Gene Transcription Signatures Predict Survival After Tamoxifen, CAF Chemotherapy
Next generation whole-genome expression analysis with RNA sequencing (NGS) identified gene-expression biomarkers.
SAN ANTONIO—Next generation whole-genome expression analysis with RNA sequencing (NGS) identified gene-expression biomarkers associated with survival among postmenopausal women with estrogen receptor-positive (ER+), node-positive breast cancer treated with tamoxifen or tamoxifen plus cyclophosphamide, dozorubicin (Adriamycin), and fluorouracil (CAF) chemotherapy, according to findings from a transcriptome expression analysis of the phase 3 SWOG-8814 trial, presented at the 2015 San Antonio Breast Cancer Symposium.1
Unique genes, functional gene clusters, pathways, and “metagenes” of functionally closely related gene groups, “including previously unreported signatures,” were identified, reported lead author Kathy S. Albain, MD, of Loyola University in Chicago, IL.
Metagenes prognostic for better disease-free survival among women treated with tamoxifen involved transcription regulation, regulation of metabolic processes and, less strongly, regulatory metagenes involved in other cellular processes, Dr Albain reported.
“Distinct metagenes and pathways were very informative for good versus poor prognosis in the tamoxifen-alone arm,” she reported. “ESR1-low plus proliferation-high metagene signatures were associated with more early DFS events, whereas proliferation-high [metagene signatures] best predicted greater risk for later events.”
Disease-free survival over 10 years among women in the tamoxifen-only arm was predicted by a 5-metagene model. That model offered “excellent long-term DFS” prediction in women treated with tamoxifen, dichotomously categorizing patients as either high- and low-risk (P = .002), Dr Albain said. In contrast, genes were “discovered for prediction of chemotherapy benefit only in the first 5 years.”
The 5-metagene signature “defined excellent prognosis for patients on tamoxifen alone, despite positive nodes,” she said.
A separate 3-metagene model differentiated patients who would benefit more from chemotherapy or tamoxifen alone, over 10 years of follow-up. “Chemotherapy is inferior to tamoxifen in the 3-metagene low-risk group, but is superior to tamoxifen in the high-risk subgroup,” she said.
If the findings are validated, the gene signatures could identify patients with “excellent DFS despite positive nodes for endocrine therapy alone as well as others for whom chemotherapy and/or biologics are also required,” she added.
The study utilized 142 tumor samples from women treated with tamoxifen alone, and 212 samples from women treated with tamoxifen plus CAF.
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To identify novel prognostic genes and gene expression clusters that might help identify patients at risk of early and late relapse, and to predict the benefit of CAF among these patients, the researchers analyzed stored RNA from SWOG-8814A participants. Gene sequencing and mRNA expression was analyzed for relationships to disease-free survival. “Gene Ontology, Cytoscape, pathway and hierarchical clustering were used for functional gene and metagene analyses,” Dr Albain concluded.
- Albain KS, Crager MR, Barlow WE, et al. Molecular predictors of outcome on adjuvant CAF plus tamoxifen (T) vs T in postmenopausal patients (pts) with ER+, node+ breast cancer – Transcriptome expression analysis of the phase III trial SWOG-8814. Oral presentation at: San Antonio Breast Cancer Symposium 2015; December 10, 2015; San Antonio, TX.