lung disease: a rare but severe complication in breast cancer treatment

Abstract Introduction: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are a class of targeted therapies that inhibit two enzymes involved in regulating the cell cycle. CDK4/6 inhibitors are widely used in patients with hormone receptor-positive (HR), human epidermal growth factor receptor-2 (HER2) negative breast cancer for early-stage and metastatic breast cancer. While these therapies have improved clinical outcomes, they carry a risk of rare but serious adverse events, including interstitial lung disease (ILD)/pneumonitis. We present a case of a patient with CDK4/6 inhibitor-induced grade 4 pneumonitis and ILD, requiring consideration for lung transplantation. Clinical Case: A 61-year-old female with a medical history of hypothyroidism, hypertension, and hormone-receptor-positive breast cancer was found to have a 3 cm irregular spiculated right breast mass and enlarged right axillary lymph nodes. A core needle biopsy revealed invasive ductal carcinoma with confirmed involvement of the right axillary lymph node, estrogen-receptor positive (ER, 90%), progesterone-receptor positive (PR, 90%), HER-2 negative (1+), and Ki-67 20%. She was clinically staged as IIB (T2N1Mx), Oncotype DX score of 28, and negative genetic testing aside from an ATM VUS. She received four cycles of neoadjuvant docetaxel/cyclophosphamide followed by bilateral mastectomy with reconstruction in October 2023. Pathology from the right total mastectomy revealed pT2N2a disease with 6/10 positive lymph nodes. Postoperative course was complicated by a tissue expander infection requiring removal in December 2023. The patient completed adjuvant radiation therapy in March 2024 and began aromatase inhibitor, anastrozole in November 2023, and CDK 4/6 inhibitor, abemaciclib in April 2024. After six months of treatment, she developed acute hypoxic respiratory failure, requiring hospitalization in November 2024. Bronchoscopy with BAL and lung biopsy indicated focal fibrosis with acute and chronic inflammation without infection, granuloma, or malignancy. She was treated with oxygen, high-dose corticosteroids (methylprednisolone 1mg/kg daily), and three doses of infliximab for abemaciclib-induced pneumonitis. Abemaciclib was permanently discontinued, and she was discharged on a prednisone taper in December 2024. The patient has no history of smoking or prior lung injury. She was evaluated by the pulmonology team given her severe, chronic pulmonary fibrosis and advanced interstitial lung disease with worsening hypoxia and dry cough despite prolonged high doses of prednisone. Mycophenolate (MMF) was initiated as a steroid-sparing agent with both anti-inflammatory and anti-fibrotic effects. The patient is referred for lung transplantation evaluation in the setting of a serious, chronic, and irreversible lung disease with poor prognosis and increased risk for sudden, unpredictable, acute, and life-threatening exacerbations. Discussion: CDK4/6 inhibitors are used for HR-positive, HER2-negative breast cancer, with expanded use in high-risk early-stage disease following the NATALEE and monarchE trials. This drug class carries a rare yet life-threatening adverse event that requires early recognition and monitoring. A meta-analysis of 12 randomized trials (>16,000 patients) reported an increased incidence of ILD/pneumonitis in treated patients (1.6% vs. 0.7%; OR 2.12, 95% CI [1.57-2.86], P < 0.00001). The exact mechanisms underlying CDK4/6 inhibitor-induced pneumonitis and ILD remain unclear, and retrospective studies have found no significant correlation between ILD and risk factors such as smoking history, lung metastases, or prior thoracic radiotherapy. This emphasizes the need for early recognition and multidisciplinary management involving medical oncology, pulmonology, and infectious disease teams. Citation Format: S. A. Haddad, D. U. Portillo, A. M. Nambiar, M. J. Kim, V. Kaklamani, K. I. Lathrop, R. Pathapati. Cdk4/6 inhibitor-induced interstitial lung disease: a rare but severe complication in breast cancer treatment [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 PS5-06-02.