Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy.
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Breast Cancer Res. 2023 Oct 2;25(1):112. doi: 10.1186/s13058-023-01718-0.
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.
尽管 ESR1 和 PIK3CA 突变对于激素受体阳性、HER2 阴性转移性乳腺癌（MBC）的生物学和可药性至关重要，但在当前的临床实践中，它们简单地分为突变型或野生型。
该研究分析了一个由 703 例具有腔型特征的 MBC 患者组成的多机构队列，这些患者通过下一代测序（NGS）对循环肿瘤 DNA 进行了特征分析。基于先前的工作（即 RTK、RAS、RAF、MEK、NRF2、ER、WNT、MYC、P53、细胞周期、Notch、PI3K）对途径分类进行了定义。通过 OncoKB 对单核苷酸变异（SNVs）进行了致癌性注释。只有致病性变异被纳入模型中。探讨了临床特征、途径分类与 ESR1/PIK3CA 密码子变异之间的关联。
研究结果显示，ESR1 和 PIK3CA 密码子变异在转移性扩散和预后方面的共发生途径改变模式存在差异。ESR1 537 与 ER 和 RAF 途径中的 SNVs、MYC 途径和骨转移中的 CNVs 相关，而 ESR1 538 与细胞周期途径和肝转移中的 SNVs 相关。PIK3CA 1047 和 542 与 PI3K 途径中的 CNVs 以及骨转移相关。
该研究表明，ESR1 和 PIK3CA 密码子变异，以及特定致癌途径中的改变，可对腔型 MBC 的生物学和临床表型产生不同的影响。随着选择性雌激素受体降解剂（SERDS）和 PI3K 抑制剂等新型内分泌治疗药物的开发，这些结果突出了 ctDNA NGS 在描述肿瘤进化和优化临床决策方面的关键作用。
