Genetics Department, Institut Curie, PSL Research University, Paris, France.
Department of Medical Oncology, Institut Curie, PSL Research University, 26 rue d'Ulm, 75005, Paris, France.
Genome Med. 2021 Mar 15;13(1):44. doi: 10.1186/s13073-021-00862-6.
Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use.
We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months).
Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology.
Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse.
The trial was registered at ClinicalTrials.gov ( NCT01956552 ).
晚期乳腺癌的预后评估和治疗策略主要基于晚期疾病的临床特征和原发性肿瘤的分子分析。很少有研究在前瞻性研究中评估初始转移事件期间转移亚分型的影响。转移性乳腺癌的基因组图谱主要在非常晚期、预处理的疾病中进行了描述，限制了其在临床应用中的可推广性。
我们开展了一项多中心、单臂、前瞻性临床试验，以解决这些问题。2010 年 11 月至 2013 年 9 月，共纳入 123 例符合条件的患者。首次未经治疗的转移性疾病患者符合入组标准。所有配对的原发性肿瘤和转移性样本均进行中心病理复查。对冷冻组织进行靶向和全外显子组测序。对 130 例患者中的 84 例（中位随访 64 个月）进行多变量总生存分析。
通过对 84 例患者（130 例中的 84 例）的中心复查，我们发现 luminal A 型乳腺癌更易发生亚型转换。通过靶向 91 个基因的测序（n=67）和全外显子组测序（n=30），在转移灶中观察到轻微的突变过度。与原发性肿瘤和配对的转移性组织相比，luminal A 型乳腺癌的突变谱最具异质性，突变特征最多。发生亚型转变的肿瘤具有更多的私有突变。晚期转移灶的特异性突变负荷明显高于新发转移灶。最常突变的基因是 TP53 和 PIK3CA。最常见的转移性靶向药物基因是 PIK3CA、PTEN、KDR、ALK、CDKN2A、NOTCH4、POLE、SETD2、SF3B1 和 TSC2。长期预后由肿瘤负荷和转移生物学的结合决定。
对乳腺癌首次未经治疗的转移事件进行分析揭示了大多数在 luminal A 型肿瘤和晚期转移灶中存在的深刻异质性。基于这种分析，可以获得与预后和治疗干预相关的信息，这支持了目前推荐在首次转移复发时进行活检的指南。
该试验在 ClinicalTrials.gov 注册（NCT01956552）。
