K.G.Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
Genome Med. 2022 Aug 11;14(1):86. doi: 10.1186/s13073-022-01090-2.
Subclonal evolution during primary breast cancer treatment is largely unexplored. We aimed to assess the dynamic changes in subclonal composition of treatment-naïve breast cancers during neoadjuvant chemotherapy.
We performed whole exome sequencing of tumor biopsies collected before, at therapy switch, and after treatment with sequential epirubicin and docetaxel monotherapy in 51 out of 109 patients with primary breast cancer, who were included in a prospectively registered, neoadjuvant single-arm phase II trial.
There was a profound and differential redistribution of subclones during epirubicin and docetaxel treatment, regardless of therapy response. While truncal mutations and main subclones persisted, smaller subclones frequently appeared or disappeared. Reassessment of raw data, beyond formal mutation calling, indicated that the majority of subclones seemingly appearing during treatment were in fact present in pretreatment breast cancers, below conventional detection limits. Likewise, subclones which seemingly disappeared were still present, below detection limits, in most cases where tumor tissue remained. Tumor mutational burden (TMB) dropped during neoadjuvant therapy, and copy number analysis demonstrated specific genomic regions to be systematically lost or gained for each of the two chemotherapeutics.
Sequential epirubicin and docetaxel monotherapy caused profound redistribution of smaller subclones in primary breast cancer, while early truncal mutations and major subclones generally persisted through treatment.
ClinicalTrials.gov, NCT00496795 , registered on July 4, 2007.
原发性乳腺癌治疗过程中的亚克隆进化在很大程度上尚未被探索。我们旨在评估新辅助化疗期间治疗初治乳腺癌中亚克隆组成的动态变化。
我们对 109 例原发性乳腺癌患者中的 51 例进行了肿瘤活检的全外显子组测序，这些患者在接受序贯表阿霉素和多西紫杉醇单药治疗前、治疗中以及治疗后进行了治疗。这些患者参加了一项前瞻性注册的新辅助单臂 II 期试验。
无论治疗反应如何，在表阿霉素和多西紫杉醇治疗期间，亚克隆都发生了深刻而不同的重新分布。虽然主干突变和主要亚克隆持续存在，但较小的亚克隆经常出现或消失。对原始数据的重新评估，超出了常规的突变检测，表明在治疗过程中看似出现的大多数亚克隆实际上在预处理的乳腺癌中存在，低于传统的检测极限。同样，在大多数仍有肿瘤组织的情况下，看似消失的亚克隆仍低于检测极限。肿瘤突变负担（TMB）在新辅助治疗期间下降，拷贝数分析表明，对于两种化疗药物中的每一种，特定的基因组区域都被系统性地丢失或获得。
序贯表阿霉素和多西紫杉醇单药治疗导致原发性乳腺癌中小亚克隆的深刻重新分布，而早期主干突变和主要亚克隆通常在治疗过程中持续存在。
ClinicalTrials.gov，NCT00496795，于 2007 年 7 月 4 日注册。
