Gene expression profiling of breast cancer patients treated with docetaxel, doxorubicin, and cyclophosphamide within the GEPARTRIO trial: HER-2, but not topoisomerase II alpha and microtubule-associated protein tau, is highly predictive of tumor response

Rody, Achim; Karn, Thomas; Gätje, Regine; Ahr, A.; Solbach, Christine; Kourtis, K.; Munnes, M.; Loibl, Sibylle; Kissler, Stefan; Ruckhäberle, Eugen; Holtrich, Uwe; Minckwitz, Gϋnter von; Kaufmann, M.

doi:10.1016/j.breast.2006.06.008

Cited by 64 publications

(50 citation statements)

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“…Finally, it is always possible that MAPTau has no true predictive value for response to taxanes, or that other molecular characteristics abrogate it: tubulin mutations, variable expression of tubulin isoforms, expression of multidrug resistance proteins, or BCL2 may contribute to taxane resistance in tumors with low MAPTau expression. Indeed, Rody et al performed gene expression profiling in breast carcinomas from 50 patients treated with taxane-based induction chemotherapy and failed to find any predictive significance of MAP-Tau gene expression for pCR [36].…”

Section: Discussionmentioning

confidence: 99%

Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

Pentheroudakis

Kalogeras

Wirtz

et al. 2008

Breast Cancer Res Treat

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Background Estrogen receptor (ER) and progesterone receptor (PgR) protein expression carry weak prognostic and moderate predictive utility for the outcome of early breast cancer patients on adjuvant chemohormonotherapy. We sought to study the predictive significance and correlations of transcriptional profiling of the ER, PgR and microtubule-associated protein Tau (MAPTau) genes in early breast cancer. Materials and methods Messenger RNA (mRNA) was extracted from 279 formalinfixed paraffin-embedded breast carcinomas (T1-3N0-1M0) of patients enrolled in the Hellenic Cooperative Oncology Group (HeCOG) trial HE 10/97, evaluating epirubicin-alkylator based adjuvant chemotherapy with or without paclitaxel (E-T-CMF versus E-CMF). Kinetic reverse transcription polymerase chain reaction (kRT-PCR) was applied for assessment of the expression of estrogen receptor, progesterone receptor and MAP-Tau genes in 274 evaluable patients. Cohort-based cut-offs were defined at the 25th percentile mRNA value for ER and PgR and the median for MAP-Tau. Results Two hundred and ten patients (77%) were ER and/or PgR-positive by immunohistochemistry (IHC). Positive ER and MAP-Tau mRNA status was significantly associated with administration of hormonal therapy and low grade, while MAP-Tau mRNA status correlated with premenopausal patient status. MAP-Tau strongly correlated with ER and PgR mRNA status (Spearmann r = 0.52 and 0.64, P\0.001). The observed chance corrected agreement between determination of hormonal receptor status by kRT-PCR and IHC was moderate (Kappa = 0.41) for ER and fair (Kappa = 0.33) for PgR. At a median follow-up of 8 years, univariate analysis adjusted for treatment showed positive ER mRNA status to be of borderline significance for reduced risk of relapse (HR = 0.65, 95% CI 0.41-1.01, P = 0.055) and death (HR = 0.62, 95% CI 0.36-1.05, P = 0.077), while positive MAP-Tau mRNA status was significantly associated with reduced risk of relapse (HR = 0.50, 95% CI 0.32-0.78, P = 0.002) and death (HR = 0.49, 95% CI 0.29-0.83, P = 0.008). In multivariate analysis, only axillary nodal metastases (HR = 2.33, 95% CI 1.05-5.16, P = 0.04) and MAP-Tau mRNA status (HR = 0.46, 95% CI 0.25-0.85, P = 0.01) independently predicted patient outcome. However, MAP-Tau mRNA levels did not predict enhanced benefit from inclusion of paclitaxel in the adjuvant chemotherapy regimen (test for interaction P = 0.99). No correlation was evident between increasing ER and PgR mRNA transcription and increasing benefit from endocrine therapy in 203 ER and/or PgR IHC-positive patients receiving adjuvant hormone therapy (Wald P = 0.54 for ER, 0.51 for PR). Conclusions ER gene transcription carries weak predictive significance for benefit from endocrine therapy or for outcome, with no apparent dose-response association. The predictive significance is possibly exerted via MAP-Tau gene expression, an ER-inducible tubulin modulator with strong predictive significance for patient outcome. However, MAP-Tau mRNA did not predict benefit from the addition...

