09/01/2021

Durable Clinical Response to the Multidisciplinary Management of Neurosurgery, Radiation and Chemoimmunotherapy in a Patient With PD-L1/PD-L2/JAK2 (PDJ)-Amplified, Refractory Triple-Negative Breast Cancer

Journal of the National Cancer Center Manuscript
Authors Hongyuan Zhao, Weijie Ma, Ruben C. Fragoso, Griffith R. Harsh IV, Arya Ashok, Tianhong Li

Patients with refractory metastatic triple-negative breast cancer (mTNBC) and symptomatic brain metastases have poor prognosis and are challenging to treat. The addition of an programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitor (pembrolizumab or atezolizumab) to first line chemotherapy has prolonged survivals in mTNBC patients with PD-L1-positive tumor and/or tumor-infiltrating immune cells. The clinical efficacy of the chemoimmunotherapy combination in patients with refractory mTNBC, especially brain metastasis, is unknown. Co-amplification of PD-L1, PD-L2, and Janus kinase 2 (PD-L1/PD-L2/JAK2) genes (PDJ amplification) is associated with high PD-L1 protein expression and a 65-87% response rate to PD-1/PD-L1 inhibitors in patients with lymphomas. But the utility of PDJ amplification as a biomarker predictive of response to PD-1/PD-L1 inhibitors is unknown for mTNBC patients. Here, we report a 46-year-old woman who had rapid tumor progression in the brain and lung within 3 months after chemotherapy, neurosurgery, and gamma knife stereotactic radiosurgery for brain metastasis. Next-generation sequencing of her brain metastasis specimen revealed 9 copies of PDJ amplification and a tumor mutational burden of 5 mutations per megabase. Although high PDJ mRNA expression levels were detected, PD-L1 protein expression was negative on tumor cells and 10% on tumor-associated immune cells. After the debulking brain tumor resection, she received pembrolizumab monotherapy, whole brain radiation, and then atezolizumab and nab-paclitaxel with good intracranial and extracranial responses for >16 months. To the best of our knowledge, this is the first report that PDJ amplification is associated with durable clinical response to the PD-1/PD-L1 inhibitor-containing, multidisciplinary management in a patient with refractory, PD-L1 protein-negative, PDJ-amplified mTNBC. Further study is warranted to understand the underlying mechanism and validate PDJ amplification as a biomarker for clinical response to PD-1/PD-L1 inhibitor-containing therapy in patients with mTNBC.

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