PIK3CA突变可影响HER2阳性乳腺癌术前吡咯替尼＋曲妥珠单抗＋新辅助化疗病理完全缓解率

　　2020年，陆军军医大学第一附属医院（西南医院）首次证实HER2阳性早期乳腺癌术前吡咯替尼＋曲妥珠单抗＋新辅助化疗有效，病理完全缓解率达73.7%。不过，仍有26.3%的患者未达病理完全缓解，故有必要对其影响因素开展进一步分析。

　　2022年11月2日，英国癌症研究中心《英国癌症杂志》在线发表陆军军医大学西南医院史绮韵、徐宏俊成、罗韬、葛佳、刘峰、蓝洋、陈庆秋、唐鹏、范林军、陈莉、梁燕、王明浩、胡滢、张毅、卞修武、齐晓伟、姜军等学者的研究报告，进一步探索了HER2阳性早期乳腺癌术前吡咯替尼＋曲妥珠单抗＋新辅助化疗患者的基因组特征。

ChiCTR1900022293: A multi-center prospective single-arm trial for neoadjuvant chemotherapy with pyrotinib plus trastuzumab for HER2-positive breast cancer

　　该单中心单组非对照前瞻研究于2019年2月～2021年3月从陆军军医大学西南医院入组HER2阳性早期乳腺癌术前吡咯替尼＋曲妥珠单抗＋新辅助化疗患者50例，通过二代测序（大规模平行测序）对手术切除肿瘤存档标本425个癌症相关基因特征进行分析，探索肿瘤生物学标志物与术后病理完全缓解的关联。

　　结果，45例患者完成新辅助化疗和最终手术，其中26例（58%）达到病理完全缓解。

　　在全部驱动基因突变中，筛选出与病理完全缓解有显著关联的PIK3CA突变。

　　PIK3CA野生型与突变型患者相比，病理完全缓解率显著较高（80.8%比26.3%，P=0.00057），经多重比较调整后仍然显著（调整后P=0.024）。

　　亚组分析表明，激素受体阳性与阴性患者相比，病理完全缓解率显著较低，尤其PIK3CA突变型患者。

　　随后，该研究将临床特征、遗传生物学标志物或两者联合建立逻辑回归模型分析病理完全缓解预测价值，两者联合模型真假阳性率曲线下面积最高，达到0.912（95%置信区间：0.827～0.997）。

　　因此，该研究数据表明，PIK3CA突变激活的HER2阳性乳腺癌不太可能对吡咯替尼＋曲妥珠单抗＋新辅助化疗获益，可能需要联合PI3K抑制剂，故有必要进一步开展多中心大样本随机对照研究进行验证。

相关链接

• 全球首项吡咯替尼治疗早期乳腺癌研究
• 吡咯替尼＋曲妥珠单抗术前治疗乳腺癌
  

Br J Cancer. 2022 Nov 2. IF: 9.075

PIK3CA mutations are associated with pathologic complete response rate to neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

Shi Q, Xuhong J, Luo T, Ge J, Liu F, Lan Y, Chen Q, Tang P, Fan L, Chen L, Liang Y, Wang M, Hu Y, Zhang Y, Bian X, Qi X, Jiang J.

Southwest Hospital, Army Medical University, Chongqing, China; Shigatse Branch, Xinqiao Hospital, Army Medical University, Shigatse, China.

BACKGROUND: Neoadjuvant treatment with a dual anti-human epidermal growth factor receptor 2 (HER2) blockade with pyrotinib and trastuzumab has been shown to be effective for HER2-positive breast cancer.

METHODS: The genomic characteristics of 425 cancer-related genes from the archived tumour blocks of 50 patients enrolled in a prospective neoadjuvant pyrotinib and trastuzumab plus chemotherapy clinical trial (ChiCTR1900022293) were assessed by next-generation sequencing (NGS). The relationship between tumour biomarkers and the postoperative pathological complete response (pCR) were explored.

RESULTS: Forty-five patients completed neoadjuvant chemotherapy and final surgery, of which 26 (58%) achieved a pCR. Among all driver gene mutations, PIK3CA mutation was screened out for having a significant relationship with the treatment response. The pCR rate of patients with wild-type PIK3CA was significantly higher than patients with mutated PIK3CA (80.8% vs. 26.3%; P = 0.00057), and remained significant after a multiple comparison adjustment (Padjusted = 0.024). We further evaluated the predictive value with logistic regression model of clinical features, genetic biomarkers or both, an AUC of 0.912 (95% CI: 0.827-0.997) was achieved in the integrated model.

CONCLUSIONS: Our data suggest that HER2-positive breast cancers with activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy.

PMID: 36323880

DOI: 10.1038/s41416-022-02021-z