Department of Clinical and Chemical Pathology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
Department of Surgical Oncology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
Asian Pac J Cancer Prev. 2024 Nov 1;25(11):4051-4059. doi: 10.31557/APJCP.2024.25.11.4051.
Different molecular subtypes, including HER2-positive, have been identified in breast cancer. The overexpression of HER2 triggers downstream signaling pathways such as the PI3K/AKT/mTOR pathway. Until recently, trastuzumab has been used as a single HER2-targeted therapy in Egypt. However, resistance to trastuzumab has been reported. Previous studies have demonstrated the genetic variants that affect the trastuzumab response. However in Egypt, few studies investigated molecular biomarkers such as p53 that might affect the trastuzumab response. Therefore, we aimed to extend the genetics workup of Her2 + BC to include important oncogenes and other vital cancer pathways.
Formalin-fixed paraffin-embedded samples were collected from 24 HER2+ BC Egyptian patients, twelve patients in complete remission for 2 years or more from the start of trastuzumab and twelve resistant patients who relapsed or developed metastasis within 2 years from the start of trastuzumab. Somatic mutations in hotspot regions of 17 genes were further investigated using next-generation sequencing.
Among the total number of identified variants (106 variants), PIK3CA showed the most frequent variants, with more variants occurring in the resistant group than in the responsive group (P= 0.004). The frequency of PIK3CA mutations was greater in resistant patients than in responsive patients (P= 0.036). Additionally, there was a significant correlation between PIK3CA mutations and pathological complete response (pCR) (P=0.036). Most of PIK3CA variants in resistant patients were detected in exon 9 and 20. The PIK3CA variants His1047Tyr, Glu545Lys, His701Pro, Lys111Glu, Val344Gly and Tyr1021Cys were found only in the resistant patients, suggesting that they are associated with trastuzumab resistance.
PIK3CA variants were more frequent in resistant HER2+ BC patients than in responsive patients, with a significant correlation between PIK3CA mutation and a lower pCR rate. PIK3CA variants within exon 9 and 20 (such as Glu545Lys and His1047Tyr respectively) were associated with trastuzumab resistance.
乳腺癌存在不同的分子亚型，包括 HER2 阳性。HER2 的过表达会触发下游信号通路，如 PI3K/AKT/mTOR 通路。直到最近，曲妥珠单抗一直被用作埃及的单一 HER2 靶向治疗药物。然而，已经报道了对曲妥珠单抗的耐药性。先前的研究已经证明了影响曲妥珠单抗反应的遗传变异。然而，在埃及，很少有研究调查可能影响曲妥珠单抗反应的分子生物标志物，如 p53。因此，我们旨在扩展 Her2+BC 的遗传学研究，包括重要的癌基因和其他重要的癌症途径。
从 24 名 HER2+BC 埃及患者中收集福尔马林固定石蜡包埋样本，其中 12 名患者在曲妥珠单抗开始治疗 2 年或以上后完全缓解，12 名耐药患者在曲妥珠单抗开始治疗 2 年内复发或发生转移。使用下一代测序进一步研究了 17 个热点区域的体细胞突变。
在总共鉴定出的变异（106 个变异）中，PIK3CA 显示出最频繁的变异，耐药组的变异比应答组多（P=0.004）。耐药患者的 PIK3CA 突变频率高于应答患者（P=0.036）。此外，PIK3CA 突变与病理完全缓解（pCR）之间存在显著相关性（P=0.036）。耐药患者中检测到大多数 PIK3CA 变异位于外显子 9 和 20。仅在耐药患者中发现 PIK3CA 变异 His1047Tyr、Glu545Lys、His701Pro、Lys111Glu、Val344Gly 和 Tyr1021Cys，提示它们与曲妥珠单抗耐药有关。
与应答患者相比，耐药的 HER2+BC 患者中 PIK3CA 变异更为频繁，PIK3CA 突变与较低的 pCR 率之间存在显著相关性。外显子 9 和 20 内的 PIK3CA 变异（如 Glu545Lys 和 His1047Tyr）与曲妥珠单抗耐药有关。
