Clinical evaluation of developed PCR-based method with hydrolysis probes for TOP2A copy number evaluation in breast cancer samples

Żaczek, Anna; Markiewicz, Aleksandra; Jaśkiewicz, Janusz; Pieńkowski, Tadeusz; Rhone, Piotr; Jassem, Jacek; Wełnicka-Jaśkiewicz, Marzena

doi:10.1016/j.clinbiochem.2010.04.060

Cited by 10 publications

(10 citation statements)

References 34 publications

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“…The most important evidence provided herein is that TOP2A gene amplification is a favorable prognostic factor in HER2-positive patients treated with trastuzumab. Patients with HER2-positive/ TOP2A non-amplified or deleted tumors did not seem to benefit from trastuzumab-based regimens and had an unfavorable outcome compared to TOP2A amplified tumors, in line with recent reports on TOP2A gene dosage [35] and TOP2A gene amplification [36]. …”

Section: Discussionsupporting

confidence: 79%

Topoisomerase II alpha gene amplification is a favorable prognostic factor in patients with HER2-positive metastatic breast cancer treated with trastuzumab

et al. 2012

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BackgroundThe vast majority of patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab eventually develop resistance to this agent. There is an unmet need therefore, for identifying biological markers with possible prognostic/predictive value in such patients. The aim of this study was to investigate the prognostic role of topoisomerase II alpha gene (TOP2A) amplification and protein (TopoIIa) expression in patients treated with trastuzumab-containing regimens.MethodsFormalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 225 eligible patients treated with trastuzumab. Protein expression of ER, PgR, Ki67, PTEN, HER2 and TopoIIa were centrally assessed by immunohistochemistry. HER2 and TOP2A gene amplification was evaluated by fluorescence in situ hybridization. PIK3CA mutations were identified by single nucleotide polymorphism genotyping. Survival was evaluated from the initiation of trastuzumab as 1st line treatment to the date of last follow-up or death.ResultsAmong the 225 samples analyzed, only 137 (61%) were found to be HER2-positive. TOP2A was amplified in 41% and deleted in 16% of such tumors. TOP2A gene amplification was more frequent in ER-negative tumors. TopoIIa protein expression was observed in the majority (65%) of the samples and was associated with ER-positive status, high Ki67 expression, presence of PTEN protein and PIK3CA mutations. Median follow-up for patients treated in the 1st line was 51 months. Survival was more prolonged with trastuzumab-containing treatment in HER2-positive patients (50 months, log-rank, p=0.007). TOP2A non-amplified or deleted tumors were associated with increased risk for death compared to TOP2A amplified tumors (HR=2.16, Wald’s p=0.010 and HR=2.67, p=0.009, respectively). In multivariate analysis, a significant interaction of TOP2A with anthracycline treatment (either in the adjuvant or the 1st line setting) was observed for survival (Wald’s p=0.015). Among the TOP2A amplified subgroup, anthracycline-treated patients were associated with decreased risk for death.ConclusionsTOP2A gene amplification was shown to be a favorable prognostic marker in HER2-positive MBC patients treated with trastuzumab, such an effect however, appears to rather be related to treatment with anthracyclines (predictive marker for benefit from anthracyclines). The results of the present retrospective study warrant validation in larger cohorts of patients treated in the context of randomized trials.

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Section: Discussionsupporting

confidence: 79%

Topoisomerase II alpha gene amplification is a favorable prognostic factor in patients with HER2-positive metastatic breast cancer treated with trastuzumab

et al. 2012

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“…A large body of literature has suggested the possibility of guiding therapy based on TOP2A status [8,11,12]; however, a recent meta-analysis did not confirm the predictive value of TOP2A alterations [9]. We recently found a relatively high frequency of TOP2A amplifications in HER-2 Ϫ breast cancers [13], which challenges the common opinion that TOP2A alteration is mostly restricted to HER-2 ϩ tumors and may be considered as a prognostic and predictive marker only in this subgroup [7,12,14]. Thus, the primary aim of this study was to investigate the clinical significance of TOP2A anomalies measured using quantitative real-time polymerase chain reaction (qPCR) in a large group of consecutive breast cancer patients with both HER-2 Ϫ and HER-2 ϩ tumors.…”

