Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Green Cross Genome, Yongin-si, Gyeonggi-do, Republic of Korea.
J Natl Cancer Inst. 2023 Sep 7;115(9):1036-1049. doi: 10.1093/jnci/djad080.
Low-pass whole-genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis is a versatile tool for somatic copy number aberration (CNA) detection, and this study aims to explore its clinical implication in breast cancer.
We analyzed LP-WGS ctDNA data from 207 metastatic breast cancer (MBC) patients to explore prognostic value of ctDNA CNA burden and validated it in 465 stage II-III triple-negative breast cancer (TNBC) patients who received neoadjuvant chemotherapy in phase III PEARLY trial (NCT02441933). The clinical implication of locus level LP-WGS ctDNA profiling was further evaluated.
We found that a high baseline ctDNA CNA burden predicts poor overall survival and progression-free survival of MBC patients. The post hoc analysis of the PEARLY trial showed that a high baseline ctDNA CNA burden predicted poor disease-free survival independent from pathologic complete response (pCR), validating its robust prognostic significance. The 24-month disease-free survival rate was 96.9% and 55.9% in [pCR(+) and low I-score] and [non-pCR and high I-score] patients, respectively. The locus-level ctDNA CNA profile classified MBC patients into 5 molecular clusters and revealed targetable oncogenic CNAs. LP-WGS ctDNA and in vitro analysis identified the BCL6 amplification as a resistance factor for CDK4/6 inhibitors. We estimated ctDNA-based homologous recombination deficiency status of patients by shallowHRD algorithm, which was highest in the TNBC and correlated with platinum-based chemotherapy response.
These results demonstrate LP-WGS ctDNA CNA analysis as an essential tool for prognosis prediction and molecular profiling. Particularly, ctDNA CNA burden can serve as a useful determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients.
基于低深度全基因组测序（LP-WGS）的循环肿瘤 DNA（ctDNA）分析是一种用于体细胞拷贝数异常（CNA）检测的多功能工具，本研究旨在探讨其在乳腺癌中的临床意义。
我们分析了 207 例转移性乳腺癌（MBC）患者的 LP-WGS ctDNA 数据，以探索 ctDNA CNA 负担的预后价值，并在接受 III 期 PEARLY 试验（NCT02441933）新辅助化疗的 465 例 II-III 期三阴性乳腺癌（TNBC）患者中进行了验证。进一步评估了基于 LP-WGS 的 ctDNA 分析在基因座水平上的临床意义。
我们发现基线时 ctDNA CNA 负担较高预示着 MBC 患者的总体生存率和无进展生存率较差。PEARLY 试验的事后分析显示，基线时 ctDNA CNA 负担较高与病理完全缓解（pCR）无关，预示着较差的无病生存率，验证了其稳健的预后意义。[pCR（+）和低 I 评分]和[非 pCR 和高 I 评分]患者的 24 个月无病生存率分别为 96.9%和 55.9%。基于基因座的 ctDNA CNA 谱将 MBC 患者分为 5 个分子簇，并揭示了可靶向的致癌性 CNA。LP-WGS ctDNA 和体外分析鉴定出 BCL6 扩增是 CDK4/6 抑制剂耐药的因素。我们通过浅层 HRD 算法估计了患者的 ctDNA 同源重组缺陷状态，该状态在 TNBC 中最高，与基于铂类的化疗反应相关。
这些结果表明 LP-WGS ctDNA CNA 分析是预后预测和分子谱分析的重要工具。特别是，ctDNA CNA 负担可以作为 TNBC 患者升级或降级（新）辅助策略的有用决定因素。
