The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R² = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R² = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.

乳腺癌对新辅助治疗的生物学反应在文献中代表性不足，这为探索接受治疗的肿瘤的基因组和微环境调节提供了机会之窗。在这里，我们描述了 35 名接受新辅助艾日布林治疗 (SOLTI-1007 NEOERIBULIN-NCT01669252) 的 HER2 阴性原发性乳腺癌患者在不同时间点的突变、基因表达、通路富集和肿瘤浸润淋巴细胞 (TIL) 动态。全外显子组数据（ N = 88 个样本）生成突变谱和候选新抗原，并与 RNA-Nanostring 545 基因表达（ N = 96 个样本）和基质 TIL（ N = 105 个样本）一起进行分析。肿瘤突变负荷在基线时因患者而异，但在每位患者的采样时间点之间没有变化。突变特征在肿瘤中并不总是保守的。当亚克隆突变的百分比较低时，有一种反应几率更高、复发风险更低的趋势，这表明同质性更强的肿瘤可能对新辅助治疗有更好的反应。很少有驱动突变（5.1%）产生假定的新抗原。突变和新抗原负载呈正相关（ R ² = 0.94， p = <0.001）；新抗原负荷与基质 TIL 呈弱相关（ R ² = 0.16， p = 0.02）。在良好反应者中使用艾日布林 12 周后，发现与免疫浸润相关的途径丰富，程序性细胞死亡表达减少。 在良好反应组中，VEGF 随着时间的推移而下调，而FABP5 （上皮间质转化 (EMT) 的诱导剂）在复发病例中上调 ( p < 0.05)。突变异质性、亚克隆结构和免疫微环境的改善以及缺氧和 EMT 的重塑可能会影响对新辅助治疗的反应。