Foundation Medicine Inc., Cambridge.
Department of Biology, Massachusetts Institute of Technology, Cambridge.
Ann Oncol. 2019 Jan 1;30(1):115-123. doi: 10.1093/annonc/mdy497.
Invasive lobular carcinoma (ILC) as a disease entity distinct from invasive ductal carcinoma (IDC) has merited focused studies of the genomic landscape, but those to date are largely limited to the assessment of early-stage cancers. Given that genomic alterations develop as acquired resistance to endocrine therapy, studies on refractory ILC are needed.
Tissue from 336 primary-enriched, breast-biopsied ILC and 485 estrogen receptor (ER)-positive IDC and metastatic biopsy specimens from 180 ILC and 191 ER-positive IDC patients was assayed with hybrid-capture-based comprehensive genomic profiling for short variant, indel, copy number variants, and rearrangements in up to 395 cancer-related genes.
Whereas ESR1 alterations are enriched in the metastases of both ILC and IDC compared with breast specimens, NF1 alterations are enriched only in ILC metastases (mILC). NF1 alterations are predominantly under loss of heterozygosity (11/14, 79%), are mutually exclusive with ESR1 mutations [odds ratio = 0.24, P < 0.027] and are frequently polyclonal in ctDNA assays. Assessment of paired specimens shows that NF1 alterations arise in the setting of acquired resistance. An in vitro model of CDH1 mutated ER-positive breast cancer demonstrates that NF1 knockdown confers a growth advantage in the presence of 4-hydroxy tamoxifen. Our study further identified a significant increase in tumor mutational burden (TMB) in mILCs relative to breast ILCs or metastatic IDCs (8.9% >20 mutations/mb; P < 0.001). Most TMB-high mILCs harbor an APOBEC trinucleotide signature (14/16; 88%).
This study identifies alteration of NF1 as enriched specifically in mILC. Mutual exclusivity with ESR1 alterations, polyclonality in relapsed ctDNA, and de novo acquisition suggest a role for NF1 loss in endocrine therapy resistance. Since NF1 loss leads to RAS/RAF kinase activation, patients may benefit from a matched inhibitor. Moreover, for an independent subset of mILC, TMB was elevated relative to breast ILC, suggesting possible benefit from immune checkpoint inhibitors.
浸润性小叶癌（ILC）作为一种与浸润性导管癌（IDC）不同的疾病实体，其基因组图谱已得到了广泛研究，但迄今为止，这些研究主要局限于早期癌症的评估。鉴于基因组改变是内分泌治疗耐药的获得性结果，需要对难治性 ILC 进行研究。
对 336 例原发性富集的乳腺活检 ILC 组织和 485 例雌激素受体（ER）阳性 IDC 组织以及 180 例 ILC 和 191 例 ER 阳性 IDC 转移性活检标本进行了杂交捕获综合基因组分析，检测了多达 395 个癌症相关基因的短变体、插入缺失、拷贝数变异和重排。
与乳腺标本相比，ESR1 改变在 ILC 和 IDC 的转移中更为丰富，而 NF1 改变仅在 ILC 转移中更为丰富（mILC）。NF1 改变主要表现为杂合性丢失（11/14，79%），与 ESR1 突变相互排斥[比值比=0.24，P<0.027]，在 ctDNA 检测中常为多克隆。配对标本评估显示，NF1 改变发生在获得性耐药的情况下。体外 CDH1 突变的 ER 阳性乳腺癌模型显示，在 4-羟基他莫昔芬存在的情况下，NF1 敲低赋予了生长优势。我们的研究还进一步发现，与乳腺 ILC 或转移性 IDC 相比，mILC 中肿瘤突变负担（TMB）显著增加（8.9%>20 个突变/mb；P<0.001）。大多数 TMB 高的 mILC 具有 APOBEC 三核苷酸特征（14/16；88%）。
本研究确定 NF1 改变在 mILC 中特异性富集。与 ESR1 改变的相互排斥性、复发 ctDNA 中的多克隆性以及新获得的改变提示 NF1 缺失在内分泌治疗耐药中起作用。由于 NF1 缺失导致 RAS/RAF 激酶激活，患者可能受益于匹配的抑制剂。此外，对于 mILC 的一个独立亚组，与乳腺 ILC 相比，TMB 升高，提示可能受益于免疫检查点抑制剂。
Zotero 插件
