Molecular and cellular composition changes after neoadjuvant letrozole and palbociclib in early luminal breast cancer

The NeoPAL trial compared neoadjuvant letrozole-palbociclib (LP) with chemotherapy (CT) in 103 patients with high-risk early luminal breast cancer. At surgery, the Nanostring BC360™ proliferation score was reduced in both arms, together with a lower median Ki67 expression in the LP arm than in the CT arm (1% (IQR 0-5) vs 5% (IQR 2-15) and upregulation of immune-related signatures (all p&lt;0.01). Overall, there was very little difference in the changes analyzed in the letrozole and palbociclib arm compared to the CT arm, even in signatures that would be expected of response to estrogen - CDK4/6 manipulation. Deconvolution of bulk RNA-seq data revealed high content at baseline in cancer cells, immunosuppressive cancer-associated fibroblasts, FOXP3+ CD4+ regulatory T lymphocytes and TREM2+ macrophages. In contrast, myoepithelial cells, normal-like fibroblasts, FOLR2+ macrophages and SELL+ CD4+ T lymphocytes accumulated after treatment (p: 0.046 to 7.2e-07). All changes were similar between the LP and CT arms. A low-ROR score was observed at surgery in 63.3% and 43.5% of patients in both LP and CT arms, respectively (p=0.10). No 3-year breast cancer-specific survival event was observed in these patients. These data demonstrate that LP is as effective as CT, and provide a rationale for chemotherapy-sparing trials in this settingNeoPAL试验在103例高危早期管腔型乳腺癌患者中，对比了新辅助来曲唑-帕博西尼（LP）方案与化疗（CT）方案的疗效。手术阶段，两组患者的Nanostring BC360™增殖评分均有所降低，且LP组的中位Ki67表达水平低于CT组（1%[四分位距0~5] vs 5%[四分位距2~15]），同时免疫相关特征表达上调（所有p<0.01）。总体而言，与CT组相比，LP组在来曲唑-帕博西尼治疗后分析的各项变化差异极小，即便在预期可反映雌激素-CDK4/6调控应答的特征中亦是如此。批量RNA测序（bulk RNA-seq）数据的反卷积分析显示，基线状态下样本中癌细胞、免疫抑制性癌相关成纤维细胞、FOXP3阳性CD4阳性调节性T淋巴细胞及TREM2阳性巨噬细胞占比颇高。与之相反，治疗后肌上皮细胞、正常样成纤维细胞、FOLR2阳性巨噬细胞及SELL阳性CD4阳性T淋巴细胞出现富集（p值范围：0.046至7.2×10^-7）。上述变化在LP组与CT组间均无显著差异。手术时，LP组与CT组患者中检出低复发风险评分（ROR score）的比例分别为63.3%与43.5%（p=0.10）。该类患者在3年内未出现乳腺癌特异性生存事件。本研究数据证实LP方案疗效与CT方案相当，可为该类人群开展去化疗临床试验提供理论依据。