Abstract
Simple SummaryIpsilateral breast tumor relapse (IBTR) occurs in 5–10% of localized breast cancers (BCs) within 10 years of incidence, despite proper treatment of the primary lesion. However, the clinical consequences of evolutionary trajectories of BC cells and their impact on IBTR remain poorly understood. Here, we conducted a longitudinal genomic analysis of 10 matched localized BC patients with IBTR. Overall, we identified the differences in homologous recombination deficiency, chromosomal instability, and somatic mutation drivers between primary and relapsed lesions. Our analyses highlighted three clonal architectures that shape by distinct mutagenic processes and subclonal diversification during relapse progression. Finally, this study provided a framework, which integrated actionable biomarkers with clonal architectures, towards improvement of future treatment decisions.The evolutionary trajectories that drive clinical and therapeutic consequences in localized breast cancers (BCs) with ipsilateral breast tumor relapse (IBTR) remain largely unknown. Analyses of longitudinal paired whole-exome sequencing data from 10 localized BC patients with IBTR reveal that, compared to primary breast tumors, homologous recombination (HR) deficiency, inactivation of the HR pathway, chromosomal instability, and somatic driver mutations are more frequent. Furthermore, three major models of evolution in IBTR are summarized, through which relative contributions of mutational signatures shift, and the subclonal diversity expansions are shown. Optimal treatment regimens are suggested by the clinically relevant molecular features, such as HR deficiency (20%) or specific alterations (30%) with sensitivity to available FDA-approved drugs. Finally, a rationale for the development of the therapeutic management framework is provided. This study sheds light on the complicated evolution patterns in IBTR and has significant clinical implications for future improvement of treatment decisions.
Highlights
Breast cancer (BC) remains the most common solid malignancy in women [1]
With the entire extinction of these subclones after treatment, we identified alterations occurring in a punctuated evolution [26], leading to relapse, which originated from an additional driver gene, BRCA2
To investigate whether additional actionable biomarkers might sensitize primary and relapsed lesions to certain targeted agents and improve treatment choices for future patients, we focused on the driver events of two types: (1) homologous recombination deficiency (HRD) phenotype for PARP inhibitors and/or DNA crosslinking agents [17,30], such as platinum salts, and (2) specific alterations presenting in the genome that are predictive of the response to available Food and Drug Administration (FDA)–approved drugs based on the OncoKB database [31]
Summary
Breast cancer (BC) remains the most common solid malignancy in women [1]. Extensive genomic heterogeneity of primary breast tumors is achieved via a sequential series of somatic events through a long mutational history, albeit a curable one when localized (node-negative) [1,2]. 5–10% of localized BCs result in ipsilateral breast tumor relapse (IBTR), a relapsed tumor/lesion occurring at the ipsilateral breast following the initial surgery, within 10 years of incidence, despite proper treatment of the primary lesion [3,4]. Available knowledge about the genomic repertoire of IBTR is limited to some preliminary observations from single tumor samples taken at one time point in the disease course, which suggest that subclonal stratification of alterations could improve the efficacy of targeted therapies [12]. This strategy, while promising, has limitations owing to the underestimation of the true extent of clonal expansion within tumors
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