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We previously reported the results of a phase II trial of anti‐PD‐1 antibody plus anti‐vascular endothelial growth factor receptor 2 inhibitors and eribulin in heavily pretreated advanced triple‐negative breast cancer with a favorable objective response rate (ORR) of 37.0% (NCT04303741). Here we report updated survival outcomes and serum metabolite changes of the study. Proton nuclear magnetic resonance spectroscopy was used to detect metabolite dynamics and explore biomarkers for response. We found that treatment‐sensitive patients had higher very low‐density lipoprotein‐related metabolite expression at baseline. A lipid proteomics model consisting of six metabolites predicted ORR and progression‐free survival at 6 months with area under the receiver operating characteristic curves of 0.88 and 0.87, respectively. Serum asparagine and sarcosine concentrations were significantly higher after treatment in treatment‐resistant patients. In conclusion, we constructed a model consisting of six metabolites to identify patients who benefit more from the triplet treatment, and asparagine and sarcosine may be associated with treatment resistance. [ABSTRACT FROM AUTHOR]

Because of its insensitivity to existing radiotherapy, namely chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/β-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated wnt/β-catenin pathway of TNBC tissues, lnc-WAL (wnt/β-catenin associated lncRNA; WAL) was selected as the top upregulated lncRNA in wnt/β-catenin pathway activation compared with the inactivation group. RIP-seq was used to compare the β-catenin and IgG groups, where lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted EMT, the proliferation, migration and invasion of breast cancer stem cells (BCSCs), and TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via Axin-mediated phosphorylation at serine 45. Subsequently, β-catenin accumulated in the nucleus and activated the target genes. Importantly, wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/Axin/β-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/β-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for TNBC patients.

We previously reported the results of a phase II trial of anti-PD-1 antibody plus anti-vascular endothelial growth factor receptor 2 inhibitors and eribulin in heavily pretreated advanced triple-negative breast cancer with a favorable objective response rate (ORR) of 37.0% (NCT04303741). Here we report updated survival outcomes and serum metabolite changes of the study. Proton nuclear magnetic resonance spectroscopy was used to detect metabolite dynamics and explore biomarkers for response. We found that treatment-sensitive patients had higher very low-density lipoprotein-related metabolite expression at baseline. A lipid proteomics model consisting of six metabolites predicted ORR and progression-free survival at 6 months with area under the receiver operating characteristic curves of 0.88 and 0.87, respectively. Serum asparagine and sarcosine concentrations were significantly higher after treatment in treatment-resistant patients. In conclusion, we constructed a model consisting of six metabolites to identify patients who benefit more from the triplet treatment, and asparagine and sarcosine may be associated with treatment resistance., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)