Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group

Fountzilas, George; Skarlos, Dimosthenis; Dafni, Urania; Gogas, Helen; Briasoulis, Evangelos; Pectasides, D.; Papadimitriou, C.; Markopoulos, Christos; Polychronis, Athanasios; Kalofonos, Haralabos P.; Siafaka, Vassiliki; Kosmidis, P.; Timotheadou, Eleni; Tsavdaridis, D.; Bafaloukos, Dimitrios; Papakostas, Pavlos; Razis, Evangelia; Makrantonakis, P.; Aravantinos, G.; Christodoulou, C.; Dimopoulos, Meletios Α.

doi:10.1093/annonc/mdi366

Cited by 100 publications

(97 citation statements)

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“…As the majority of the E-T-CMF patients in our cohort received endocrine therapy after chemotherapy, it is possible that any predictive significance of low MAP-Tau mRNA expression for taxane benefit was cancelled out by resistance to hormonal therapy, resulting in no detectable differences in outcome. Moreover, in the entire HE10/97 trial, the addition of taxanes reduced the hazard of death only in ER-negative patients [15]. Given the correlation of ER and MAP-Tau gene activity, it is probable that ER negative patients who benefit from taxanes are mostly MAP-Tau negative.…”

Section: Discussionmentioning

confidence: 99%

“…The HeCOG prospective trial HE10/97 randomised a total of 595 high-risk (T1-3N1M0 or T3N0M0) breast cancer patients in the period 1997-2000, to receive either four cycles of epirubicin followed by four cycles of intensified cyclophosphamide, methotrexate and 5-fluorouracil combination chemotherapy (E-CMF) or three cycles of epirubicin followed by three cycles of paclitaxel and three cycles of intensified CMF (E-T-CMF) [15]. Chemotherapy cycles were administered every 2 weeks and patients received granulocyte-colony stimulating factor (GCSF) support.…”

Section: Clinical Trialmentioning

confidence: 99%

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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%

Section: Clinical Trialmentioning

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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“…Dose-dense therapy generally requires the use of growth factors, such as granulocyte colony-stimulating factor (G-CSF), to reduce the risk of haematological adverse events. The feasibility of dose densification of a number of chemotherapy regimens in patients with breast cancer has been investigated, including epirubicin (E)/paclitaxel, with or without CMF [8][9][10][11][12], ET-CMF [13] and TEC [14].…”

Section: Introductionmentioning

confidence: 99%

Delivery of adjuvant sequential dose-dense FEC–Doc to patients with breast cancer is feasible, but dose reductions and toxicity are dependent on treatment sequence

Wildiers

Dirix

Neven

et al. 2008

Breast Cancer Res Treat

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International audienceThis study prospectively investigates the impact of dose densification and altering sequence of fluorouracil, epirubicin and cyclophosphamide [FEC] and docetaxel [Doc] on dose delivery and tolerability of adjuvant chemotherapy in breast cancer patients. 117 patients with high-risk primary operable breast cancer were randomized (1:1:2:2) to conventional (three cycles of 3-weekly FEC then three cycles of 3-weekly Doc 100 mg/m or reverse sequence) or dose-dense (dd) treatment (four 10- to 11-day cycles of FEC then four 2-weekly cycles of Doc 75 mg/m, or the reverse). In the dd arms, pegfilgrastim was given on day 2 of each cycle, but only as secondary prophylaxis in conventional arms. The primary endpoint was the proportion of patients completing intended cycles at relative dose intensity ≥85% and this was achieved by 95% of patients in each group except for the ddDoc→FEC group (90%). Dose intensity in the dd arms increased by 48% for FEC and 11% for docetaxel, compared with the conventional arms (both < 0.001). Doc dose reductions were more frequent with dd treatment and when Doc was given after FEC. Grade 3–4 neutropenia was significantly more frequent with conventional treatment, while fatigue and hand–foot syndrome were numerically more common with dd treatment, particularly when Doc was given after FEC. Delivery of adjuvant sequential ddFEC and Doc is feasible with growth factor support, and chemotherapy sequence appeared to affect delivery of target doses and toxicity

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“…The characteristics of these trials are described in brief in S1 Table and detailed information about them can be found in the respective original papers [11][12][13]. At that time, trastuzumab was not licensed as adjuvant treatment; however it was administered in HER2 positive patients upon relapse [14].…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

1976 Significance of PIK3CA mutations in patients with early breast cancer treated with adjuvant chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) study

Papaxoinis¹,

Kotoula²,

Alexopoulou³

et al. 2015

European Journal of Cancer

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Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group

Abstract: The present study failed to demonstrate a significant difference in DFS or OS between the two treatment groups. However, our study has shown clearly that high-dose paclitaxel can be safely incorporated to dose-dense sequential chemotherapy.

Cited by 100 publications

References 16 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

Delivery of adjuvant sequential dose-dense FEC–Doc to patients with breast cancer is feasible, but dose reductions and toxicity are dependent on treatment sequence

1976 Significance of PIK3CA mutations in patients with early breast cancer treated with adjuvant chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) study

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