术前新辅助治疗可为诊断时无法手术的早期乳腺癌患者提供手术机会，并可选择保乳手术而非乳房切除术。NeoALTTO和CHER-LOB研究表明，HER1和HER2酪氨酸激酶可逆抑制剂拉帕替尼可显著提高HER2单克隆抗体曲妥珠单抗＋新辅助化疗的病理完全缓解率。吡咯替尼是中国原创的HER1、HER2、HER4酪氨酸激酶不可逆抑制剂。既往研究证实，对于HER2阳性晚期乳腺癌联合卡培他滨化疗时，吡咯替尼显著优于拉帕替尼。小样本研究也支持吡咯替尼＋曲妥珠单抗＋化疗用于HER2阳性早期乳腺癌术前新辅助治疗。此外，肿瘤免疫微环境可影响肿瘤进展和治疗效果，肿瘤浸润淋巴细胞是浸润于肿瘤组织的单核免疫细胞，新辅助治疗前肿瘤浸润淋巴细胞高水平患者的病理完全缓解率显著较高，有助于预测新辅助治疗效果。
2022年2月27日，欧洲癌症治疗研究组织《欧洲癌症杂志》在线发表郑州大学附属肿瘤医院（河南省肿瘤医院）刘真真、王承正、陈秀春、朱久俊、孙献甫、夏庆欣、卢振铎、乔江华、王艺、闫敏、新乡市中心医院周勇、安阳市肿瘤医院王海学等学者的Panphila研究报告，探讨了HER2阳性早期乳腺癌术前吡咯替尼＋多西他赛＋卡铂＋曲妥珠单抗新辅助治疗的有效性和安全性，以及肿瘤浸润淋巴细胞对病理完全缓解的预测作用。
该多中心单组非盲二期临床研究于2019年2月26日～2020年8月12日从3家医院入组HER2阳性早期（T2-3 N0-3 M0）乳腺癌术前患者75例，给予吡咯替尼＋多西他赛＋卡铂＋曲妥珠单抗共计6个周期，每个周期21天，随后手术。主要终点为病理完全缓解率。通过苏木精伊红染色和多重免疫组织化学评定肿瘤浸润淋巴细胞。
结果，3例患者失访且未手术，3例患者接受其他靶向治疗，61例患者完成6个周期治疗，1例患者缺少安全性数据。
对于接受研究方案治疗后完成手术的69例患者，其中38例（55.1%）获得病理完全缓解。
对于安全性数据完整的74例患者，≥3级不良事件主要包括腹泻、贫血、呕吐、血小板计数减少，发生率分别为43.2%、37.8%、16.2%、10.8%。未发生治疗相关死亡。
根据单一免疫亚群分析，病理完全缓解与治疗前间质CD20、CD8、CD4阳性肿瘤浸润淋巴细胞显著相关。
根据间质免疫标志物未分类层次聚类，确定间质CD20、CD8、CD4、FOXP3阳性免疫细胞浸润与病理完全缓解独立相关。
Eur J Cancer. 2022 Feb 27;165:157-168. Online ahead of print.
Pathological response and predictive role of tumour-infiltrating lymphocytes in HER2-positive early breast cancer treated with neoadjuvant pyrotinib plus trastuzumab and chemotherapy (Panphila): a multicentre phase 2 trial.
Liu Z, Wang C, Chen X, Zhu J, Sun X, Xia Q, Lu Z, Qiao J, Zhou Y, Wang H, Wang Y, Yan M.
Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China; Xinxiang Central Hospital, Xinxiang, Henan, China; Anyang Tumour Hospital, Anyang, Henan, China.
HIGHLIGHTS
This study evaluated pyrotinib plus trastuzumab as neoadjuvant therapy for human epidermal growth factor receptor 2+ early breast cancer.
The predictive role of immune cell subpopulations was also investigated.
The pathological complete response rate was 55.1%, and the toxicity was manageable.
An association of baseline stromal-CD20+, CD8+, and CD4+ tumour infiltrating lymphocytes with pathological complete response was found.
PURPOSE: Panphila evaluated pyrotinib plus trastuzumab, docetaxel and carboplatin as neoadjuvant therapy for early breast cancer (BC), and investigated the predictive role of immune cell subpopulations.
PATIENTS AND METHODS: In this multicentre phase 2 study, patients with human epidermal growth factor receptor 2-positive, stage T2-3N0-3M0 BC received pyrotinib 400 mg once daily plus docetaxel (75 mg/m2, day 1), carboplatin (6 mg/mL/min, day 1) and trastuzumab (8 mg/kg loading dose and 6 mg/kg maintenance dose, day 1) for 6 cycles of 21 days each. Simon's 2-stage design was adopted. The primary end-point was pathological complete response (pCR, ypT0/is ypN0) rate. Tumour-infiltrating lymphocytes (TILs) were assessed by haematoxylin and eosin staining and multiplex immunohistochemistry.
RESULTS: In the modified intention-to-treat population (n = 69), 38 patients (55.1%) achieved pCR. In the safety population (n = 74), the most common grade ≥3 adverse events were diarrhoea (43.2%), anaemia (37.8%), vomiting (16.2%) and platelet count decrease (10.8%). No treatment-related deaths occurred. Analysis of single immune subpopulations revealed a significant association of pCR with higher baseline infiltration by stromal (s)-CD20+, s-CD8+ and s-CD4+ TILs. Unsupervised hierarchical clustering of stromal immune markers identified a group of patients characterised by high s-CD20+, s-CD8+, s-CD4+ and s-FOXP3+ immune cells infiltration, which was independently associated with pCR.
CONCLUSION: Neoadjuvant pyrotinib plus trastuzumab-based chemotherapy exhibits promising efficacy and manageable toxicity in patients with human epidermal growth factor receptor 2-positive early BC, and thus phase 3 trials are warranted. Our findings also contribute to understanding the potential role of the immune microenvironment in response to neoadjuvant pyrotinib-based therapy.
KEYWORDS: Breast cancer; Human epidermal growth factor receptor 2; Neoadjuvant therapy; Pathological complete response; Pyrotinib; Tumour-infiltrating lymphocytes
PMID: 35235873
DOI: 10.1016/j.ejca.2022.01.022
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