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Section: Discussionmentioning

confidence: 99%

Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

Pentheroudakis

Kalogeras

Wirtz

et al. 2008

Breast Cancer Res Treat

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“…In fact, recent trials suggest that the model of a direct relationship between TOP2A amplification, overexpression of TOP2A protein, and benefit from anthracyclines is overly simplistic [10,11]. Thus, although there is a stronger theoretical underpinning for a relationship between the TOP2A gene and in particular its protein product and anthracycline efficacy, there are as much or more data supporting the role of HER2 in predicting differential anthracycline benefit [2,12]. However, while not yet published, data of 2990 ErbB2 positive patients from the second interim analysis of the BCIRG 006 trial had been interpreted to suggest that those 1,057 (35%) patients with TOP2A co-amplification may not require trastuzumab in addition to an anthracycline-containing regimen [13].…”

Section: Introductionmentioning

confidence: 99%

Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is highly prognostic in estrogen receptor (ER) positive breast cancer

Rody

Karn

Ruckhäberle

et al. 2008

Breast Cancer Res Treat

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Introduction Overexpression of Topoisomerase II alpha (TOP2A) has been implicated with gene amplification of the 17q21 amplicon and consecutively with ErbB2 overexpression and amplification. However, gene amplification does not necessarily correlate with RNA and protein expression. There is growing evidence that TOP2A protein expression is a strong prognostic and TOP2A gene amplification might be a predictive marker (particularly for the use of anthracyclines). Methods Large scale analysis was performed using Affymetrix microarray data from n = 1,681 breast cancer patients to evaluate TOP2A expression. Results TOP2A expression showed a strong correlation with tumor size (v 2 -test, P \ 0.001), grading (P \ 0.001), ErbB2 (P \ 0.001) and Ki67 expression (P \ 0.001) as well as nodal status (P = 0.042). Survival analysis revealed a significant prognostic value in ER positive (n = 994; log rank P \ 0.001), but not in ER negative breast cancer patients (n = 369, P = 0.35). The prognostic impact of TOP2A expression was independent of Ki67 expression in ER positive tumors (P = 0.002 and P = 0.007 for high and low Ki67, respectively). Moreover a worse prognosis of high TOP2A expressing tumors was found in the subgroup of ErbB2 negative tumors (P \ 0.001) and a trend among ErbB2 positive tumors (P = 0.11). The prognostic value of TOP2A was independent of whether the patients were untreated or had received adjuvant therapy. In multivariate Cox regression analysis including standard parameters TOP2A emerged to be the top prognostic marker (HR 2.40, 95% CI 1.68-3.43, P \ 0.001). Conclusion TOP2A expression is an independent prognostic factor in ER positive breast cancer and could be helpful for risk assessment in ER positive breast cancer patients.

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“…Although it has been used in the clinical practice as a parameter to indicate those patients who would better benefit from trastuzumab treatment, almost all HER-2-positive tumors develop resistance to this monotherapy (2). Controversial data arise out of the predictor role of this receptor in response to conventional chemotherapy, because it has been described as conferring either sensitivity (3)(4)(5), relative resistance (6)(7)(8), or exerting no influences (9) on anthracycline-based regimes, including doxorubicin. Doxorubicin intercalates in the DNA double strand and forms a stable complex with the enzyme topoisomerase II (TOP2A), the direct target of anthracyclines.…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profile in Response to Doxorubicin–Rapamycin Combined Treatment of HER-2–Overexpressing Human Mammary Epithelial Cell Lines

Trapé

Katayama

Roela

et al. 2012

Molecular Cancer Therapeutics

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HER-2-positive breast cancers frequently sustain elevated AKT/mTOR signaling, which has been associated with resistance to doxorubicin treatment. Here, we investigated whether rapamycin, an mTOR inhibitor, increased the sensitivity to doxorubicin therapy in two HER-2-overexpressing cell lines: C5.2, which was derived from the parental HB4a by transfection with HER-2 and SKBR3, which exhibits HER-2 amplification. The epithelial mammary cell line HB4a was also analyzed. The combined treatment using 20 nmol/L of rapamycin and 30 nmol/L of doxorubicin arrested HB4a and C5.2 cells in S to G 2 -M, whereas SKBR3 cells showed an increase in the G 0 -G 1 phase. Rapamycin increased the sensitivity to doxorubicin in HER-2-overexpressing cells by approximately 2-fold, suggesting that the combination displayed a more effective antiproliferative action. Gene expression profiling showed that these results might reflect alterations in genes involved in canonical pathways related to purine metabolism, oxidative phosphorylation, protein ubiquitination, and mitochondrial dysfunction. A set of 122 genes modulated by the combined treatment and specifically related to HER-2 overexpression was determined by finding genes commonly regulated in both C5.2 and SKBR3 that were not affected in HB4a cells. Network analysis of this particular set showed a smaller subgroup of genes in which coexpression pattern in HB4a cells was disrupted in C5.2 and SKBR3. Altogether, our data showed a subset of genes that might be more robust than individual markers in predicting the response of HER-2-overexpressing breast cancers to doxorubicin and rapamycin combination. Mol Cancer Ther; 11(2); 464-74. Ó2011 AACR.

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Gene expression profiling of breast cancer patients treated with docetaxel, doxorubicin, and cyclophosphamide within the GEPARTRIO trial: HER-2, but not topoisomerase II alpha and microtubule-associated protein tau, is highly predictive of tumor response

Cited by 64 publications

References 19 publications

Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial

Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is highly prognostic in estrogen receptor (ER) positive breast cancer

Gene Expression Profile in Response to Doxorubicin–Rapamycin Combined Treatment of HER-2–Overexpressing Human Mammary Epithelial Cell Lines

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