Division of Medical Oncology for Melanoma & Sarcoma, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Division of Medical Oncology for Melanoma & Sarcoma, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Breast. 2021 Oct;59:94-101. doi: 10.1016/j.breast.2021.06.011. Epub 2021 Jun 26.
We report here for the first time, a comprehensive characterization of biological and clinical features of early-stage triple negative Invasive Lobular Carcinomas(TN-ILCs) METHODS: We analyzed all consecutive patients with early-stage TN-ILC operated at two reference cancer-centers between 1994 and 2012. Primary objective was to assess the invasive disease-free survival(iDFS). Co-primary objective was to assess biological features of TN-ILCs, including molecular intrinsic subtypes based on PAM-50 assay, expression of androgen receptor (AR) and mutational status of ERBB2-gene. Additionally, DNA mutational status of an independent cohort of 45 TN-ILCs from three databases were analyzed, to confirm mutations in ERBB2-gene and to identify other recurrently mutated genes.
Among 4152 ILCs, 74(1.8%) were TN and were analyzed. The iDFS at 5 and 10 years of FUP were 50.4%(95%CI,38.0-61.6) and 37.2%(95%CI,25.5-48.8), respectively. The molecular subtype was defined through PAM50-classifier for 31 out of 74 TN-ILCs: 48% were Luminal-A(15/31), 3% luminal-B(1/31), 32% HER2-enriched (10/31), and only 16% basal-like(5/31). Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 94% of luminal tumors versus 53% in non-luminal tumors; p-value = 0.001). 20% of TN-ILCs analyzed(7/35), harbored a pathogenetic and actionable mutation in the ERBB2-gene. Analysis of the independent cohort of 45 TN-ILCs from three different databases, confirmed similar percentage of pathogenetic and actionable mutations in ERBB2-gene(20%; 9/45). Among the top 10 molecular pathways significantly enriched for recurrently mutated genes in TN-ILCs(FDR<0.05), there were ErbB-signaling and DNA-damage-response pathways.
TN-ILCs are rare tumors with poor prognosis. Their specific biological features require newly defined targeted therapeutic strategies.
我们首次全面描述了早期三阴性浸润性小叶癌（TN-ILC）的生物学和临床特征。
我们分析了 1994 年至 2012 年在两个参考癌症中心接受治疗的所有连续早期 TN-ILC 患者。主要目的是评估无侵袭性疾病生存（iDFS）。共同的主要目的是评估 TN-ILC 的生物学特征，包括基于 PAM-50 检测的分子固有亚型、雄激素受体（AR）的表达和 ERBB2 基因突变状态。此外，还分析了来自三个数据库的 45 例 TN-ILC 的独立队列的 DNA 突变状态，以确认 ERBB2 基因突变，并鉴定其他经常发生突变的基因。
在 4152 例 ILC 中，74 例（1.8%）为 TN，并进行了分析。5 年和 10 年随访的 iDFS 分别为 50.4%（95%CI，38.0-61.6）和 37.2%（95%CI，25.5-48.8）。通过 PAM50 分类器确定了 74 例 TN-ILC 中的 31 例的分子亚型：48%为 Luminal-A（31 例中的 15 例），3%为 luminal-B（31 例中的 1 例），32%为 HER2 富集型（31 例中的 10 例），只有 16%为基底样（31 例中的 5 例）。Luminal 肿瘤比非 Luminal 肿瘤更常表达 AR（在 94%的 Luminal 肿瘤中 AR≥1%，而非 Luminal 肿瘤中为 53%；p 值=0.001）。分析的 35 例 TN-ILC 中有 20%（7/35）携带 ERBB2 基因的致病性和可操作性突变。对来自三个不同数据库的 45 例 TN-ILC 的独立队列的分析证实了 ERBB2 基因中类似比例的致病性和可操作性突变（20%；9/45）。在 TN-ILC 中经常发生突变的前 10 个分子途径中（FDR<0.05），有 ErbB 信号和 DNA 损伤反应途径。
TN-ILC 是罕见的肿瘤，预后不良。它们特定的生物学特征需要新定义的靶向治疗策略。
