Microsatellite instability predicts poor short-term survival in patients with advanced breast cancer after high-dose chemotherapy and autologous stem-cell transplantation.
OBJECTIVE
The purpose is to define molecular prognostic factors in patients with advanced breast cancer treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT).


METHODS
Thirty-nine patients with breast cancer and extensive lymph node (level III) and/or systemic metastases from a prospective single-center study of sequential HDCT/ASCT were studied. Microsatellite analysis was performed after laser microdissection using 15 markers selected for sensitive detection of microsatellite instability (MSI) in breast cancer. Exons 5-9 of the P53 gene were directly sequenced. Expression of P53, HER-2/neu, and the mismatch repair proteins hMSH2 and hMLH1 was evaluated by immunohistochemistry.


RESULTS
MSI of at least three markers was detected in 13 of 39 patients (33%) and was predominantly found at tetranucleotide markers. All MSI-positive tumors showed normal expression of hMSH2 and hMLH1. Complete sequence analysis of exons 5-9 of the P53 gene was successful in 34 cases; 18% (n = 6) revealed a mutation. Overexpression of HER-2/neu and P53 was observed in 7 (22%) and 12 (46%) of 26 evaluated cases, respectively. The presence of MSI strongly correlated with shorter overall survival (OS; P = 0.0004) and progression-free survival (PFS; P = 0.02). None of the other investigated clinical or molecular factors correlated with OS in univariate analyses, with the exception of menopausal status and previous adjuvant chemotherapy. Testing various multivariate Cox regression models, MSI remained a highly significant, independent, and adverse risk factor for OS.


CONCLUSIONS
MSI is frequent in advanced breast cancer and could be an indicator of chemotherapy resistance and poor prognosis in breast cancer patients treated with HDCT/ASCT.
Wild
Peter J
PJ
Departments of Pathology and Hematology and Oncology, University of Regensburg, Regensburg, Germany.
Reichle
Albrecht
A
Andreesen
Reinhard
R
Röckelein
Georg
G
Dietmaier
Wolfgang
W
Rüschoff
Josef
J
Blaszyk
Hagen
H
Hofstädter
Ferdinand
F
Hartmann
Arndt
A
D000328:Adult; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D005091:Exons; D005260:Female; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008593:Menopause; D018895:Microsatellite Repeats; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D033581:Stem Cell Transplantation; D013997:Time Factors; D016896:Treatment Outcome
D018719:Erb-b2 Receptor Tyrosine Kinases