CHEK2
1100delC is a moderate-risk cancer susceptibility allele that confers a high breast cancer risk in a polygenic setting. Gene expression profiling of
CHEK2
1100delC breast cancers may reveal ...clues to the nature of the polygenic
CHEK2
model and its genes involved. Here, we report global gene expression profiles of a cohort of 155 familial breast cancers, including 26
CHEK2
1100delC mutant tumors. In line with previous work, all
CHEK2
1100delC mutant tumors clustered among the hormone receptor-positive breast cancers. In the hormone receptor-positive subset, a 40-gene
CHEK2
signature was subsequently defined that significantly associated with
CHEK2
1100delC breast cancers. The identification of a
CHEK2
gene signature implies an unexpected biological homogeneity among the
CHEK2
1100delC breast cancers. In addition, all 26
CHEK2
1100delC tumors classified as luminal intrinsic subtype breast cancers, with 8 luminal A and 18 luminal B tumors. This biological make-up of
CHEK2
1100delC breast cancers suggests that a relatively limited number of additional susceptibility alleles are involved in the polygenic
CHEK2
model. Identification of these as-yet-unknown susceptibility alleles should be aided by clues from the 40-gene
CHEK2
signature.
Few studies have examined whether modern radiotherapy and chemotherapy affect the risk of contralateral breast cancer (CBC), and results are inconclusive.
We assessed long-term risk of CBC in a ...predominantly young breast cancer (BC) population (n = 7,221), focusing on the effects of radiation dose, chemotherapy, and family history of BC. Risk of CBC was evaluated using Cox proportional hazards regression models.
Radiotherapy-associated risk of CBC increased with decreasing age at first treatment (age < 35 years, hazard ratio HR = 1.78; 95% CI, 0.85 to 3.72; age > 45 years, HR = 1.09; 95% CI, 0.82 to 1.45). Postmastectomy radiotherapy using direct electron fields led to a significantly lower radiation exposure to the contralateral breast than postlumpectomy radiotherapy using tangential fields. Women treated before age 45 years with postlumpectomy radiotherapy experienced 1.5-fold increased risk of CBC compared with those who had postmastectomy radiotherapy. The joint effects of postlumpectomy radiotherapy and strong family history for BC on risk of CBC were greater than expected when individual risks were summed (HR = 3.52; 95% CI, 2.07 to 6.02; P(departure from additivity) = .043). Treatment with adjuvant chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) was associated with a nonsignificantly decreased risk of CBC in the first 5 years of follow-up but did not reduce CBC risk in subsequent years.
Young patients with BC irradiated with breast tangentials experience increased risk of CBC, especially in those with a positive family history of BC. This finding should be taken into account when advising breast radiation with tangential fields to young patients with BC. Adjuvant chemotherapy seemed to reduce the risk of CBC during the first 5 years after treatment only.
Background: Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces ...high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing hormone-releasing hormone agonist buserelin and estradiol receptor blockade with tamoxifen to determine whether the high estradiol levels induced by tamoxifen could be reduced and whether the antitumor effects would be better. Methods: In a three-arm, randomized, prospective trial, from 1988 through 1995, a total of 161 premenopausal patients with advanced breast cancer were randomly assigned to treatment with buserelin, tamoxifen, or both. Patients with steroid receptor-negative tumors or with tumors of unknown receptor status who had a disease-free interval of less than 2 years were excluded. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer. Patient and tumor characteristics were well balanced among treatment groups. All P values are from two-sided tests. Results: Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated, respectively; P = .11 χ2 test), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P = .03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P = .01). Actuarial 5-year survival percentages were 34.2% (95% confidence interval CI = 20.4%–48.0%), 14.9% (95% CI = 3.9%–25.9%), and 18.4% (95% CI = 7.0%–29.8%), respectively. No differences in antitumor effects were observed between single-agent treatment groups. During combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally; in contrast, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over pretreatment levels. Conclusion: Combined treatment with buserelin and tamoxifen was more effective and resulted in longer overall survival than treatment with either drug alone.
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast ...cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To understand the biological basis of resistance to endocrine therapy is of utmost importance in patients with steroid hormone receptor-positive breast cancer. Not only will this allow us prediction ...of therapy success, it may also lead to novel therapies for patients resistant to current endocrine therapy. DNA methylation in the promoter regions of genes is a prominent epigenetic gene silencing mechanism that contributes to breast cancer biology. In the current study, we investigated whether promoter DNA methylation could be associated with resistance to endocrine therapy in patients with recurrent breast cancer. Using a microarray-based technology, the promoter DNA methylation status of 117 candidate genes was studied in a cohort of 200 steroid hormone receptor-positive tumors of patients who received the antiestrogen tamoxifen as first-line treatment for recurrent breast cancer. Of the genes analyzed, the promoter DNA methylation status of 10 genes was significantly associated with clinical outcome of tamoxifen therapy. The association of the promoter hypermethylation of the strongest marker, phosphoserine aminotransferase (PSAT1) with favorable clinical outcome was confirmed by an independent quantitative DNA methylation detection method. Furthermore, the extent of DNA methylation of PSAT1 was inversely associated with its expression at the mRNA level. Finally, also at the mRNA level, PSAT1 was a predictor of tamoxifen therapy response. Concluding, our work indicates that promoter hypermethylation and mRNA expression of PSAT1 are indicators of response to tamoxifen-based endocrine therapy in steroid hormone receptor-positive patients with recurrent breast cancer.
