激素治疗耐药的激素受体阳性、人表皮生长因子受体2阴性乳腺癌的基因组图谱
Genomic landscape of hormone therapy-resistant HR-positive, HER2-negative breast cancer.
作者信息
Chaubal Rohan, Talker Elizabeth, Chitra Jaya, Kadam Rasika, Gardi Nilesh, Ursekar Riddhi, Kadam Anushree, Singh Ankita, Sale Suhani, Pandey Shwetali, Madhav Mrudula, Raja Aishwarya, Mukhare Rushikesh, Parab Pallavi, Shetty Nitin, Gala Kunal, Kulkarni Suyash, Gandhi Khushboo A, Gulia Seema, Joshi Shalaka, Shet Tanuja, Gupta Sudeep
机构信息
Department of Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, Maharashtra, 400012, India.
Hypoxia and Clinical Genomics Lab (Clinician Scientist Laboratory), Advanced Centre for Treatment, Research, and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, 410210, India.
出版信息
Breast Cancer Res Treat. 2025 Jul 12. doi: 10.1007/s10549-025-07759-7.
PURPOSE
We aimed to characterize the genomic landscape of hormone receptor-positive (HR+)/HER2-negative breast cancer in patients with hormone therapy-resistant and -sensitive phenotypes.
METHODS
HR+/HER2-negative patients who were disease-free for ≥2 years were considered hormone therapy-sensitive (n = 19), while those who experienced disease progression within 2 years were considered hormone therapy-resistant (n = 48). Whole-exome sequencing (WES) was performed on paired (treatment-naïve and relapse-site) tumor and germline-derived DNA from resistant patients (n = 19), and targeted next-generation sequencing (NGS) was performed on plasma-derived circulating tumor DNA (ctDNA) from resistant (n = 35) and sensitive (n = 19) patients.
RESULTS
In 19 resistant patients, the mutation burden was higher in relapse-site compared with treatment-naïve samples (median 0.883 vs 0.655 mutations/mb, p = 0.03), there were 64 driver mutations (median treatment-naïve versus relapse-site; 2/sample vs. 3/relapse), of which 21 mutations in 8 genes in 15 (78.9%) patients were classified as actionable, and branching evolutionary trajectories were seen in 18 (94.7%) patients, with the presence of PIK3CA and/or TP53 mutations in stem clones of 13 (68.4%) patients. ctDNA analysis in 35 resistant patients identified 27 actionable hotspot mutations, such as PIK3CA H1047X, AKT1 p.E17K, CDH1 p.R63X, CDKN2A p.X50*, ERBB2 p.D769Y, and ESR1 p.E380Q, in 25 (71.4%) patients. Among 19 patients with hormone therapy-sensitive disease who were in remission at the time of sample collection, ctDNA analysis showed driver mutations in 10 (52.6%) patients, of whom 2 patients subsequently experienced relapse and died.
CONCLUSION
Hormone therapy-resistant HR+/HER2-negative breast cancers are polyclonal, acquire actionable alterations at relapse, and moderate-depth ctDNA successfully identifies many clonal mutations, suggesting a role for liquid biopsy monitoring in these patients.
目的
我们旨在描述激素受体阳性（HR+）/人表皮生长因子受体2阴性（HER2-）乳腺癌患者中激素治疗耐药和敏感表型的基因组格局。
方法
无病生存期≥2年的HR+/HER2-阴性患者被视为激素治疗敏感型（n = 19），而在2年内出现疾病进展的患者被视为激素治疗耐药型（n = 48）。对19例耐药患者的配对（未经治疗和复发部位）肿瘤及种系来源的DNA进行全外显子组测序（WES），并对35例耐药患者和19例敏感患者血浆来源的循环肿瘤DNA（ctDNA）进行靶向二代测序（NGS）。
结果
在19例耐药患者中，复发部位的突变负荷高于未经治疗的样本（中位数0.883对0.655个突变/mb，p = 0.03），有64个驱动突变（中位数：未经治疗样本与复发部位样本；2/样本对3/复发样本），其中15例（78.9%）患者的8个基因中的21个突变被分类为可操作突变，18例（94.7%）患者出现分支进化轨迹，13例（68.4%）患者的干细胞克隆中存在PIK3CA和/或TP53突变。对35例耐药患者的ctDNA分析在25例（71.4%）患者中鉴定出27个可操作的热点突变，如PIK3CA H1047X、AKT1 p.E17K、CDH1 p.R63X、CDKN2A p.X50*、ERBB2 p.D769Y和ESR1 p.E380Q。在样本采集时处于缓解期的19例激素治疗敏感型疾病患者中，ctDNA分析显示10例（52.6%）患者存在驱动突变，其中2例患者随后复发并死亡。
结论
激素治疗耐药的HR+/HER2-阴性乳腺癌是多克隆性的，在复发时获得可操作的改变，中等深度的ctDNA成功鉴定出许多克隆性突变，提示液体活检监测在这些患者中具有一定作用。
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