Section: Introductionmentioning

confidence: 86%

Prognostic Significance of TOP2A Gene Dosage in HER-2-Negative Breast Cancer

et al. 2012

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After completing this course, the reader will be able to:1. Describe the prognostic role of TOP2A gene dosage determined by quantitative PCR in HER-2-negative breast cancer.2. Describe the relationship between HER-2 status and TOP2A status in breast cancer tumors.3. Gain greater understanding of methods used for TOP2A status determination, including the advantages of quantitative PCR.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTBackground. Previous studies showed the prognostic and predictive impact of human epidermal growth factor receptor 2 (HER-2) gene alterations analyzed separately and

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“…From this clinical cohort, 349 patient cases, 442 paraffin blocks, and 527 RNA samples were included in the present study according to (a) availability of gene expression data for all five mRNA markers examined, (b) matched non-macrodissected (NMD) and macrodissected (MD) RNA samples, and (c) matched primary/lymph node RNA samples. Gene expression was analyzed in three series of matched RNA samples: (a) MD vs NMD from primary tumors (P); (b) MD vs NMD from metastatic lymph nodes [39]; and (c) matched P and LN samples (mP, mLN). The outline of these study groups is shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Sample parameters affecting the clinical relevance of RNA biomarkers in translational breast cancer research

et al. 2012

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In the frame of translational breast cancer research, eligibility criteria for formalin-fixed paraffin-embedded tissue (FFPE) material processing for gene expression studies include tumor cell content (TCC) and sample site (primary vs metastatic tumors). Herein we asked whether the observed differences in gene expression between paired samples with respect to TCC and sample site also have different clinical significance. We assessed ESR1, ERBB2, MAPT, MMP7, and RACGAP1 mRNA expression with real time PCR in paired samples before (NMD) and after macrodissection (MD) from 98 primary tumors (PMD, PNMD) and 72 metastatic lymph nodes (LNMD, LNNMD), as well as from 93 matched P (mP) and LN (mLN). TCC range was 2.5–75 % in the NMD series and 28–98 % in the MD and in the mP/mLN series. The prognostic effect of these markers, individually or in clusters, remained stable between paired PMD/NMD. In comparison, cluster classification failed in the LNNMD group with lower TCC. In the mP/mLN cohort, RACGAP1 mRNA expression was of prognostic significance when tested in mLN samples (p < 0.001). Similarly, luminal B, HER2, and triple negative tumors were of dismal prognosis when classified in the LN component of the same series (mLN, overall survival: p = 0.013, p = 0.034, and p = 0.007, respectively). In conclusion, the clinical relevance of the RNA markers examined may be affected by TCC in metastatic LN samples but not in primary tumors, while it differs between primary tumors and matched metastases. These data will facilitate the design of translational studies involving FFPE sample series.Electronic supplementary materialThe online version of this article (doi:10.1007/s00428-012-1357-1) contains supplementary material, which is available to authorized users.

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Clinical evaluation of developed PCR-based method with hydrolysis probes for TOP2A copy number evaluation in breast cancer samples

Cited by 10 publications

References 34 publications

Topoisomerase II alpha gene amplification is a favorable prognostic factor in patients with HER2-positive metastatic breast cancer treated with trastuzumab

Topoisomerase II alpha gene amplification is a favorable prognostic factor in patients with HER2-positive metastatic breast cancer treated with trastuzumab

Prognostic Significance of TOP2A Gene Dosage in HER-2-Negative Breast Cancer

Sample parameters affecting the clinical relevance of RNA biomarkers in translational breast cancer research

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