Abstract
Adjuvant hormonal therapy is administered to all early stage ER+ breast cancers, and has led to significantly improved survival. Unfortunately, a subset of ER+ breast cancers suffer early relapse despite hormonal therapy. To identify molecular markers associated with early relapse in ER+ breast cancer, an outlier analysis method was applied to a published gene expression dataset of 268 ER+ early-stage breast cancers treated with tamoxifen alone. Increased expression of sets of genes that clustered in chromosomal locations consistent with the presence of amplicons at 8q24.3, 8p11.2, 17q12 (HER2 locus) and 17q21.33-q25.1 were each found to be independent markers for early disease recurrence. Distant metastasis free survival (DMFS) after 10 years for cases with any amplicon (DMFS = 56.1%, 95% CI = 48.3–63.9%) was significantly lower (P = 0.0016) than cases without any of the amplicons (DMFS = 87%, 95% CI = 76.3% –97.7%). The association between presence of chromosomal amplifications in these regions and poor outcome in ER+ breast cancers was independent of histologic grade and was confirmed in independent clinical datasets. A separate validation using a FISH-based assay to detect the amplicons at 8q24.3, 8p11.2, and 17q21.33-q25.1 in a set of 36 early stage ER+/HER2- breast cancers treated with tamoxifen suggests that the presence of these amplicons are indeed predictive of early recurrence. We conclude that these amplicons may serve as prognostic markers of early relapse in ER+ breast cancer, and may identify novel therapeutic targets for poor prognosis ER+ breast cancers.
Highlights
Hormone therapy is widely used for treatment of estrogen receptor positive (ER+) breast cancer and has been shown to result in significantly improved survival and lower rates of recurrence
Survival analysis of these clusters showed that one cluster contained genes whose over-expression associated with poor prognosis, and the other two contained genes over-expressed in good prognosis samples
The presence of genomic amplification in any of these regions leads to outlier expression of their genes, and is a marker of poor prognosis in ER+ breast cancer
Summary
Hormone therapy is widely used for treatment of estrogen receptor positive (ER+) breast cancer and has been shown to result in significantly improved survival and lower rates of recurrence (reviewed in [1,2]). A significant subset of ER+ breast cancer patients treated with adjuvant hormone therapy suffer early disease recurrence. These poor prognosis ER+ tumors tend to have higher grade and show higher proliferative indices and may not be ‘‘addicted’’ to ER –dependent signalling, making them resistant to hormone therapy and prone to early relapse (reviewed in [3,4,5,6]). Several studies have shown that, when the prognostic assays are compared to the gene expression based sub-classification of breast cancers, these assays are essentially identifying Luminal A tumors (low grade, highly ER+ breast cancers, HER2-) as being good prognosis, and Luminal B, ER+ breast cancers (which are ER+, mostly intermediate-to-high grade, some with HER2 amplification) as poor prognosis [12,13,14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
