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Christina Bjerre,
Ann Knoop,
Karsten Bjerre,
Mathilde S Larsen, Katrine L Henriksen,
Maria B Lyng,
Henrik J Ditzel,
Birgitte B Rasmussen,
Nils Brünner,
Bent Ejlertsen,
Anne-Vibeke Lænkholm
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ABSTRACT: Background. The role of tissue inhibitor of metalloproteinases-1 (TIMP-1) in estrogen receptor (ER) positive breast cancer remains to be fully elucidated. We evaluated TIMP-1 as a prognostic marker in patients treated with adjuvant tamoxifen and investigated TIMP-1s association with Ki67 and ER/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) profiles. Material and methods. TIMP-1 expression was evaluated by immunohistochemistry (IHC) on formalin fixed paraffin embedded primary tumor tissue in two independent cohorts comprised of 236 and 192 patients, respectively. Results. No differences in disease free survival (HR 0.98; 95% CI 0.63-1.53; p = 0.92) and overall survival (HR 0.94; 95% CI 0.63-1.43; p = 0.79) were observed according to TIMP-1 status. A significant negative association between TIMP-1 and Ki67 was identified (p = 0.015). TIMP-1 expression did not differ significantly according to ER/PR/HER2 profiles. When analyzed as separate variables PR and HER2 status tended to have a positive but non-significant association with TIMP-1 (PR: p = 0.08; OR 2.54; 95% CI 0.91-7.10, HER2: p = 0.08; OR 0.48; 95% CI 0.21-1.08) whereas ER status was not associated with TIMP-1 expression (p = 0.48; OR 0.68; 95% CI 0.23-1.99). Conclusion. TIMP-1 does not appear to be prognostic in breast cancer patients receiving adjuvant tamoxifen. We identified a negative association between TIMP-1 and Ki67. We did not confirm our previous in vitro findings of a negative association between TIMP-1 and PR.
Acta oncologica (Stockholm, Sweden) 12/2012; · 2.27 Impact Factor
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ABSTRACT: The four human epidermal growth factor receptors (HER1-4) are involved in growth stimulation and may play a role in endocrine resistance. The receptors form dimers, leading to activation by mutual phosphorylation. Our purpose was to explore the role of the activated receptors (pHER1, pHER2, pHER3) in endocrine treated breast cancer in terms of co-expression and association with disease-free survival (DFS) in 1062 patients with ER-positive tumors. Furthermore, HER2 amplification was evaluated. We found positive associations between the phosphorylated receptors. pHER1 and pHER3 were co-expressed with one or two of the other activated receptors in 85% and 89% of tumors, respectively, whereas pHER2 was co-expressed with the other activated receptors in 54% of tumors. Except for HER2, which was associated with poor prognosis, none of the remaining markers were associated with DFS. However, frequent co-expression indicates a role of the other HER-family members in activation of HER2.
Breast (Edinburgh, Scotland) 07/2012; 21(5):662-8. · 2.09 Impact Factor
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ABSTRACT: Estrogen receptor (ER) status is not an optimal marker for response to adjuvant endocrine therapy since approximately 30% of patients with ER-positive tumors eventually relapse. Bcl-2 is regulated by ER and may thus be considered as an indicator of ER activity and a candidate supplementary marker to ER status.
Tumor tissue from 257 patients with ER-positive breast cancer treated with tamoxifen was used for determination of the best threshold for immunohistochemical Bcl-2 assessment as prognostic marker. Subsequently, samples from the Danish patients of the randomized clinical trial BIG 1-98 comprising 1191 ER-positive patients treated with tamoxifen, letrozole or a sequence of the two were immunohistochemically stained for Bcl-2 to further explore the prognostic value of Bcl-2.
Two Bcl-2 levels were found to divide the population of the primary study into significantly different groups according to disease-free survival (DFS). Multivariate analysis confirmed the significance of the lowest level, and showed Bcl-2 to be an independent prognostic marker. Analysis of the Danish cohort of the BIG 1-98 confirmed that Bcl-2 was a significant predictor of DFS, independent of known prognostic markers. However, in an additional analysis of a subset of the Danish cohort of BIG 1-98 including only HER-2 normal patients, the effect of Bcl-2 was not statistically significant.
Low Bcl-2 can predict poor outcome of patients with ER-positive tumors treated with adjuvant endocrine therapy, whereas the use of Bcl-2 for determination of addition of chemotherapy was not supported by this study.
Acta oncologica (Stockholm, Sweden) 03/2012; 51(6):781-9. · 2.27 Impact Factor
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BMC Cancer 07/2009; · 3.01 Impact Factor
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ABSTRACT: Today, the decision to treat breast cancer patients with endocrine therapy relies solely on tumor expression of two predictive factors, the estrogen receptor and the progesterone receptor. Expression of these hormone receptors are, however, not a guarantee for a response to treatment and patients who experience response at first may become resistant after prolonged treatment. This paper describes the use of preclinical models to identify mechanisms and new markers for endocrine sensitivity and resistance and the translation of these data to clinical utility.
