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携 Pik3CA 突变的 ER+/HER2- 晚期乳腺癌患者接受 taselisib 和氟维司群治疗：基因组图谱和相关临床结局。

ER+, HER2- advanced breast cancer treated with taselisib and fulvestrant: genomic landscape and associated clinical outcomes.

机构信息

Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA.

Institut du Cancer de Montpellier (ICM) Val d'Aurelle, Montpellier University, INSERM U1194, France.

出版信息

Mol Oncol. 2023 Oct;17(10):2000-2016. doi: 10.1002/1878-0261.13416. Epub 2023 Mar 25.

DOI:10.1002/1878-0261.13416
PMID:36892268
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10552898/
Abstract

Taselisib is a potent β-sparing phosphatidylinositol 3-kinase (PI3K) inhibitor that, with endocrine therapy, improves outcomes in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated (PIK3CAmut) advanced breast cancer. To understand alterations associated with response to PI3K inhibition, we analysed circulating tumour DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CAmut or PIK3CA no mutation was detected (NMD) per baseline ctDNA. The top mutated genes and tumour fraction estimates identified were analysed for their association with outcomes. In participants with PIK3CAmut ctDNA treated with taselisib + fulvestrant, tumour protein p53 (TP53; encoding p53) and fibroblast growth factor receptor 1 (FGFR1) alterations were associated with shorter progression-free survival (PFS) compared to participants with NMD in these genes. Conversely, participants with PIK3CAmut ctDNA harbouring a neurofibromin 1 (NF1) alteration or high baseline tumour fraction estimate experienced improved PFS upon treatment with taselisib + fulvestrant compared to placebo + fulvestrant. Broadly, alterations in oestrogen receptor (ER), PI3K and p53 pathway genes were associated with resistance to taselisib + fulvestrant in participants with PIK3CAmut ctDNA. Altogether, we demonstrated the impact of genomic (co-)alterations on outcomes with one of the largest clinico-genomic datasets of ER+, HER2-, PIK3CAmut breast cancer patients treated with a PI3K inhibitor.

摘要

塔西利昔单抗是一种强效的β 选择性磷脂酰肌醇 3-激酶（PI3K）抑制剂，与内分泌治疗联合使用，可改善磷脂酰肌醇-4,5-二磷酸 3-激酶催化亚单位α（PIK3CA）突变（PIK3CAmut）的晚期乳腺癌患者的结局。为了了解与 PI3K 抑制反应相关的改变，我们分析了 SANDPIPER 试验中入组患者的循环肿瘤 DNA（ctDNA）。根据基线 ctDNA 将患者指定为 PIK3CAmut 或未检测到 PIK3CA 突变（NMD）。对鉴定出的最常见突变基因和肿瘤分数估计值进行分析，以评估它们与结局的关系。在接受塔西利昔单抗+氟维司群治疗的 PIK3CAmut ctDNA 患者中，与 NMD 患者相比，肿瘤蛋白 p53（TP53；编码 p53）和成纤维细胞生长因子受体 1（FGFR1）的改变与较短的无进展生存期（PFS）相关。相反，在携带神经纤维瘤 1（NF1）改变或基线肿瘤分数估计值较高的 PIK3CAmut ctDNA 患者中，与安慰剂+氟维司群相比，接受塔西利昔单抗+氟维司群治疗可改善 PFS。总的来说，在携带 PIK3CAmut ctDNA 的患者中，雌激素受体（ER）、PI3K 和 p53 通路基因的改变与对塔西利昔单抗+氟维司群的耐药性相关。综上所述，我们展示了基因组（协同）改变对接受 PI3K 抑制剂治疗的最大型之一的 ER+、HER2-、PIK3CAmut 乳腺癌患者临床基因组数据集的影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/7d4aaf68902a/MOL2-17-2000-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/c7b1b21bd1f8/MOL2-17-2000-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/038380bc4e6e/MOL2-17-2000-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/86cf2ea2011b/MOL2-17-2000-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/ffea072f25c9/MOL2-17-2000-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/7d4aaf68902a/MOL2-17-2000-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/c7b1b21bd1f8/MOL2-17-2000-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/87176fec1acc/MOL2-17-2000-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/038380bc4e6e/MOL2-17-2000-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/86cf2ea2011b/MOL2-17-2000-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f96/10552898/7d4aaf68902a/MOL2-17-2000-g007.jpg

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