在 HR(+)HER2(-)转移性乳腺癌中进行 ESR1、PIK3CA、AKT1 和 PTEN 的全面基因组分析：在真实世界实践中治疗过程中的流行率和内分泌治疗耐药的预测价值。

Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice.

机构信息

Winship Cancer Institute, Emory University, 1365 Clifton Rd NE, Building B, Suite 4000, Atlanta, GA, 30322, USA.

Foundation Medicine, Inc, 400 Summer Street, Boston, MA, 02210, USA.

出版信息

Breast Cancer Res Treat. 2024 Oct;207(3):599-609. doi: 10.1007/s10549-024-07376-w. Epub 2024 Jun 14.

BACKGROUND

The treatment landscape for HR(+)HER2(-) metastatic breast cancer (MBC) is evolving for patients with ESR1 mutations (mut) and PI3K/AKT pathway genomic alterations (GA). We sought to inform clinical utility for comprehensive genomic profiling (CGP) using tissue (TBx) and liquid biopsies (LBx) in HR(+)HER2(-) MBC.

METHODS

Records from a de-identified breast cancer clinicogenomic database for patients who underwent TBx/LBx testing at Foundation Medicine during routine clinical care at ~ 280 US cancer clinics between 01/2011 and 09/2023 were assessed. GA prevalence [ESR1mut, PIK3CAmut, AKT1mut, PTENmut, and PTEN homozygous copy loss (PTENloss)] were calculated in TBx and LBx [stratified by ctDNA tumor fraction (TF)] during the first three lines of therapy. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared between groups by Cox models adjusted for prognostic factors.

RESULTS

~ 60% of cases harbored 1 + GA in 1st-line TBx (1266/2154) or LBx TF ≥ 1% (80/126) and 26.5% (43/162) in LBx TF < 1%. ESR1mut was found in 8.1% TBx, 17.5% LBx TF ≥ 1%, and 4.9% LBx TF < 1% in 1st line, increasing to 59% in 3rd line (LBx TF ≥ 1%). PTENloss was detected at higher rates in TBx (4.3%) than LBx (1% in TF ≥ 1%). Patients receiving 1st-line aromatase inhibitor + CDK4/6 inhibitor (n = 573) with ESR1mut had less favorable rwPFS and rwOS versus ESR1 wild-type; no differences were observed for fulvestrant + CDK4/6 inhibitor (n = 348).

CONCLUSION

Our study suggests obtaining TBx for CGP at time of de novo/recurrent diagnosis, followed by LBx for detecting acquired GA in 2nd + lines. Reflex TBx should be considered when ctDNA TF < 1%.

背景

对于存在 ESR1 突变（mut）和 PI3K/AKT 通路基因组改变（GA）的 HR(+)HER2(-)转移性乳腺癌（MBC）患者，其治疗格局正在不断发展。我们旨在通过组织（TBx）和液体活检（LBx）为 HR(+)HER2(-)MBC 患者的全面基因组分析（CGP）提供临床实用性信息。

方法

评估了 2011 年 1 月至 2023 年 9 月期间，在 280 家美国癌症诊所的常规临床护理期间，在 Foundation Medicine 进行 TBx/LBx 检测的患者的匿名乳腺癌临床基因组数据库中的记录。在一线治疗的前 3 个疗程中，根据 ctDNA 肿瘤分数（TF）对 TBx 和 LBx 中 GA 流行率（ESR1mut、PIK3CAmut、AKT1mut、PTENmut 和 PTEN 纯合性拷贝丢失（PTENloss））进行了计算。通过 Cox 模型调整预后因素，比较各组间的真实无进展生存期（rwPFS）和总生存期（rwOS）。

结果

在一线 TBx（1266/2154）或 LBx TF≥1%（80/126）中，约 60%的病例存在 1 种+GA，而在 LBx TF<1%中则为 26.5%（43/162）。在一线治疗中，TBx 中发现 ESR1mut 为 8.1%，LBx TF≥1%为 17.5%，LBx TF<1%为 4.9%，而在三线治疗中增加到 59%（LBx TF≥1%）。在 TBx 中检测到的 PTENloss 率高于 LBx（TBx 中为 4.3%，而 LBx 中为 1%，TF≥1%）。与 ESR1 野生型相比，接受一线芳香酶抑制剂+CDK4/6 抑制剂（n=573）治疗的 ESR1mut 患者的 rwPFS 和 rwOS 较差；而在接受氟维司群+CDK4/6 抑制剂（n=348）治疗的患者中未观察到差异。