Differential response of immunohistochemically defined breast cancer subtypes to anthracycline-based adjuvant chemotherapy with or without paclitaxel.
BACKGROUND
The aim of the present study was to investigate the efficacy of adjuvant dose-dense sequential chemotherapy with epirubicin, paclitaxel, and CMF in subgroups of patients with high-risk operable breast cancer, according to tumor subtypes defined by immunohistochemistry (IHC).


METHODS
Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 1,039 patients participating in two adjuvant dose-dense sequential chemotherapy phase III trials were centrally assessed in tissue micro-arrays by IHC for 6 biological markers, that is, estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki67, cytokeratin 5 (CK5), and EGFR. The majority of the cases were further evaluated for HER2 amplification by FISH. Patients were classified as: luminal A (ER/PgR-positive, HER2-negative, Ki67(low)); luminal B (ER/PgR-positive, HER2-negative, Ki67(high)); luminal-HER2 (ER/PgR-positive, HER2-positive); HER2-enriched (ER-negative, PgR-negative, HER2-positive); triple-negative (TNBC) (ER-negative, PgR-negative, HER2-negative); and basal core phenotype (BCP) (TNBC, CK5-positive and/or EGFR-positive).


RESULTS
After a median follow-up time of 105.4 months the 5-year disease-free survival (DFS) and overall survival (OS) rates were 73.1% and 86.1%, respectively. Among patients with HER2-enriched tumors there was a significant benefit in both DFS and OS (log-rank test; p = 0.021 and p = 0.006, respectively) for those treated with paclitaxel. The subtype classification was found to be of both predictive and prognostic value. Setting luminal A as the referent category, the adjusted for prognostic factors HR for relapse for patients with TNBC was 1.91 (95% CI: 1.31-2.80, Wald's p = 0.001) and for death 2.53 (95% CI: 1.62-3.60, p<0.001). Site of and time to first relapse differed according to subtype. Locoregional relapses and brain metastases were more frequent in patients with TNBC, while liver metastases were more often seen in patients with HER2-enriched tumors.


CONCLUSIONS
Triple-negative phenotype is of adverse prognostic value for DFS and OS in patients treated with adjuvant dose-dense sequential chemotherapy. In the pre-trastuzumab era, the HER2-enriched subtype predicts favorable outcome following paclitaxel-containing treatment.
Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. fountzil@auth.gr
George
G
Fountzilas
Urania
U
Dafni
Mattheos
M
Bobos
Anna
A
Batistatou
Vassiliki
V
Kotoula
Helen
H
Trihia
Vassiliki
V
Malamou-Mitsi
Spyros
S
Miliaras
Sofia
S
Chrisafi
Savvas
S
Papadopoulos
Maria
M
Sotiropoulou
Theodoros
T
Filippidis
Helen
H
Gogas
Triantafyllia
T
Koletsa
Dimitrios
D
Bafaloukos
Despina
D
Televantou
Konstantine T
KT
Kalogeras
Dimitrios
D
Pectasides
Dimosthenis V
DV
Skarlos
Angelos
A
Koutras
Meletios A
MA
Dimopoulos
D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017024:Chemotherapy, Adjuvant / Q000379:methods*; D003520:Cyclophosphamide / Q000627:therapeutic use; D018572:Disease-Free Survival; D015251:Epirubicin / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D053555:Keratin-5 / Q000378:metabolism; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D017239:Paclitaxel / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D055815:Young Adult
D018943:Anthracyclines; D003520:Cyclophosphamide; D015251:Epirubicin; D066246:ErbB Receptors; D005472:Fluorouracil; D053555:Keratin-5; D008727:Methotrexate; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C512478:EGFR protein, human