Institute of Life Science, Yinfeng Biological Group, Jinan, Shandong Province, China.
Jinan University, Jinan, Shandong Province, China.
Appl Biochem Biotechnol. 2022 Sep;194(9):3961-3973. doi: 10.1007/s12010-022-03946-0.
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.
循环肿瘤 DNA（ctDNA）与肿瘤负荷相关，并能早期检测乳腺癌的治疗反应和肿瘤遗传改变。新辅助化疗（NACT）已成为局部晚期乳腺癌（LABC）的标准治疗方法。本研究旨在探讨血浆 ctDNA 作为接受 NACT 治疗的 LABC 患者预后的预测标志物。共有 56 例 LABC 患者参与了这项研究。使用 100 个基因 panel-靶向捕获下一代测序来研究 ctDNA 突变。然后，患者接受标准的 NACT 治疗：阿霉素和环磷酰胺加紫杉醇（AC-T）或 AC-TH（AC-T+曲妥珠单抗）方案。通过 Miller-Payne 分级系统评估 NACT 的疗效。使用预测和权重模型筛选 NACT 的 ctDNA 点突变生物标志物。确定了 LABC 患者的 ctDNA 突变特征。对于非同义突变，排名前 5 的突变基因是 MTHFR（56 例中有 51 例，91.1%）、XPC（56 例中有 50 例，89.3%）、ABCB1（51 例中有 48 例，94.1%）、BRCA2（56 例中有 38 例，67.9%）和 XRCC1（56 例中有 38 例，67.9%）。此外，PIK3CA 和 TP53 的突变频率分别为 32.1%（56 例中有 18 例）和 26.8%（56 例中有 15 例）。预测模型表明，XRCC1 44055726（TG>）突变（56 例中有 25 例，44.6%）与 Miller-Payne 4-5 和 Miller-Payne 3-5 反应显著相关。而 mTOR 11249132（G>C）突变（56 例中有 23 例，41.1%）与 Miller-Payne 1-4 或 Miller-Payne 1-3 反应相关。此外，XRCC1 44055726（TG>）突变伴有 mTOR 野生型，可预测所有反应分类系统的 NACT 疗效良好。创建了区分良好的新辅助化疗效果（Miller-Payne 4-5）和较差效果（Miller-Payne 1-3）的 ROC 曲线，AUC 值为 0.77。我们的研究结果表明，XRCC1 44055726（TG>）的 ctDNA 突变可能是 LABC 中 NACT 治疗的阳性生物标志物，而 mTOR 11249132（G>C）突变可能与 NACT 耐药相关。
