Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2021 Feb 15;27(4):1105-1118. doi: 10.1158/1078-0432.CCR-20-1720. Epub 2020 Dec 8.
In contrast to recurrence after initial diagnosis of stage I-III breast cancer [recurrent metastatic breast cancer (rMBC)], metastatic breast cancer (dnMBC) represents a unique setting to elucidate metastatic drivers in the absence of treatment selection. We present the genomic landscape of dnMBC and association with overall survival (OS).
Targeted DNA sequencing (OncoPanel) was prospectively performed on either primary or metastatic tumors from 926 patients (212 dnMBC and 714 rMBC). Single-nucleotide variants, copy-number variations, and tumor mutational burden (TMB) in treatment-naïve dnMBC primary tumors were compared with primary tumors in patients who ultimately developed rMBC, and correlated with OS across all dnMBC.
When comparing primary tumors by subtype, amplification was enriched in triple-negative dnMBC versus rMBC (21.1% vs. 0%, = 0.0005, = 0.111). Mutations in , and were more prevalent, and and less prevalent, in primary HR/HER2 tumors of dnMBC versus rMBC, though not significant after multiple comparison adjustment. Alterations associated with shorter OS in dnMBC included TP53 (wild-type: 79.7 months; altered: 44.2 months; = 0.008, = 0.107), MYC (79.7 vs. 23.3 months; = 0.0003, = 0.011), and cell-cycle (122.7 vs. 54.9 months; = 0.034, = 0.245) pathway genes. High TMB correlated with better OS in triple-negative dnMBC ( = 0.041).
Genomic differences between treatment-naïve dnMBC and primary tumors of patients who developed rMBC may provide insight into mechanisms underlying metastatic potential and differential therapeutic sensitivity in dnMBC. Alterations associated with poor OS in dnMBC highlight the need for novel approaches to overcome potential intrinsic resistance to current treatments.
与初始诊断为 I-III 期乳腺癌[复发性转移性乳腺癌(rMBC)]后的复发不同，转移性乳腺癌(dnMBC)代表了一个独特的环境，可以在没有治疗选择的情况下阐明转移性驱动因素。我们展示了 dnMBC 的基因组特征及其与总生存期(OS)的关联。
前瞻性地对 926 名患者的原发或转移肿瘤进行靶向 DNA 测序(OncoPanel)，其中 212 名为 dnMBC，714 名为 rMBC。在 dnMBC 原发肿瘤的治疗-naive 状态下，比较原发性肿瘤的单核苷酸变异、拷贝数变异和肿瘤突变负荷(TMB)与最终发生 rMBC 的患者的原发性肿瘤，并在所有 dnMBC 中与 OS 相关。
当按亚型比较原发性肿瘤时，三阴性 dnMBC 中扩增更为丰富，而 rMBC 中则没有(21.1%对 0%，=0.0005，=0.111)。在 dnMBC 的 HR/HER2 原发性肿瘤中，与 dnMBC 相比，中的突变和 更常见，而 和 则不常见，尽管在多次比较调整后并不显著。与 dnMBC 较短 OS 相关的改变包括 TP53(野生型：79.7 个月；改变型：44.2 个月；=0.008，=0.107)、MYC(79.7 对 23.3 个月；=0.0003，=0.011)和细胞周期(122.7 对 54.9 个月；=0.034，=0.245)途径基因。高 TMB 与三阴性 dnMBC 的 OS 相关(=0.041)。
治疗-naive dnMBC 与发生 rMBC 的患者的原发性肿瘤之间的基因组差异可能为 dnMBC 中的转移潜能和治疗敏感性的差异提供潜在机制的见解。与 dnMBC 中不良 OS 相关的改变突出了需要采用新方法来克服对当前治疗的潜在内在耐药性。
