Abstract
BackgroundDiscrepant data have been published on the incidence and prognostic significance of ESR1 gene amplification in early breast cancer.Patients and MethodsFormalin-fixed paraffin-embedded tumor blocks were collected from women with early breast cancer participating in two HeCOG adjuvant trials. Messenger RNA was studied by quantitative PCR, ER protein expression was centrally assessed using immunohistochemistry (IHC) and ESR1 gene copy number by dual fluorescent in situ hybridization probes.ResultsIn a total of 1010 women with resected node-positive early breast adenocarcinoma, the tumoral ESR1/CEP6 gene ratio was suggestive of deletion in 159 (15.7%), gene gain in 551 (54.6%) and amplification in 42 cases (4.2%), with only 30 tumors (3%) harboring five or more ESR1 copies. Gene copy number ratio showed a significant, though weak correlation to mRNA and protein expression (Spearman's Rho <0.23, p = 0.01). ESR1 clusters were observed in 9.5% (57 gain, 38 amplification) of cases. In contrast to mRNA and protein expression, which were favorable prognosticators, gene copy number changes did not obtain prognostic significance. When ESR1/CEP6 gene ratio was combined with function (as defined by ER protein and mRNA expression) in a molecular classifier, the Gene Functional profile, it was functional status that impacted on prognosis. In univariate analysis, patients with functional tumors (positive ER protein expression and gene ratio normal or gain/amplification) fared better than those with non-functional tumors with ESR1 gain (HR for relapse or death 0.49–0.64, p = 0.003). Significant interactions were observed between gene gain/amplification and paclitaxel therapy (trend for DFS benefit from paclitaxel only in patients with ESR1 gain/amplification, p = 0.066) and Gene Functional profile with HER2 amplification (Gene Functional profile prognostic only in HER2-normal cases, p = 0.029).ConclusionsESR1 gene deletion and amplification do not constitute per se prognostic markers, instead they can be classified to distinct prognostic groups according to their protein-mediated functional status.
Highlights
Breast adenocarcinoma is the most common malignant tumor in females with 60–70% of affected patients presenting with localized disease [1]
The Hellenic Cooperative Oncology Group (HeCOG) prospective trial HE10/97 randomised a total of 595 high-risk (T1-3N1M0 or T3N0M0) breast cancer patients to either four cycles of epirubicin followed by four cycles of intensified cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) or three cycles of epirubicin followed by three cycles of paclitaxel and three cycles of intensified CMF (E-T-CMF) every two weeks [12]
No statistically significant Disease-free survival (DFS) or Overall survival (OS) survival difference was seen between E-T-CMF, E-CMF, ET-CMF in the HeCOG trials nor in our patient cohort under study [12,13]
Summary
Breast adenocarcinoma is the most common malignant tumor in females with 60–70% of affected patients presenting with localized disease [1]. Gene amplification of the ESR1 gene, encoding the ER, has been the focus of recently published studies, as gene amplification is the major mechanism behind the cancer-related changes of many oncogenes, including ERBB2 (HER2) [6,7,8,9,10,11]. These studies reported discrepant results and generated much debate about the frequency of ESR1 amplification, its association to clinicopathologic tumor charasteristics and its prognostic significance. Discrepant data have been published on the incidence and prognostic significance of ESR1 gene amplification in early breast cancer
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