PDF(Pubmed)
Abstract：
although being central for the biology and druggability of hormone-receptor positive, HER2 negative metastatic breast cancer (MBC), ESR1 and PIK3CA mutations are simplistically dichotomized as mutated or wild type in current clinical practice.
The study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among clinical characteristics, pathway classification, and ESR1/PIK3CA codon variants were explored.
The results showed a differential pattern of associations for ESR1 and PIK3CA codon variants in terms of co-occurring pathway alterations patterns of metastatic dissemination, and prognosis. ESR1 537 was associated with SNVs in the ER and RAF pathways, CNVs in the MYC pathway and bone metastases, while ESR1 538 with SNVs in the cell cycle pathway and liver metastases. PIK3CA 1047 and 542 were associated with CNVs in the PI3K pathway and with bone metastases.
The study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDS) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making.
The study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among clinical characteristics, pathway classification, and ESR1/PIK3CA codon variants were explored.
The results showed a differential pattern of associations for ESR1 and PIK3CA codon variants in terms of co-occurring pathway alterations patterns of metastatic dissemination, and prognosis. ESR1 537 was associated with SNVs in the ER and RAF pathways, CNVs in the MYC pathway and bone metastases, while ESR1 538 with SNVs in the cell cycle pathway and liver metastases. PIK3CA 1047 and 542 were associated with CNVs in the PI3K pathway and with bone metastases.
The study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDS) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making.
摘要：
背景：虽然是激素受体阳性的生物学和药物的中心，HER2阴性转移性乳腺癌（MBC），在目前的临床实践中,ESR1和PIK3CA突变被简单地二分为突变或野生型。
方法：该研究分析了一个多机构队列，该队列包括703名通过下一代测序（NGS）表征为循环肿瘤DNA的腔样MBC患者。路径分类是根据以前的工作定义的(即，RTK,RAS,英国皇家空军,MEK,NRF2,ER,WNT,MYC,P53，细胞周期，凹口,PI3K)。通过OncoKB注释了单核苷酸变异（SNV）的致癌性。模型中仅包括致病变体。临床特征之间的关联，途径分类，和ESR1/PIK3CA密码子变体进行了探索。
结果：结果显示ESR1和PIK3CA密码子变体在转移播散的共现途径改变模式方面的关联模式不同，和预后。ESR1537与ER和RAF途径中的SNV相关，MYC通路中的CNV与骨转移,而ESR1538与SNV在细胞周期通路和肝转移中。PIK3CA1047和542与PI3K通路中的CNV和骨转移相关。
结论：该研究证明了ESR1和PIK3CA密码子变体，连同特定致癌途径的改变，可以区别地影响管腔样MBC的生物学和临床表型。随着新型内分泌治疗药物如选择性雌激素受体降解剂（SERDS）和PI3K抑制剂的开发，这些结果凸显了ctDNANGS在描述肿瘤演变和优化临床决策方面的关键作用.
方法：该研究分析了一个多机构队列，该队列包括703名通过下一代测序（NGS）表征为循环肿瘤DNA的腔样MBC患者。路径分类是根据以前的工作定义的(即，RTK,RAS,英国皇家空军,MEK,NRF2,ER,WNT,MYC,P53，细胞周期，凹口,PI3K)。通过OncoKB注释了单核苷酸变异（SNV）的致癌性。模型中仅包括致病变体。临床特征之间的关联，途径分类，和ESR1/PIK3CA密码子变体进行了探索。
结果：结果显示ESR1和PIK3CA密码子变体在转移播散的共现途径改变模式方面的关联模式不同，和预后。ESR1537与ER和RAF途径中的SNV相关，MYC通路中的CNV与骨转移,而ESR1538与SNV在细胞周期通路和肝转移中。PIK3CA1047和542与PI3K通路中的CNV和骨转移相关。
结论：该研究证明了ESR1和PIK3CA密码子变体，连同特定致癌途径的改变，可以区别地影响管腔样MBC的生物学和临床表型。随着新型内分泌治疗药物如选择性雌激素受体降解剂（SERDS）和PI3K抑制剂的开发，这些结果凸显了ctDNANGS在描述肿瘤演变和优化临床决策方面的关键作用.
