A comparison among HER2, TP53, PAI-1, angiogenesis, and proliferation activity as prognostic variables in tumours from 408 patients diagnosed with early breast cancer.
BACKGROUND
The prognostic potential of HER2, TP53 mutations, PAI-1 protein levels, angiogenesis and proliferation were investigated in tumours from 408 patients with early breast cancer followed >10 years. One hundred and sixty seven patients (41%) died from breast cancer.


METHODS
Tumour sections were stained for HER2, CD34, and MIB-1. HER2 scores were based on staining intensity, 3+ being considered HER2+. Angiogenesis was scored by the Chalkley method. MIB-1 was evaluated using systematic random sampling. PAI-1 was measured by ELISA. TP53 mutations were evaluated by DGGE analysis and DNA sequencing.


RESULTS
Ninety one patients (22%) were HER2 positive. TP53 was mutated in 101 cases (25%). Median PAI-1, Chalkley and MIB-1 was 0.72 ng/mg protein (range, 0-90 ng/mg protein), 5.00 (range, 2.67-12.00) and 15% (range, 1-83%). MIB-1 was correlated with HER2+, Chalkley counts, TP53 mutations (all p <0.0001), and PAI-1 (p =0.002). In univariate analyses with DSS as endpoint, HER2+ (p <0.0001), mutated TP53 (p <0.0001), high Chalkley (p =0.008), MIB-1 (p =0.002), tumour size (p =0.008), grade (p <0.0001), negative estrogen receptor (p =0.0001), and lymph node status (p <0.0001) were prognostic markers. Among node-negative patients, HER2+ (p =0.0002), mutated TP53 (p =0.001), high PAI-1 levels (p =0.02), and grade (p =0.03) indicated poor DSS. In node-positive patients, HER2+ (p =0.0002), mutated TP53 (p <0.0001), MIB-1 (p =0.01), Chalkley scores (p =0.007), negative estrogen receptor (p <0.0001) and grade (p =0.001) indicated poor prognosis. In multivariate analysis, metastatic nodes (1-3 positive: RR 1.56 95% CI 1.02-2.38; >3 positive: RR 3.70 95% CI 2.54-5.38), HER2+ (RR 1.91, 95% CI 1.35-2.70), mutated TP53 (RR 1.70, 95% CI 1.21-2.38), PAI-1 (RR 1.04, 95% CI 1.01-1.07) and grade 3 (RR 1.96, 95% CI 1.83-3.22) were independent markers of poor outcome.


CONCLUSIONS
Compared to PAI-1 protein levels, Chalkley counts and MIB-1, HER2+ and mutations of TP53 were the strongest independent markers of poor prognosis irrespective of nodal status.
Offersen
Birgitte Vrou
BV
Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
Alsner
Jan
J
Ege Olsen
Karen
K
Riisbro
Rikke
R
Brünner
Nils
N
Sørensen
Flemming Brandt
FB
Sørensen
Boe Sandahl
BS
Schlemmer
Birgitte Olrik
BO
Overgaard
Jens
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C051321:SERPINE1 protein, human; C495901:TP53 protein, human; C513496:MIB1 ligase, human