Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy.
Department of Medical Sciences, University of Turin, Turin, Italy.
Genome Med. 2022 Aug 29;14(1):98. doi: 10.1186/s13073-022-01104-z.
The "HER2-low" nomenclature identifies breast carcinomas (BCs) displaying a HER2 score of 1+/2+ in immunohistochemistry and lacking ERBB2 amplification. Whether HER2-low BCs (HLBCs) constitute a distinct entity is debated.
We performed DNA and RNA high-throughput analysis on 99 HLBC samples (n = 34 cases with HER2 score 1+/HLBC-1, n = 15 cases with HER2 score 2+ and ERBB2 not amplified/HLBC-2N, and n = 50 cases with score 2+ and ERBB2 copy number in the equivocal range/HLBC-2E). We compared the mutation rates with data from 1317 samples in the Memorial Sloan-Kettering Cancer Center (MSKCC) BC cohort and gene expression data with those from an internal cohort of HER2-negative and HER2-positive BCs.
The most represented mutations affected PIK3CA (31/99, 31%), GATA3 (18/99, 18%), TP53 (17/99, 17%), and ERBB2 (8/99, 8%, private to HLBC-2E). Tumor mutational burden was significantly higher in HLBC-1 compared to HLBC-2E/N (P = 0.04). Comparison of mutation spectra revealed that HLBCs were different from both HER2-negative and HER2-positive BCs, with HLBC-1 resembling more HER2-negative tumors and HLBC-2 mutationally related to HER2-addicted tumors. Potentially actionable alterations (annotated by using OncoKB/ESCAT classes) affected 52 patients. Intra-group gene expression revealed overlapping features between HLBC-1 and control HER2-negative BCs, whereas the HLBC-2E tumors showed the highest diversity overall. The RNA-based class discovery analysis unveiled four subsets of tumors with (i) lymphocyte activation, (ii) unique enrichment in HER2-related features, (iii) stromal remodeling alterations, and (iv) actionability of PIK3CA mutations (LAURA classification).
HLBCs harbor distinct genomic features when compared with HER2-positive and HER2-negative BCs; however, differences across IHC classes were also unveiled thus dissecting the full picture of heterogeneity across HER2-low disease. The HLBC-2E category harbors most distinctive features, whereas HLBC-1 seems superimposable to HER2-negative disease. Further studies are needed to ascertain whether the four genomic-driver classes of the LAURA classification hold prognostic and/or predictive implications.
“HER2-低”命名法用于识别免疫组织化学检测 HER2 评分为 1+/2+且 ERBB2 无扩增的乳腺癌（BC）。HER2-低 BC（HLBC）是否构成一个独特的实体存在争议。
我们对 99 例 HLBC 样本（n=34 例 HER2 评分 1+/HLBC-1，n=15 例 HER2 评分 2+且 ERBB2 无扩增/HLBC-2N，n=50 例 HER2 评分 2+且 ERBB2 拷贝数处于不确定范围/HLBC-2E）进行了 DNA 和 RNA 高通量分析。我们将突变率与 Memorial Sloan-Kettering Cancer Center（MSKCC）BC 队列的 1317 个样本数据进行比较，并将基因表达数据与内部 HER2 阴性和 HER2 阳性 BC 队列的数据进行比较。
最常见的突变影响 PIK3CA（31/99，31%）、GATA3（18/99，18%）、TP53（17/99，17%）和 ERBB2（8/99，8%，仅存在于 HLBC-2E 中）。与 HLBC-2E/N 相比，HLBC-1 的肿瘤突变负担显著更高（P=0.04）。突变谱的比较表明，HLBC 与 HER2 阴性和 HER2 阳性 BC 均不同，HLBC-1 更类似于 HER2 阴性肿瘤，HLBC-2 在突变上与依赖 HER2 的肿瘤相关。可能的靶向治疗改变（使用 OncoKB/ESCAT 类进行注释）影响了 52 例患者。组内基因表达显示 HLBC-1 与对照 HER2 阴性 BC 之间存在重叠特征，而 HLBC-2E 肿瘤总体上表现出最高的多样性。基于 RNA 的分类发现分析揭示了具有以下特征的四个肿瘤亚组：（i）淋巴细胞激活，（ii）HER2 相关特征的独特富集，（iii）基质重塑改变，以及（iv）PIK3CA 突变的可操作性（LAURA 分类）。
与 HER2 阳性和 HER2 阴性 BC 相比，HLBC 具有独特的基因组特征；然而，还揭示了 IHC 分类之间的差异，从而全面剖析了 HER2 低疾病的异质性全貌。HLBC-2E 类别具有最独特的特征，而 HLBC-1 似乎与 HER2 阴性疾病重叠。需要进一步的研究来确定 LAURA 分类的四个基因组驱动类是否具有预后和/或预测意义。
