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1.
Breast ; 22(5): 643-9, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23968863

ABSTRACT

BACKGROUND: According to current guidelines, patients with primary breast cancer and 1-3 lymph node metastases will in general be offered adjuvant chemotherapy. AIM: Our objective was to investigate the relationship between markers of proliferation and apoptosis with survival for patients subjected to adjuvant tamoxifen solely. MATERIAL AND METHODS: Tumour cytosol samples from 409 consecutive patients with operable oestrogen receptor positive BC, stage I-III and treated with tamoxifen for 2 or 5 years were assessed for levels of caspase-cleaved cytokeratin-18 (ccCK18), an indicator of apoptosis, by use of an ELISA assay. Data on S-phase fraction (SPF) were available for 370 patients. Survival analyses were performed according to levels of ccCK18 and SPF separately, as well as combined. RESULTS: A wide range of ccCK18 protein levels was found, median 9.97, range 0.0-87.3 pg/µgDNA. Increasing SPFs were significantly associated with a lower distant recurrence-free survival (DRFS) (p = 0.025) and breast cancer survival (BCS) (p = 0.046). In the group with low SPF (below mean), low amounts of ccCK/18 correlated with a shorter DRFS (p = 0.0028) and BCS (p = 0.0027). A Proliferation Index (PI); a quotient of ccCK18/SPF was constructed. Low PI (high ccCK18/SPF ratios) were significantly correlated with an improved survival both when analysed as continuous variables; DRFS (p = 0.021), BCS (p = 0.038) and when divided into quartiles; DRFS (p < 0.001) and BCS (p = 0.0012). A similar correlation was found in patients with 1-3 lymph node metastases; DRFS (p = 0.089) and BCS (p = 0.019). A Cox's proportional hazard model including age, tumour size, lymph node status, PgR and ccCK18/SPF was used for multivariate analysis. High ccCK18/SPF ratios correlated with improved survival; DRFS (HR = 0.47 (0.22-0.98), p = 0.043), and BCS (HR = 0.39 (0.16-1.00), p = 0.049), respectively. CONCLUSION: By use of a proliferation index based on markers of proliferation and apoptosis, a group of patients with 1-3 lymph node metastases with good outcome following adjuvant tamoxifen was identified; this group could possibly be spared adjuvant chemotherapy.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Breast Neoplasms/drug therapy , DNA, Neoplasm/analysis , Keratin-18/analysis , Tamoxifen/therapeutic use , Apoptosis , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Caspases/metabolism , Cell Proliferation , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Keratin-18/metabolism , Lymphatic Metastasis , Middle Aged , Retrospective Studies , Risk Factors , S Phase
2.
Breast ; 22(6): 1142-7, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23968864

ABSTRACT

BACKGROUND: Several anticancer agents including paclitaxel have an inhibitory effect on angiogenesis. AIMS: To compare the overall response rate and time to progression with changes in circulating angiogenic factors during palliative treatment with weekly paclitaxel. MATERIAL AND METHODS: Patients with metastatic BC, ECOG 0-2, received weekly paclitaxel, concomitant with trastuzumab if HER2+ BC (n = 7). Circulating vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were determined at base-line and before start of new course. RESULTS: Fifty-five of 63 included patients were evaluable. The overall response rate including stable disease ≥24 weeks (CR + PD + SD) was obtained in 25 of the evaluable patients (45%). The median time to progression (TTP) was 5.3 months and overall survival (OS) 16.7 months. Patients with triple negative breast cancer (TNBC) showed a trend towards higher base-line VEGF compared with hormone receptor positive or HER2+ tumours and had shorter TTP. Significant differences in VEGF and bFGF levels at 12 weeks were found between patients with longer versus shorter TTP (VEGF: p = 0.046, bFGF: p = 0.005) and between patients gaining versus lacking clinical benefit (VEGF: p = 0.05, bFGF: p = 0.02). CONCLUSIONS: The clinical utility of circulating VEGF may be a useful tool for monitoring treatment efficacy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Fibroblast Growth Factor 2/blood , Paclitaxel/therapeutic use , Vascular Endothelial Growth Factor A/blood , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/chemistry , Disease Progression , Disease-Free Survival , Female , Humans , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Receptor, ErbB-2/analysis , Time Factors , Trastuzumab , Triple Negative Breast Neoplasms/blood , Triple Negative Breast Neoplasms/drug therapy
3.
Breast ; 21(1): 20-6, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21983489

