Targeted Sequencing of HER2-Positive Breast Cancer Mutations Revealed a Potential Association between PIK3CA and Trastuzumab Resistance.

Q2 Medicine Asian Pacific Journal of Cancer Prevention Pub Date : 2024-11-01 DOI:10.31557/APJCP.2024.25.11.4051

Asmaa Mohamed Mekhamer, Marwa Hanafi Saied, Dalia Abd Elmoaty Elneily, Tarek Abdel Halim El-Fayoumi, Doaa Ibrahim Hashad

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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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her2阳性乳腺癌突变的靶向测序揭示了PIK3CA与曲妥珠单抗耐药性之间的潜在关联。

背景：不同的分子亚型，包括her2阳性，已经在乳腺癌中被发现。HER2过表达触发下游信号通路，如PI3K/AKT/mTOR通路。直到最近，曲妥珠单抗在埃及被用作单一her2靶向治疗。然而，曲妥珠单抗耐药已被报道。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，我们的目标是扩大Her2 + BC的遗传学检查，以包括重要的癌基因和其他重要的癌症途径。方法：收集24例HER2+ BC埃及患者的福尔马林固定石蜡包埋标本，其中12例曲妥珠单抗开始治疗后2年及以上完全缓解，12例曲妥珠单抗开始治疗后2年内复发或发生转移的耐药患者。利用新一代测序技术进一步研究了17个基因热点区域的体细胞突变。结果：在所鉴定的变异总数（106个）中，PIK3CA是最常见的变异，耐药组的变异发生率高于反应组（P= 0.004）。耐药患者的PIK3CA突变频率高于反应性患者（P= 0.036）。此外，PIK3CA突变与病理完全反应（pCR）之间存在显著相关性（P=0.036）。耐药患者中大多数PIK3CA变异位于外显子9和20。PIK3CA变体His1047Tyr、Glu545Lys、His701Pro、Lys111Glu、Val344Gly和Tyr1021Cys仅在耐药患者中被发现，这表明它们与曲珠单抗耐药有关。结论：PIK3CA变异在HER2+ BC耐药患者中比在应答患者中更常见，PIK3CA突变与较低的pCR率有显著相关性。外显子9和20内的PIK3CA变异（分别为Glu545Lys和His1047Tyr）与曲妥珠单抗耐药相关。

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来源期刊

Asian Pacific Journal of Cancer Prevention 医学-肿瘤学

CiteScore

2.80

自引率

0.00%

发文量

779

审稿时长

3 months

期刊介绍： Cancer is a very complex disease. While many aspects of carcinoge-nesis and oncogenesis are known, cancer control and prevention at the community level is however still in its infancy. Much more work needs to be done and many more steps need to be taken before effective strategies are developed. The multidisciplinary approaches and efforts to understand and control cancer in an effective and efficient manner, require highly trained scientists in all branches of the cancer sciences, from cellular and molecular aspects to patient care and palliation. The Asia Pacific Organization for Cancer Prevention (APOCP) and its official publication, the Asia Pacific Journal of Cancer Prevention (APJCP), have served the community of cancer scientists very well and intends to continue to serve in this capacity to the best of its abilities. One of the objectives of the APOCP is to provide all relevant and current scientific information on the whole spectrum of cancer sciences. They aim to do this by providing a forum for communication and propagation of original and innovative research findings that have relevance to understanding the etiology, progression, treatment, and survival of patients, through their journal. The APJCP with its distinguished, diverse, and Asia-wide team of editors, reviewers, and readers, ensure the highest standards of research communication within the cancer sciences community across Asia as well as globally. The APJCP publishes original research results under the following categories: -Epidemiology, detection and screening. -Cellular research and bio-markers. -Identification of bio-targets and agents with novel mechanisms of action. -Optimal clinical use of existing anti-cancer agents, including combination therapies. -Radiation and surgery. -Palliative care. -Patient adherence, quality of life, satisfaction. -Health economic evaluations.