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富含 HER2 的亚型和新型分子亚群可导致早期 ER+/HER2+乳腺癌对芳香化酶抑制剂产生耐药性，并增加复发风险。

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer.

机构信息

Clinical Trials and Statistics Unit (ICR-CTSU)- Division of Clinical Studies, The Institute of Cancer Research, London, UK.

Royal Marsden Hospital, London, UK; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

出版信息

EBioMedicine. 2022 Sep;83:104205. doi: 10.1016/j.ebiom.2022.104205. Epub 2022 Aug 16.

DOI:10.1016/j.ebiom.2022.104205
PMID:35985932
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9482930/
Abstract

BACKGROUND

Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks' presurgical AI treatment in ER+/HER2+ BCs.

METHODS

All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki67). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering.

FINDINGS

HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki67 (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki67. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14-5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes.

INTERPRETATION

Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse.

FUNDING

Cancer Research UK (CRUK/07/015).

摘要

背景

雌激素受体阳性/人表皮生长因子受体阳性（ER+/HER2+）乳腺癌（BC）对内分泌治疗的反应不如 ER+/HER2-肿瘤敏感。ER+HER2+肿瘤表现出不同行为的机制尚未得到充分描述。我们的目的是确定 ER+/HER2+BC 接受 2 周术前 AI 治疗的反应生物标志物。

方法

POETIC 试验中所有可用的 ER+/HER2+BC 基线肿瘤（n=342）均使用 BC360™（NanoString）进行基因表达谱分析，涵盖了内在亚型和 46 个关键生物学特征。通过 Ki67 表达的变化和 2 周时的残留 Ki67（Ki67）来评估 AI 的早期反应。使用 Kaplan-Meier 方法和 Cox 模型估计无复发生存时间（TTR），并调整了标准临床病理变量。使用共识聚类识别新的分子亚群（MS）。

发现

HER2 富集（HER2-E）亚型 BC（占总数的 44.7%）的 Ki67 反应较差，Ki67 更高（p<0.0001），而非 HER2-E BC 则相反。ERBB2 表达高、同源重组缺陷（HRD）和 TP53 突变评分与不良反应相关，而免疫相关特征与高 Ki67 相关。鉴定出与 AI 反应差异相关的 5 个新 MS。与 Luminal BC 相比，HER2-E 的 TTR 显著更差（HR 2.55，95%CI 1.14-5.69；p=0.0222）。新的 MS 是 TTR 的独立预测因子，除了内在亚型之外，还具有显著的附加价值。

结论

我们的结果表明，HER2-E 是一种与 AI 反应不良和 ER+/HER2+不良预后相关的标准化生物标志物。HRD、TP53 突变评分和免疫肿瘤耐受是 AI 反应不良的预测生物标志物。最后，新的 MS 确定了另外一些对 AI 无反应的非 HER2-E 肿瘤，这些肿瘤复发风险增加。

资金来源

英国癌症研究中心（CRUK/07/015）。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/5cd60cef2f05/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/efc421f65f2b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/3be2fda0b56a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/e0b2e512f4ab/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/203124505ef5/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/5cd60cef2f05/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/efc421f65f2b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/3be2fda0b56a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/e0b2e512f4ab/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/203124505ef5/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc99/9482930/5cd60cef2f05/gr5.jpg

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