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HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy.

Fountzilas G, Valavanis C, Kotoula V, Eleftheraki AG, Kalogeras KT, Tzaida O, Batistatou A, Kronenwett R, Wirtz RM, Bobos M, Timotheadou E, Soupos N, Pentheroudakis G, Gogas H, Vlachodimitropoulos D, Polychronidou G, Aravantinos G, Koutras A, Christodoulou C, Pectasides D, Arapantoni P - J Transl Med (2012)

Bottom Line: TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001).Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively).None of the parameters tested was associated with response to paclitaxel.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. fountzil@auth.gr

ABSTRACT

Background: HER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy.

Methods: In a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry).

Results: HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel.

Conclusions: This study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines.

Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12611000506998.

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Representative examples of HER2 and TopoIIa protein expression and corresponding gene status. A-D: immunohistochemistry at a magnification of 100Χ (A: HER2 3+, B: HER2 0, C: TopoIIa positive and D: TopoIIa negative). E-H: CISH at a magnification of 600Χ (E: HER2 positive/amplified, F: HER2 negative/diploid, G: TOP2A positive and H: TOP2A negative).
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Figure 2: Representative examples of HER2 and TopoIIa protein expression and corresponding gene status. A-D: immunohistochemistry at a magnification of 100Χ (A: HER2 3+, B: HER2 0, C: TopoIIa positive and D: TopoIIa negative). E-H: CISH at a magnification of 600Χ (E: HER2 positive/amplified, F: HER2 negative/diploid, G: TOP2A positive and H: TOP2A negative).

Mentions: CISH analysis for HER2 was informative in 285 cases (Figure 1, Table 2) with representative examples shown in Figure 2A and 2B. HER2 gene amplification (low and high) was observed in 64 cases (22.5%). Polysomy with 3 to 5 signals was observed in 60 cases, while the rest 161 cases were diploid. Relative quantification (RQ) of HER2 mRNA expression was informative in 314 cases. The distribution of HER2 RQ values was bimodal (Figure 3A) and thus the 75th percentile (37.41 arbitrary units) was used to classify HER2-low and HER2-high expressing tumors, since it was close to the natural cut-off. IHC analysis for HER2 was applicable in 297 cases (Figure 1, 2E and 2F) with the majority of cases (71%) scored as HER2 0-1+, 17.5% as 3+, and 11% as 2+ (Table 2).


HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy.

Fountzilas G, Valavanis C, Kotoula V, Eleftheraki AG, Kalogeras KT, Tzaida O, Batistatou A, Kronenwett R, Wirtz RM, Bobos M, Timotheadou E, Soupos N, Pentheroudakis G, Gogas H, Vlachodimitropoulos D, Polychronidou G, Aravantinos G, Koutras A, Christodoulou C, Pectasides D, Arapantoni P - J Transl Med (2012)

Representative examples of HER2 and TopoIIa protein expression and corresponding gene status. A-D: immunohistochemistry at a magnification of 100Χ (A: HER2 3+, B: HER2 0, C: TopoIIa positive and D: TopoIIa negative). E-H: CISH at a magnification of 600Χ (E: HER2 positive/amplified, F: HER2 negative/diploid, G: TOP2A positive and H: TOP2A negative).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3275536&req=5

Figure 2: Representative examples of HER2 and TopoIIa protein expression and corresponding gene status. A-D: immunohistochemistry at a magnification of 100Χ (A: HER2 3+, B: HER2 0, C: TopoIIa positive and D: TopoIIa negative). E-H: CISH at a magnification of 600Χ (E: HER2 positive/amplified, F: HER2 negative/diploid, G: TOP2A positive and H: TOP2A negative).
Mentions: CISH analysis for HER2 was informative in 285 cases (Figure 1, Table 2) with representative examples shown in Figure 2A and 2B. HER2 gene amplification (low and high) was observed in 64 cases (22.5%). Polysomy with 3 to 5 signals was observed in 60 cases, while the rest 161 cases were diploid. Relative quantification (RQ) of HER2 mRNA expression was informative in 314 cases. The distribution of HER2 RQ values was bimodal (Figure 3A) and thus the 75th percentile (37.41 arbitrary units) was used to classify HER2-low and HER2-high expressing tumors, since it was close to the natural cut-off. IHC analysis for HER2 was applicable in 297 cases (Figure 1, 2E and 2F) with the majority of cases (71%) scored as HER2 0-1+, 17.5% as 3+, and 11% as 2+ (Table 2).

Bottom Line: TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001).Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively).None of the parameters tested was associated with response to paclitaxel.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. fountzil@auth.gr

ABSTRACT

Background: HER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy.

Methods: In a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry).

Results: HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel.

Conclusions: This study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines.

Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12611000506998.

Show MeSH
Related in: MedlinePlus