ABSTRACT

In trials in triple negative breast cancer (TNBC), oestrogen and progesterone receptor negativity should be defined as < 1% positive cells. Negativity is a ratio of <2 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less. In routine practice, immunohistochemistry is acceptable given stringent quality assurance. Triple negativity emerging after neoadjuvant treatment differs from primary TN and such patients should not enter TNBC trials. Patients relapsing with TN metastases should be eligible even if their primary was positive. Rare TN subtypes such as apocrine, adenoid-cystic and low-grade metaplastic tumours should be excluded. TN and basal-like (BL) signatures overlap but are not equivalent. Since the significance of basal cytokeratin or EGFR overexpression is not known and we lack validated assays, these features should not be used to subclassify TN tumours. Tissue collection in trials is mandatory so the effect on outcome of different tumour phenotypes and BRCA mutation can be explored. No prospective studies have established that TN tumours have particular sensitivity or resistance to any specific chemotherapy agent or radiation. TNBC patients should be treated according to tumour and clinical characteristics.


Subject(s)
Breast Neoplasms/therapy , Neoplasm Metastasis , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Clinical Trials as Topic , Female , Genes, erbB-2/physiology , Humans , Neoplasm Staging , Research Design
4.
Eur J Cancer ; 46(9): 1580-7, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20413297

ABSTRACT

Previous retrospective studies have shown that high intratumoural levels of vascular endothelial growth factor (VEGF) correlate with an inferior outcome for patients treated with adjuvant tamoxifen. Our objectives were to validate the impact of VEGF on survival after adjuvant tamoxifen and to investigate the interaction between VEGF and treatment duration. For this purpose tumour homogenates from 402 patients with operable oestrogen receptor positive breast cancer (BC), treated with tamoxifen for 2 (n=149) or 5 years (n=253) as the only systemic adjuvant therapy were included. The median follow-up time for surviving patients was 9.8 years (range 0.5-14.8 years). Expression of VEGF was assessed by an enzyme-linked immunosorbent assay and investigated in relation to the standard BC parameters and survival. In the total population, higher VEGF was significantly correlated with shorter recurrence-free survival (RFS) (HR=1.63, 95%CI=1.11-2.39, p=0.010), breast cancer corrected survival (BCCS) (HR=1.82, 95%CI=1.13-2.93, p=0.014) and overall survival (OS) (HR=1.51, 95%CI=1.11-2.05, p=0.009). High VEGF was significantly associated with reduced RFS (HR=2.61, 95%CI=1.45-4.70, p=0.001) after two years of tamoxifen, whilst no difference was seen in patients treated for five years (HR=1.09, 95%CI=0.64-1.84, p=0.760). A statistically significant interaction was observed between high VEGF expression and improved RFS after 5-year tamoxifen (p=0.034). In concordance with previous studies, high VEGF was significantly correlated with shorter survival. We present data not reported previously revealing that patients expressing high levels of VEGF display a better outcome provided that tamoxifen is given for five years. Further studies on the impact of VEGF on a 5-year regimen are motivated.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Neoplasm Proteins/metabolism , Tamoxifen/therapeutic use , Vascular Endothelial Growth Factor A/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/surgery , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Mastectomy, Radical/mortality , Middle Aged , Neoplasm Recurrence, Local/mortality , Receptors, Estrogen/metabolism
5.
Ann Oncol ; 20(10): 1639-46, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19549711

