20 research outputs found
Treatment of breast cancer with different antiprogestins: Preclinical and clinical studies
Abstract
Treatment with antiprogestins in a new treatment modality for breast cancer. Previously, in rats with DMBA-induced mammary tumors we observed significant growth inhibitory effects of chronic treatment with the antiprogestin mifepristone (RU486). In addition, in 11 postmenopausal breast cancer patients, we observed one objective response, six instances of short-term stable disease, and four instances of progressive disease. Side-effects appeared mainly due to antiglucocorticoid properties of the drug. Increased plasma estradiol levels were observed which probably resulted from ovarian (rat) and adrenal (patients) steroidogenesis.
Combined treatment with an antiestrogen in the rat model caused additive growth inhibitory effects. Tumor inhibition after single treatment with mifepristone or tamoxifen was 90 and 75%, respectively. In contrast, when combined, tumor remission similar to that caused by LHRH-agonist treatment (50%) was observed. Even higher tumor remission was found after combined treatment with mifepristone plus LHRH-agonist (75%). In first studies in the rat model we observed significant tumor growth inhibitory effects with two new antiprogestins of seemingly greater potency which cause less unfavorable endocrine side-effects.
In conclusion: combined treatment (antiprogestin plus antiestrogen or LHRH-agonist) may be of value in endocrine therapy of breast cancer
The somatostatin analog Sandostatin (SMS201-995) in treatment of DMBA-induced rat mammary tumors
The effects of treatment with a somatostatin analog (Sandostatin, SMS201-995) were investigated in female rats with dimethylbenzanthracene(DMBA)-induced rat mammary tumors. A 3-week treatment was performed using sandostatin, the LHRH-agonist buserelin alone, or buserelin in combination with sandostatin. Twice daily sandostatin treatment was performed with dosages of 0.05 μg, 0.2 μg, 1 μg, 5 μg, and 20 μg. Buserelin was used in a 2 × 5 μg/day dosage. The combined results from six different experiments show that the various dosages of sandostatin caused no tumor growth inhibition. Somatostatin receptors could not be demonstrated in these mammary tumors. Sandostatin treatment by daily injections did not suppress levels of growth hormone, prolactin, or epidermal growth factor-like activities. Estrogen (ER) and progest
Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer
Combined vascular endothelial growth factor and TP53 status predicts poor response to tamoxifen therapy in estrogen receptor-positive advanced breast cancer
PURPOSE: In recent studies, we showed that TP53 gene mutation or high
levels of cytosolic vascular endothelial growth factor (VEGF) in estrogen
receptor (ER)-alpha-positive primary breast tumors predict a poor disease
outcome for patients treated with first-line tamoxifen for advanced
disease. Mutant TP53 may up-regulate VEGF, whereas, on the other hand,
wild-type TP53 may decrease VEGF production. EXPERIMENTAL DESIGN: In the
present study, we aimed to assess the combined predictive value of TP53
gene mutation and VEGF status of 160 advanced breast cancer patients with
ER-positive tumors who were treated with tamoxifen (median follow-up from
start of tamoxifen treatment, 64 months). To assess TP53 gene mutation
status, the entire open reading frame was sequenced; for VEGF status, an
ELISA was used. RESULTS: In univariate analysis, both TP53 gene mutation
(28% of the tumors) and a VEGF level above the median value were
significantly associated with a short progression-free survival,
post-relapse overall survival, and a poor rate of response to tamoxifen.
In Cox multivariate regression analysis including the traditional
predictive factors, the addition of TP53 gene mutation and VEGF status,
alone or in combination, significantly predicted a poor efficacy of
tamoxifen treatment. When the two factors were combined, a significantly
decreased odds ratio was seen for the rate of response (odds ratio, 0.27).