Acta oncologica (Stockholm, Sweden) 02/2008; 47(4):795-801. · 2.27 Impact Factor
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Birgitte B Rasmussen,
Meredith M Regan,
Anne E Lykkesfeldt,
Patrizia Dell'Orto,
Barbara Del Curto, Katrine L Henriksen,
Mauro G Mastropasqua,
Karen N Price,
Eliane Méry,
Magali Lacroix-Triki,
Stephen Braye,
Hans J Altermatt,
Richard D Gelber,
Monica Castiglione-Gertsch,
Aron Goldhirsch,
Barry A Gusterson,
Beat Thürlimann,
Alan S Coates,
Giuseppe Viale
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ABSTRACT: The Breast International Group (BIG) 1-98 trial (a randomised double-blind phase III trial) has shown that letrozole significantly improves disease-free survival (DFS) compared with tamoxifen in postmenopausal women with endocrine-responsive early breast cancer. Our aim was to establish whether the benefit of letrozole versus tamoxifen differs according to the ERBB2 status of tumours.
The BIG 1-98 trial consists of four treatment groups that compare 5 years of monotherapy with letrozole or tamoxifen, and sequential administration of one drug for 2 years followed by the other drug for 3 years. Our study includes data from the 4922 patients randomly assigned to the two monotherapy treatment groups (letrozole or tamoxifen for 5 years; 51 months median follow-up [range <1 to 90 months]). A central assessment of oestrogen receptor (ER), progesterone receptor (PgR) and ERBB2 status using paraffin-embedded primary tumour material was possible for 3650 (74%) patients. ER, PgR, and ERBB2 expression were measured by immunohistochemistry (IHC) and ERBB2-positivity was confirmed by fluorescence in-situ hybridisation (FISH). Positive staining in at least 1% of cells was considered to show presence of ER or PgR expression. Tumours were deemed ERBB2-positive if amplified by FISH, or, for the few tumours with unassessable or unavailable FISH results, if they were IHC 3+. Hazard ratios (HR) estimated by Cox modelling were used to compare letrozole with tamoxifen for DFS, which was the primary endpoint, and to assess treatment-by-covariate interactions. The BIG 1-98 trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00004205.
By central assessment 7% (257 of 3650) of tumours were classified as ERBB2-positive. In 3533 patients with tumours confirmed to express ER, DFS was poorer in patients with ERBB2-positive tumours (n=239) than in those with ERBB2-negative tumours (n=3294; HR 2.09 [95% CI 1.59-2.76]; p<0.0001). There was no statistical evidence of heterogeneity in the treatment effect according to ERBB2 status of the tumour (p=0.60 for interaction), thus, letrozole improves DFS compared with tamoxifen regardless of ERBB2 status. The observed HRs were 0.62 (95% CI 0.37-1.03) for ERBB2-positive tumours and 0.72 (0.59-0.87) for ERBB2-negative tumours.
A benefit of letrozole over tamoxifen was noted, irrespective of ERBB2 status of the tumour, and, therefore, ERBB2 status does not seem to be a selection criterion for treatment with letrozole versus tamoxifen in postmenopausal women with endocrine-responsive early breast cancer.
The lancet oncology 01/2008; 9(1):23-8. · 14.47 Impact Factor
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ABSTRACT: To assess whether immunohistochemically stained tissue microarrays (TMA) of 2 mm cores from paraffin embedded tumour tissue may replace whole sections in semi-quantitative evaluation of selected potential markers for endocrine treatment.
Whole sections and 2 mm cores on TMA were used for immunohistochemical staining of potential markers for endocrine treatment. The Allred scoring system was used for the markers with nuclear localisation: the oestrogen receptor, the progesterone receptor, p27 and the oestrogen receptor co-regulator amplified in breast cancer 1 (AIB1). The Allred scoring system was also used for the non-nuclear markers Bcl-2, pS2 and cyclooxygenase 2 (COX-2); the membrane receptors HER-2, insulin-like growth factor I receptor (IGF-IR) and epidermal growth factor receptor were quantified according to the guidelines for the Herceptest.
The data and statistical analyses showed that the semi-quantitative evaluation of oestrogen receptor, progesterone receptor, AIB1, COX-2, HER-2 and IGF-IR on TMA blocks was comparable with analysis on whole sections.
This study shows that semi-quantitative scoring of 2 mm cores on TMA is feasible for several potential markers for endocrine therapy. Considering the small size of many breast tumours, the speed and cost-effectiveness of immunohistochemistry on TMA compared with whole sections, and the importance of the expression level of the proteins, semi-quantitative scoring on TMA has great potential in both retrospective and prospective studies aiming at improving the prediction of response to endocrine treatment.
Journal of Clinical Pathology 05/2007; 60(4):397-404. · 2.31 Impact Factor
