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 cel...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 effi-cacy 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 in-hibitors 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 radio-surgery 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 ex-pression 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 clin-ical 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 mech-anism and validate PDJ amplification as a biomarker for clinical response to PD-1/PD-L1 inhibitor-containing therapy in patients with mTNBC.展开更多
文摘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 effi-cacy 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 in-hibitors 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 radio-surgery 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 ex-pression 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 clin-ical 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 mech-anism and validate PDJ amplification as a biomarker for clinical response to PD-1/PD-L1 inhibitor-containing therapy in patients with mTNBC.