Similarly, an increased hazard ratio (HR) was seen for progression-free
survival (HR, 2.32) and post-relapse overall survival (HR, 1.68) in the
group with mutant TP53 and high VEGF compared with the group with both
risk factors absent. CONCLUSIONS: Combined TP53 gene mutation status and
high VEGF levels of ER-positive primary breast tumors independently
predict a poor course of the disease of patients with advanced breast
cancer treated with tamoxifen. These patients, having unfavorable tumor
characteristics, might benefit more from other types of (individualized)
treatment protocols
The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients
The antigen levels of components of the urokinase-type plasminogen
activator (uPA) system of plasminogen activation are correlated with
prognosis in several types of cancers, including breast cancer. In the
present study involving 2780 patients with primary invasive breast cancer,
we have evaluated the prognostic importance of the four major components
of the uPA system [uPA, the receptor uPAR (CD87), and the inhibitors PAI-1
and PAI-2]. The antigen levels were determined by ELISA in cytosols
prepared from primary breast tumors. The levels of the four factors
significantly correlated with each other; the Spearman rank correlation
coefficients (r(s)) ranged from 0.32 (between PAI-2 and PAI-1 or uPAR) to
0.59 (between uPA and PAI-1). The median duration of follow-up of patients
still alive was 88 months. In the multivariate analyses for relapse-free
survival (RFS) and overall survival (OS), we defined a basic model
including age, menopausal status, tumor size and grade, lymph node status,
adjuvant therapy, and steroid hormone receptor status. uPA, uPAR, PAI-1,
and PAI-2 were considered as categorical variables, each with two cut
points that were established by isotonic regression analysis. Compared
with tumors with low levels, those with intermediate and high levels
showed a relative hazard rate (RHR) and 95% confidence interval (95% CI)
of 1.22 (1.02-1.45) and 1.69 (1.39-2.05) for uPA, and 1.32 (1.14-1.54) and
2.17 (1.74-2.70) for PAI-1, respectively, in multivariate analysis for RFS
in all patients. Compared with tumors with high PAI-2 levels, those with
intermediate and low levels showed a poor RFS with a RHR (95% CI) of 1.30
(1.14-1.48) and 1.76 (1.38-2.24), respectively. Similar results were
obtained in the multivariate analysis for OS in all patients. Furthermore,
uPA and PAI-1 were independent predictive factors of a poor RFS and OS in
node-negative and node-positive patients. PAI-2 also added to the
multivariate models for RFS in node-negative and node-positive patients,
and in the analysis for OS in node-negative patients. uPAR did not further
contribute to any of the multivariate models. A prognostic score was
calculated based on the estimates from the final multivariate model for
RFS. Using this score, the difference between the highest and lowest 10%
risk groups was 66% in the analysis for RFS at 10 years and 61% in the
analysis for OS. Moreover, separate prognostic scores were calculated for
node-negative and node-positive patients. In the 10% highest risk groups,
the proportion of disease-free patients was only 27 +/- 6% and 9 +/- 3% at
10 years for node-negative and node-positive patients, respectively. These
proportions were 86 +/- 4% and 61 +/- 6% for the corresponding 10% lowest
risk groups of relapse. We conclude that several components of the uPA
system are potential predictors of RFS and OS in patients with primary
invasive breast cancer. Knowledge of these factors could be helpful to
assess the individual risk of patients, to select various types of
adjuvant treatment and to identify patients who may benefit from targeted
therapies that are currently being developed
Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer
TP53 has been implicated in regulation of the cell cycle, DNA repair, and
apoptosis. We studied, in primary breast tumors through direct cDNA
sequencing of exons 2-11, whether TP53 gene mutations can predict response
in patients with advanced disease to either first-line tamoxifen therapy
(202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41
patients, of whom 46% responded). TP53 mutations were detected in 90 of
243 (37%) tumors, and one-fourth of these mutations resulted in a
premature termination of the protein. The mutations were observed in 32%
(65 of 202) of the primary tumors of tamoxifen-treated patients and in 61%
(25 of 41) of the primary tumors of the chemotherapy patients. TP53
mutation was significantly associated with a poor response to tamoxifen
[31% versu