Abstract Background: Leptomeningeal disease (LMD) is a rare complication occurring in up to 5% of breast cancer patients and is associated with a poor prognosis. In a large institutional study of 233 patients with LMD, the median overall survival for those with HR+/HER2− disease was 3.7 months, despite multimodal therapy. Standard treatments include intrathecal chemotherapy and CNS radiation; however, no consensus guidelines or randomized trials exist as most patients are excluded from clinical trials due to poor performance status. Systemic therapy has been associated with modest survival benefits, though responses remain unpredictable. Here, we report a case of LMD in a HR+/HER2- metastatic breast cancer patient with initial poor performance status who has achieved sustained functional recovery with endocrine and CDK4/6 inhibitor therapy alone. Case Presentation: A 76-year-old woman with hypertension and hyperlipidemia presented with fatigue, constipation, and dizziness. CT imaging revealed a soft tissue mass involving the uterus, adnexa, bladder, and left ureter with resulting hydroureteronephrosis. Further workup showed extensive metastatic disease, including osseous metastases, omental/peritoneal carcinomatosis, nodal involvement, and soft tissue metastases to the gluteal and paraspinal musculature, as well as the left breast. MRI brain and spine performed for evaluation of altered mental status demonstrated leptomeningeal disease. Right inguinal lymph node biopsy revealed metastatic carcinoma consistent with breast primary (ER 99%, PR 80-90%, HER2 IHC 0, Ki-67 50%). A left breast biopsy confirmed invasive lobular carcinoma. Subsequently, the patient presented to the MD Anderson emergency room for dyspnea on exertion and right shoulder pain. The patient was noted to be bed bound consistent with an ECOG performance status of 4 and had an early-stage sacral wound. Further evaluation revealed left pulmonary emboli and a large right sided pleural effusion. She underwent thoracentesis with pleural studies revealing malignant cells consistent with adenocarcinoma favoring breast primary. Based on the right choice trial, the patient was started on an aromatase inhibitor and CDK 4/6 inhibitor in August of 2023. When considering a CDK inhibitor, the decision was made to utilize palbociclib based on the side effect profile. Additionally, zoledronic acid was initiated for her diffuse osseous disease. After 22 months, the patient remains on first-line therapy with anastrozole and palbociclib. MRI Brain, Bone Scan, and CT Abdomen and Pelvis show stable disease. She has demonstrated remarkable functional recovery, evidenced by her transition to an ECOG of 0 with resolution of her prior sacral wound- all without CNS-directed therapy. Discussion: This case highlights an unusual response of LMD in HR+/HER- breast cancer to systemic therapy with an aromatase inhibitor and CDK 4/6 inhibitor. Emerging evidence suggests that CDK inhibitors may have meaningful central nervous system activity in patients with HR+/HER2− breast cancer. In a prospective phase II trial, abemaciclib achieved CSF and brain metastasis concentrations well above the IC50 for CDK4/6 inhibition and was associated with clinical benefit in a subset of patients with brain and leptomeningeal metastases. Our patient’s recovery challenges the conventional guidelines regarding recommendations of intrathecal and/or radiation therapy for LMD and supports further investigation into systemic CDK4/6 inhibition for select patients. Citation Format: E. Sargent, A. Buzdar, D. Ramirez. A Functional Reversal of Leptomeningeal Disease without CNS Directed Therapy 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 PS5-06-23.
Sargent et al. (Tue,) studied this question.