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Identifying Circulating Tumor DNA Mutations Associated with Neoadjuvant Chemotherapy Efficacy in Local Advanced Breast Cancer

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Abstract

Circulating tumor DNA (ctDNA) correlates with tumor burden and provides early detection of treatment response and tumor genetic alterations in breast cancer. Neoadjuvant chemotherapy (NACT) has become standard therapy for local advanced breast cancer (LABC). The aim of our study was to investigate plasma ctDNA as a prognostic marker for outcome in patients with LABC treated with NACT. A total of 56 patients with LABC were involved in this study. ctDNA mutations were investigated by using a 100 gene panel-target capture next-generation sequencing. The patients then received standard NACT therapy: adriamycin and cyclophosphamide and paclitaxel (AC-T) or AC-TH (AC-T+ Trastuzumab) regimen. The efficacy of NACT was evaluated by Miller-Payne grading system. A predictive and weight model was used to screen ctDNA point mutation biomarkers for NACT. The ctDNA mutational profile of LABC patients was identified. For nonsynonymous mutations, the top 5 mutated genes were MTHFR (51/56, 91.1%), XPC (50/56, 89.3%), ABCB1 (48/51, 94.1%), BRCA2 (38/56, 67.9%), and XRCC1 (38/56, 67.9%). In addition, the mutation frequencies of PIK3CA and TP53 were 32.1% (18/56) and 26.8% (15/56), respectively. The predictive model indicated that XRCC1 44055726 (TG>-) mutation (25/56, 44.6%) was significantly associated with Miller-Payne 4-5 and Miller-Payne 3-5 responses. While mTOR 11249132(G>C) mutation (23/56, 41.1%) was associated with Miller-Payne 1-4 or Miller-Payne 1-3 responses. Furthermore, XRCC1 44055726 (TG>-) accompanied by mTOR wild type predicted a good NACT efficacy in all response classification systems. The ROC curves to discriminate good neoadjuvant chemotherapy efficiency (Miller-Payne 4-5) and poor efficiency (Miller-Payne 1-3) were created, and AUC value was 0.77. Our results suggested that ctDNA mutation of XRCC1 44055726 (TG>-) might be a positive biomarker for NACT therapy in LABC, while mTOR 11249132(G>C) mutation was potentially associated with NACT resistance.

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Funding

This study was supported by the Science and Technology Key Project of Hainan Provincial Department of Science and Technology (NO. ZDYF2018127) and Science and Technology Project of Jilin Provincial Department of Science and Technology (NO. 20170311005YY).

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    Authors and Affiliations

    1. Institute of Life Science, Yinfeng Biological Group, Jinan, Shandong Province, China

      Benjie Wei, Guirong Zhang & Hongbin Zuo

    2. Jinan University, Jinan, Shandong Province, China

      Benjie Wei & Dong Song

    3. Jilin University, Changchun, 130000, China

      Yanhong Shan

    4. Yinfeng Gene Technology Co., Ltd, Jinan, 250000, China

      Zhaoli Du & Qianqian Zhang

    5. Changchun Obstetrics-Gynecology Hospital, Changchun, 130000, China

      Chunxia Yin

    6. Hainan Boao Yinfeng Kangyang International Hospital Co., Ltd., Qionghai, 571400, Hainan Province, China

      Haifeng Lin

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    1. Benjie Wei
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    Contributions

    XW and ZF performed the experiments, analyzed the data, and wrote the manuscript. BY and HM performed the experiments and edited the manuscript. YZ, CJ, and GT provided reagents, facilities, and funding and edited the manuscript.

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    Correspondence to Dong Song or Hongbin Zuo.

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    Benjie Wei, Yanhong Shan, and Zhaoli Du are co-first authors.

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    Wei, B., Shan, Y., Du, Z. et al. Identifying Circulating Tumor DNA Mutations Associated with Neoadjuvant Chemotherapy Efficacy in Local Advanced Breast Cancer. Appl Biochem Biotechnol 194, 3961–3973 (2022). https://doi.org/10.1007/s12010-022-03946-0

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