Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.

中文翻译：

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无细胞 DNA 肿瘤分数和体细胞拷贝数改变与转移性三阴性乳腺癌生存的关系


目的 游离 DNA (cfDNA) 提供了在无需肿瘤活检的情况下对肿瘤变化进行微创全基因组分析的潜力，并且可能与患者预后相关。三阴性乳腺癌 (TNBC) 的特点是突变很少，但体细胞拷贝数改变 (SCNA) 广泛，但对于转移性 TNBC 中的 SCNA 知之甚少。我们试图仅通过 cfDNA 评估转移性 TNBC 中的 SCNA，并确定 cfDNA 肿瘤分数是否与转移性 TNBC 的总生存率相关。患者和方法 在这项回顾性队列研究中，我们在一家三级医疗机构中确定了 164 名经活检证实为转移性 TNBC 的患者，这些患者之前接受过（新）辅助或转移性化疗。我们对血浆 cfDNA 进行了低覆盖率全基因组测序。结果 在事先不了解肿瘤突变的情况下，我们确定了 96.3% 患者的 cfDNA 肿瘤分数和 63.9% 患者的 SCNA。转移性 TNBC 和原发性 TNBC 之间的拷贝数概况和基因组改变百分比非常相似。在公开数据集癌症基因组图谱和 METABRIC 中，相对于配对的原发性肿瘤和原发性 TNBC，某些 SCNA 在转移性 TNBC 中更为常见，包括驱动程序 NOTCH2、AKT2 和 AKT3 中的染色体增益。预设的 cfDNA 肿瘤分数阈值≥ 10% 与显着较差的转移生存相关（中位，6.4 vs 15.9 个月），并且仍然显着独立于临床病理因素（风险比，2.14；95% CI，1.4 至 3.8；P < .001） 。结论 我们提出了据我们所知，仅来自 cfDNA 的最大转移性 TNBC 基因组特征。 cfDNA 肿瘤分数的评估对于几乎所有患者都是可行的，在这个大型转移性 TNBC 队列中，肿瘤分数≥ 10% 与显着较差的生存率相关。特定的 SCNA 在转移性 TNBC 中丰富并具有预后意义，对转移、耐药性和新的治疗方法具有影响。