Association of GATA3, P53, Ki67 status and vascular peritumoral invasion are strongly prognostic in luminal breast cancer.
BACKGROUND
Breast cancers are traditionally divided into hormone-receptor positive and negative cases. This classification helps to guide patient management. However, a subgroup of hormone-receptor positive patients relapse irrespective of hormonal therapy. Gene expression profiling has classified breast tumours into five major subtypes with significant different outcome. The two luminal subtypes, A and B, show high expression of ESR1, GATA3 and FOXA1 genes. Prognostic biomarkers for oestrogen receptor (ER)-positive cases include progesterone receptor (PR) and androgen receptor (AR), and proteins related to proliferation or apoptotic resistance. The aim of this study was to identify the best predictors of success of hormonal therapy.


METHODS
By immunohistochemistry we studied 10 markers in a consecutive series of 832 cases of breast carcinoma treated at the Paoli-Calmettes Institute from 1990 to 2002 and deposited onto tissue microarrays (TMA). These markers were luminal-related markers ER, PR, AR, FOXA1 and GATA3 transcription factors, proliferation-related Ki67 and CCND1, ERBB2, anti-apoptotic BCL2 and P53. We also measured vascular peritumoural invasion (VPI), size, grade and lymph node involvement. For 143 cases, gene expression profiles were available. Adjuvant chemotherapy and hormonal therapy were given to high- and low-risk patients, respectively. The 162 events observed and taken into account were metastases.


RESULTS
Molecular expression of the 10 parameters and subtype with ER status were strongly correlated. Of the 67 luminal A cases of this series, 63 were ER-positive. Multivariate analyses showed the highly significant prognostic value of VPI (hazard ratio (HR) = 2.47), Ki67 (HR = 2.9), P53 (HR = 2.9) and GATA3 (HR = 0.5) for the 240 patients who received hormonal therapy.


CONCLUSIONS
A panel of three antibodies (Ki67, P53 and GATA3) associated with VPI can significantly improve the traditional prognosticators in predicting outcome for ER-positive breast cancer patients receiving hormonal therapy.
Jacquemier
Jocelyne
J
Département d'Oncologie Moléculaire Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, UMR891 Inserm, IFR137, 232 Bd sainte Marguerite Marseille, France. jacquemierj@marseille.fnclcc.fr
Charafe-Jauffret
Emmanuelle
E
Monville
Florence
F
Esterni
Benjamin
B
Extra
Jean Marc
JM
Houvenaeghel
Gilles
G
Xerri
Luc
L
Bertucci
François
F
Birnbaum
Daniel
D
D000230:Adenocarcinoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D019254:Genes, bcl-2; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics* / Q000378:metabolism; D008207:Lymphatic Metastasis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D050990:GATA3 Transcription Factor; D051541:Hepatocyte Nuclear Factor 3-alpha; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53; C506487:ESR1 protein, human; C496499:FOXA1 protein, human; C494749:GATA3 protein, human; C495901:TP53 protein, human