Breast Cancer Research and Treatment

, Volume 144, Issue 2, pp 307–318 | Cite as

Benefit from anthracyclines in relation to biological profiles in early breast cancer

  • Andrea Rocca
  • Sara Bravaccini
  • Emanuela Scarpi
  • Anita Mangia
  • Stella Petroni
  • Maurizio Puccetti
  • Laura Medri
  • Luigi Serra
  • Monica Ricci
  • Serenella Cerasoli
  • Nicoletta Biglia
  • Roberta Maltoni
  • Donata Casadei Giunchi
  • Lorenzo Gianni
  • Amelia Tienghi
  • Mario Brandi
  • Monica Faedi
  • Piero Sismondi
  • Angelo Paradiso
  • Rosella Silvestrini
  • Dino Amadori
Clinical Trial

Abstract

There are no validated predictors of benefit from anthracyclines. We compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF), and epirubicin in different sequences with CMF alone in a phase III trial on operable breast cancers. Outcomes were analyzed in relation to tumor biological profiles to identify potential predictors of the efficacy of different treatments/drug combinations. Patients with N− or 1–3N+ tumors, were randomized to receive (a) epirubicin (4 cycles) followed by CMF (4 cycles); (b) CMF (4 cycles) followed by epirubicin (4 cycles), or (c) CMF (6 cycles) alone. Immunohistochemical assessments of estrogen (ER) and progesterone (PgR) receptors, HER2 and Ki67 were available for 705 patients (arm A/B/C: 276/269/160). Prognostic and predictive relevance was analyzed by log-rank tests and Cox models. Ki67 > 20 % and absent/low expression of ER and PgR were associated with worsen disease-free (DFS) and overall survival (OS). In patients with triple negative tumors (ER−, PgR−, HER2−), epirubicin-containing regimens yielded better DFS (HR 0.33, 95 % CI 0.17–0.62, P = 0.0007) and OS (HR 0.24, 95 % CI 0.10–0.57, P = 0.001) compared with CMF alone, whereas no differences were found in patients with HER2-positive (HER2+, ER−, PgR−) subtype. Treatment by subtype interaction (HER2-positive vs. others) was significant for DFS (χ 2 = 6.72, P = 0.009). In triple unfavorable (ER−, PgR−, Ki67 > 20 %) tumors, the use of epirubicin yielded better DFS (HR 0.45,95 % CI 0.26–0.78, P = 0.005) and OS (HR 0.30, 95 % CI 0.15–0.63, P = 0.001). Epirubicin-containing regimens seem to be superior to CMF alone in patients with highly proliferating, triple negative or triple unfavorable tumors .

Keywords

Breast cancer Tumor subtypes Adjuvant Predictive factors Anthracyclines 

Abbreviations

CEF

Cyclophosphamide, epirubicin, fluorouracil

CIN

Chromosomal instability

Ch17CEP

Chromosome 17 centromere enumeration probe

CMF

Cyclophosphamide, methotrexate, and fluorouracil

DFS

Disease-free

ER

Estrogen receptor

HR

Hazard ratio

OS

Overall survival

PgR

Progesterone receptor

RPBC

Rapidly proliferating breast cancer

Notes

Acknowledgments

The authors thank Granato Anna Maria and Roagna Riccardo for technical support, Federica Zumaglini, Alessandra Piancastelli, Emanuela Montanari, Britt Rudnas, Ilaria Massa, Patrizia Serra, Monia Dall’Agata and Chiara Tison for data management, and Ursula Elbling for editing the manuscript.

Conflict of interest

The authors have declared no conflicts of interest.

Ethical standards

All patients provided written informed consent before participating in the trial.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Andrea Rocca
    • 1
  • Sara Bravaccini
    • 1
  • Emanuela Scarpi
    • 1
  • Anita Mangia
    • 2
  • Stella Petroni
    • 2
  • Maurizio Puccetti
    • 3
  • Laura Medri
    • 4
  • Luigi Serra
    • 4
  • Monica Ricci
    • 5
  • Serenella Cerasoli
    • 7
  • Nicoletta Biglia
    • 6
  • Roberta Maltoni
    • 1
  • Donata Casadei Giunchi
    • 4
  • Lorenzo Gianni
    • 5
  • Amelia Tienghi
    • 3
  • Mario Brandi
    • 2
  • Monica Faedi
    • 7
  • Piero Sismondi
    • 6
  • Angelo Paradiso
    • 2
  • Rosella Silvestrini
    • 1
  • Dino Amadori
    • 1
  1. 1.Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCSMeldola (FC)Italy
  2. 2.National Cancer Research CentreIstituto Tumori ‘‘Giovanni Paolo II’’BariItaly
  3. 3.Santa Maria delle Croci HospitalRavennaItaly
  4. 4.Morgagni-Pierantoni HospitalForlìItaly
  5. 5.Infermi HospitalRiminiItaly
  6. 6.University of Turin, A.O. Mauriziano “Umberto I” HospitalTurinItaly
  7. 7.Bufalini HospitalCesenaItaly

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