TY - JOUR
TI - 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
AU - Pentheroudakis, George
AU - Kalogeras, Konstantine T.
AU - Wirtz, Ralph M.
AU - and Grimani, Irene
AU - Zografos, George
AU - Gogas, Helen
AU - Stropp, Udo
AU - and Pectasides, Dimitrios
AU - Skarlos, Dimosthenis
AU - Hennig, Guido and
AU - Samantas, Epaminondas
AU - Bafaloukos, Dimitrios
AU - Papakostas, Pavlos
AU - and Kalofonos, Haralabos P.
AU - Pavlidis, Nicholas
AU - Fountzilas,
AU - George
JO - Breast Cancer Research and Treatment
PY - 2009
VL - 116
TODO - 1
SP - 131-143
PB - Springer-Verlag
SN - 0167-6806, 1573-7217
TODO - 10.1007/s10549-008-0144-9
TODO - Estrogen receptor; Progesterone receptor; Microtubule; MAP-Tau;
Predictive value; Breast cancer
TODO - 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 (MAP-Tau) genes in early breast
cancer. Materials and methods Messenger RNA (mRNA) was extracted from
279 formalin-fixed 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 of a taxane to adjuvant
chemotherapy. Further study of the biologic function and utility of
MAP-Tau for individualising adjuvant therapy is warranted.
ER -