ABSTRACT

BACKGROUND: Triple-negative breast cancer (TNBC) lacking expression of steroid receptors and human epidermal growth factor receptor 2, having chemotherapy as the only therapeutic option, is characterised by early relapses and poor outcome. We investigated intratumoural (i.t.) levels of the pro-angiogenic cytokine vascular endothelial growth factor (VEGF) and survival in patients with TNBC compared with non-TNBC. PATIENTS AND METHODS: VEGF levels were determined by an enzyme immunosorbent assay in a retrospective series consisting of 679 consecutive primary breast cancer patients. RESULTS: Eighty-seven patients (13%) were classified as TNBC and had significantly higher VEGF levels; median value in TNBC was 8.2 pg/microg DNA compared with 2.7 pg/microg DNA in non-TNBC (P < 0.001). Patients with TNBC had statistically significant shorter recurrence-free survival [hazard ratio (HR) = 1.8; P = 0.0023], breast cancer-corrected survival (HR = 2.2; P = 0.004) and overall survival (HR = 1.8; P = 0.005) compared with non-TNBC. Patients with TNBC relapsed earlier than non-TNBC; mean time from diagnosis to first relapse was 18.8 and 30.7 months, respectively. The time between first relapse and death was also shorter in TNBC: 7.5 months versus 17.5 months in non-TNBC (P = 0.087). CONCLUSIONS: Our results show that TNBC have higher i.t. VEGF levels compared with non-TNBC. Ongoing clinical trials will answer if therapy directed towards angiogenesis may be an alternative way to improve outcome in this poor prognosis group.


Subject(s)
Breast Neoplasms/genetics , Vascular Endothelial Growth Factor A/genetics , Adult , Aged , Aged, 80 and over , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Disease-Free Survival , Female , Follow-Up Studies , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Neoplasm Recurrence, Local , Neovascularization, Pathologic/genetics , Receptor, ErbB-2/analysis , Receptor, ErbB-2/genetics , Receptors, Estrogen/analysis , Receptors, Estrogen/genetics , Receptors, Progesterone/analysis , Receptors, Progesterone/genetics , Survival Analysis , Treatment Outcome , Vascular Endothelial Growth Factor A/analysis , Vascular Endothelial Growth Factor A/metabolism
6.
Cancer Res ; 61(5): 2256-60, 2001 Mar 01.
Article in English | MEDLINE | ID: mdl-11280795

ABSTRACT

Wild-type p53 protein has been shown to inhibit angiogenesis through thrombospondin in the preclinical setting. Here, we determined the associations between the expression of the angiogenic factor vascular endothelial growth factor (VEGF) and the p53 status, including different mutation sites and types, in primary breast cancer. Cytosols from 224 primary breast cancer patients were analyzed with an enzyme immunoassay for determination of human VEGF165 protein content. p53 status was determined by cDNA-based sequencing of the entire coding region, by immunohistochemistry (IHC), and by a p53 luminometric immunoassay (LIA) method. Statistically significant associations was found between higher VEGF content and non-wild-type p53 status for all methods; sequence-based data (P = 0.0019), IHC data (P = 0.0068), and the LIA method (r = 0.427; P > 0.001). Highest VEGF values were detected in tumors with p53 insertions, deletions, and stop codon mutations (P = 0.0043). Combining p53 status and VEGF content resulted in additional prognostic information, relapse-free survival (RFS; P = 0.0377), overall survival (OS; P = 0.0319), and breast cancer corrected survival (BCCS; P = 0.0292). In multivariate analysis, the relative hazard increased when the VEGF data were added to the p53 status, with a relative hazard of 1.7 for RFS and 3.0 for BCCS, compared with 1.1 for RFS and 1.4 for BCCS among the patients with either high VEGF content or p53 mutation. Higher VEGF content was statistically significantly correlated with a worse outcome for patients with estrogen receptor-positive tumors receiving adjuvant tamoxifen: RFS (P = 0.0471), OS (P = 0.0134), BCCS (P = 0.0064), as well as in multivariate analysis with point estimates of 3.4 and 2.1 for BCCS and RFS, respectively. VEGF expression is related to p53 status in human breast cancer patients. Combining VEGF with p53 status resulted in better prognostic prediction.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Endothelial Growth Factors/biosynthesis , Genes, p53/genetics , Lymphokines/biosynthesis , Mutation , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Follow-Up Studies , Humans , Immunohistochemistry , Middle Aged , Multivariate Analysis , Sequence Analysis, DNA , Survival Rate , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
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