Abstract
BackgroundIn breast cancer, gene signatures that predict the risk of metastasis after surgical tumor resection are mainly indicative of early events. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery.MethodsAffymetrix HG U133A and Plus 2.0 array datasets with information on metastasis-free, disease-free or overall survival were accessed via public repositories. Time restricted Cox regression models were used to identify genes associated with metastasis during or after the first three years post-surgery (early- and late-type genes). A sequential validation study design, with two non-adjuvantly treated discovery cohorts (n = 409) and one validation cohort (n = 169) was applied and identified genes were further evaluated in tamoxifen-treated breast cancer patients (n = 923), as well as in patients with non-small cell lung (n = 1779), colon (n = 893) and ovarian (n = 922) cancer.ResultsTen late- and 243 early-type genes were identified in adjuvantly untreated breast cancer. Adjustment to clinicopathological factors and an established proliferation-related signature markedly reduced the number of early-type genes to 16, whereas nine late-type genes still remained significant. These nine genes were associated with metastasis-free survival (MFS) also in a non-time restricted model, but not in the early period alone, stressing that their prognostic impact was primarily based on MFS more than three years after surgery. Four of the ten late-type genes, the ribosome-related factors EIF4B, RPL5, RPL3, and the tumor angiogenesis modifier EPN3 were significantly associated with MFS in the late period also in a meta-analysis of tamoxifen-treated breast cancer cohorts. In contrast, only one late-type gene (EPN3) showed consistent survival associations in more than one cohort in the other cancer types, being associated with worse outcome in two non-small cell lung cancer cohorts. No late-type gene was validated in ovarian and colon cancer.ConclusionsRibosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients. In contrast, high expression of epsin (EPN3) was associated with increased risk of late metastasis. This is of clinical relevance considering the well-understood role of epsins in tumor angiogenesis and the ongoing development of epsin antagonizing therapies.
Highlights
Breast cancer survival time is closely linked to distant metastatic recurrence
Epsin 3 (EPN3) and Ribosome-Related Genes Are Associated with Late Events in estrogen receptor (ER)+ Breast and Lung Cancer
Ribosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients
Summary
Breast cancer survival time is closely linked to distant metastatic recurrence. The absence of metastasis within the first years after diagnosis and primary therapy generally indicates a good long-term prognosis, but late metastatic events do still occur more than five years after diagnosis, with a slowly decreasing risk [1,2,3]. As breast cancer survival is closely linked to distant metastatic recurrence, accurate prediction of late metastasis is of high clinical relevance. While unnecessary treatment of patients with a low risk of late metastasis could be avoided, high-risk patients could benefit from extended adjuvant endocrine therapy [4]. Clinicopathological factors, such as positive nodal status, large tumor size and positive estrogen receptor (ER) status, have been linked to late metastasis [3, 5,6,7,8,9,10,11]. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery.
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