Dong Menghao, Shan Benjie, Han Xinghua, Zhao Xiaotian, Wang Fufeng, Zhu Liuqing, Ou Qiuxiang, Ma Xiaopeng, Pan Yueyin
Department of Medical Oncology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, China.
Front Oncol. 2022 Apr 4;11:784985. doi: 10.3389/fonc.2021.784985. eCollection 2021.
Neoadjuvant chemotherapy (NAC) has been expanded to hormone receptor (HR) positive breast cancer (BC) patients with operable disease, to increase the likelihood of breast-conserving surgery. Genomic profiling at baseline would reveal NAC response relevant genomic features and signaling pathways, guiding clinical NAC utilization based on patients' genomic characteristics.
We prospectively studied stage II/III BC patients who were eligible for breast-conserving surgery. Patients received epirubicin and cyclophosphamide for 4 cycles, followed by another 4-cycle docetaxel, and human epidermal growth factor receptor (HER2) positive patients were additionally treated with herceptin when using docetaxel (EC-T(H)). NAC responses were evaluated as pathologic complete response (pCR) or non-pathologic complete response (non-pCR). Genomic features related to NAC responses were identified by profiling baseline tumor tissues sampled one day before NAC, using whole-exome sequencing. Differentially expressed genes and up-/down-regulated pathways were investigated by performing RNA-sequencing.
A total of 25 stage II/III BC patients were enrolled, including 5 patients ultimately evaluated as pCR and 20 patients evaluated as non-pCR. (48%) and (40%) mutations were enriched in patients not achieving pCR. Mutated phosphatidylinositol-3-kinase-AKT (PI3K-AKT) pathway and homologous recombinational repair pathway were also more frequently observed in patients evaluated as non-pCR. Significant arm-level amplifications (8q24.23 and 17q12) and deletions (1p32.2, 4p14, 7q11.23, 10q21.3, 11q23.3, etc.) were identified among patients not achieving pCR, while patients achieving pCR displayed no significant copy number alterations. Significantly up-regulated expression of PI3K-AKT pathway genes was also detected among patients failed to achieve pCR, compared to patients achieving pCR.
Compared to BC patients achieving pCR to NAC, aberrant activation of PI3K-AKT pathway genes were more frequently observed in patients not achieving pCR, consistent with the significant up-regulation of PI3K-AKT pathway gene expression in the non-pCR subgroup. Together, these findings indicate that upregulated PI3K-AKT pathway serves as a potential indicator of lack of response to NAC in stage II/III BC patients, and other effective therapeutic options are urgently needed for those resistant patients.
新辅助化疗（NAC）已扩展至患有可手术疾病的激素受体（HR）阳性乳腺癌（BC）患者，以提高保乳手术的可能性。基线时的基因组分析将揭示与NAC反应相关的基因组特征和信号通路，从而根据患者的基因组特征指导临床NAC的使用。
我们前瞻性地研究了符合保乳手术条件的II/III期BC患者。患者接受表柔比星和环磷酰胺治疗4个周期，随后再接受4个周期的多西他赛治疗，HER2阳性患者在使用多西他赛时额外接受赫赛汀治疗（EC-T(H)）。NAC反应被评估为病理完全缓解（pCR）或非病理完全缓解（非pCR）。通过对NAC前一天采集的基线肿瘤组织进行全外显子测序来确定与NAC反应相关的基因组特征。通过RNA测序研究差异表达基因和上调/下调的信号通路。
共纳入25例II/III期BC患者，其中5例最终评估为pCR，20例评估为非pCR。未达到pCR的患者中富集了（48%）和（40%）的突变。在评估为非pCR的患者中也更频繁地观察到磷脂酰肌醇-3-激酶-AKT（PI3K-AKT）通路和同源重组修复通路的突变。在未达到pCR的患者中发现了显著的臂级扩增（8q24.23和17q12）和缺失（1p32.2、4p14、7q11.23、10q21.3、11q23.3等），而达到pCR的患者未显示出显著的拷贝数改变。与达到pCR的患者相比，在未达到pCR的患者中也检测到PI3K-AKT通路基因的显著上调表达。
与对NAC达到pCR的BC患者相比，未达到pCR的患者中更频繁地观察到PI3K-AKT通路基因的异常激活，这与非pCR亚组中PI3K-AKT通路基因表达的显著上调一致。总之，这些发现表明PI3K-AKT通路的上调是II/III期BC患者对NAC无反应的潜在指标，对于那些耐药患者迫切需要其他有效的治疗选择。