Mutations in the breast cancer susceptibility genes BRCA1, BRCA2, and CHEK2 are known risk factors for female breast cancer. Mutations in BRCA1 and BRCA2 also are associated with male breast cancer ...(MBC). Similarly, it had been suggested in the original CHEK2 identification report that the CHEK2 1100delC mutation confers an increased risk for MBC. Here, we have evaluated the risk of CHEK2 1100delC for MBC by genotyping CHEK2 1100delC in 23 familial and 71 unselected Dutch MBC cases. None of the 23 familial MBC cases carried the CHEK2 1100delC mutation. In contrast, CHEK2 1100delC was present in 3 of the 71 (4.2%) unselected MBC cases, which was significantly more prevalent than the 1.1% Dutch population frequency assessed in 1,692 individuals (P = 0.05, OR = 4.1, 95% CI 1.2-14.3). Our data suggest that, in the Netherlands, CHEK2 1100delC is associated with an increased risk for MBC.
Background: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor ...prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer–Receptor and Biomarker Group (EORTC-RBG). Methods: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. Results: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). Conclusions: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategies.
Purpose: In the present study, we investigated the association between tumor tissue levels of tissue inhibitor of metalloproteinase-1
(TIMP-1) and prognosis in patients with primary breast cancer and ...analyzed whether TIMP-1 may be useful as a prognostic marker
in combination with urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1).
Experimental Design: In cytosolic extracts of 2984 primary breast tumors, total levels of TIMP-1 were determined using an established, validated
ELISA. Levels of uPA and PAI-1 have previously been determined in the extracts.
Results: Univariate survival analysis showed a significant relationship between higher levels of TIMP-1 (continuous log-transformed
variable) and poor prognosis recurrence-free survival (RFS), overall survival (OS); P < 0.001. Performing isotonic regression analysis, we identified a cut point to classify tumors as TIMP-1-low or TIMP-1-high.
Using this cut point, high levels of TIMP-1 were significantly associated with shorter survival in univariate analysis, both
in the total patient group (RFS, OS; P < 0.001), in the node-negative subgroup (RFS, hazard ratio = 1.28, P = 0.006), and in the node-positive subgroup (RFS, hazard ratio = 1.43, P < 0.001). In multivariate analysis, including uPA and PAI-1, TIMP-1 was significantly associated with shorter RFS, both when
included as a continuous log-transformed ( P = 0.03) and as a dichotomized variable ( P = 0.002).
Conclusions: This study validates previous findings that tumor tissue levels of TIMP-1 are associated with prognosis in patients with
primary breast cancer. It confirms that TIMP-1 may be useful as a prognostic marker in combination with uPA/PAI-1 and adds
substantial positive information on the use of TIMP-1 as a prognostic marker in breast cancer.
The aim of this study was to investigate whether expression of particular drug resistance genes in primary operable breast cancer correlates with response to first-line chemotherapy in advanced ...disease.
We determined mRNA levels of BCRP, LRP, MRP1, MRP2, and MDR1 in 59 primary breast tumor specimens of patients who received chemotherapy as first-line systemic treatment after diagnosis of advanced disease. The relative expression levels were measured by quantitative real-time reverse transcription-PCR and subsequently analyzed in relation to the type of response to chemotherapy, the length of progression-free survival (PFS), and post-relapse overall survival.
For each of these drug resistance genes, a large variation in expression level was observed among the tumors of the different patients. When analyzing mRNA expression in relation to overall response, it was found that the median expression level of these five drug resistance genes in the responding tumors, as compared with nonresponding tumors, was markedly lower. Classification of tumors as high versus low with respect to the expression level of these genes showed that the overall response in the MDR1-high subset (17%), as compared with the MDR1-low subset (68%), was significantly lower (P = 0.005). Although similar differences in response rate were found for subsets of tumors stratified by the expression level of the other drug resistance genes, none of the observed differences were statistically significant. However, in the subgroup of patients treated with anthracycline-based chemotherapy (5-fluorouracil, Adriamycin/epirubicin, and cyclophosphamide), a correlation between response and the expression of BCRP and MRP1 (only PFS) was found, whereas such an association was not present in the cyclophosphamide, methotrexate, and 5-fluorouracil-treated group of patients. Furthermore, high expression of LRP as well as MDR1 was found to be significantly associated with a poor PFS (P = 0.04 and P < 0.001, respectively). For lung resistance-related protein, this association was limited to 5-fluorouracil, Adriamycin/epirubicin, and cyclophosphamide. Expression levels of BCRP, MRP1, or MRP2 were not related with the length of PFS. Furthermore, no correlation between the expression level of these drug resistance genes and post-relapse overall survival was found.
In this pilot study, MDR1 expression in primary breast tumors was inversely related with the efficacy of first-line chemotherapy, and high expression level was a significant predictor of poor prognosis for patients with advanced disease. Apart from MDR1, the expression levels of BCRP, LRP, and MRP1 might have some additional predictive value for clinical outcome.
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