| 1. |
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| 2. |
- Alkner, Sara, et al.
(författare)
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Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women : Results from a controlled randomised trial
- 2009
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 45:14, s. 2496-2502
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial. Patients and methods: Premenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years. Results: In the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p = 0.02). In subgroup analysis the risk reduction was most pronounced in patients less than40 years of age (HR 0.09, p = 0.02). A risk reduction was also seen in women 40-49 years of age or ≥50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time. Conclusion: In this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women less than40 years of age. The effect of tamoxifen was not significantly dependent on time.
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| 3. |
- Borgquist, Signe, et al.
(författare)
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Prognostic impact of tumour-specific HMG-CoA reductase expression in primary breast cancer
- 2008
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:5, s. R79-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: We have previously reported that tumour-specific expression of the rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR), in the mevalonate pathway is associated with more favourable tumour parameters in breast cancer. In the present study, we examined the prognostic value of HMG-CoAR expression in a large cohort of primary breast cancer patients with long-term follow up. METHODS: The expression of HMG-CoAR was assessed by immunohistochemistry on tissue microarrays with tumour specimens from 498 consecutive cases of breast cancer with a median follow-up of 128 months. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the rate of recurrence-free survival (RFS) and breast cancer specific survival (BCSS). RESULTS: In line with our previous findings, tumour-specific HMG-CoAR expression was associated with low grade (p < 0.001), small size (p = 0.007), oestrogen receptor (ER) positive (p = 0.01), low Ki-67 (p = 0.02) tumours. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS, even when adjusted for established prognostic factors (relative risk [RR] = 0.60, 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In ER-negative tumours, however, there was a trend, that was not significantly significant, towards a shorter RFS in HMG-CoAR expressing tumours. CONCLUSIONS: HMG-CoAR expression is an independent predictor of a prolonged RFS in primary breast cancer. This may, however, not be true for ER-negative tumours. Further studies are needed to shed light on the value of HMG-CoAR expression as a surrogate marker of response to statin treatment, especially with respect to hormone receptor status.
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| 4. |
- Brennan, Donal J., et al.
(författare)
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CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance
- 2006
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:21, s. 6421-6431
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Hypoxia in breast cancer is associated with poor prognosis and down-regulation of the estrogen receptor. Carbonic anhydrase IX (CA IX) is a hypoxia-inducible gene that has been associated with poor outcome in many epithelial cancers. Previous studies of CA IX in breast cancer have been carried out on mixed cohorts of premenopausal and postmenopausal patients with locally advanced disease and varying treatment regimens. We examined the potential prognostic and predictive role of CA IX in premenopausal breast cancer patients. Experimental Design: Using tissue microarrays, we analyzed CA IX expression in 400 stage 11 breast cancers from premenopausal women. The patients had previously participated in a randomized control trial comparing 2 years of tamoxifen to no systemic adjuvant treatment. Median follow-up was 13.9 years. Results: CA IX expression correlated positively with tumor size, grade, hypoxia-inducible factor 1 alpha Ki-67, cyclin E, and cyclin A2 expression. CA IX expression correlated negatively with cyclin D1, estrogen receptor, and progesterone receptor. CA IX expression was associated with a reduced relapse-free survival (P = 0.032), overall survival (P = 0.022), and breast cancer specific survival (P = 0.005). Multivariate analysis revealed that CA IX was an independent prognostic marker in untreated patients with one to three positive lymph nodes (hazard ratio, 3.2; 95% confidence interval, 1.15-9.13; P = 0.027). Conclusion: CA IX is marker of poor prognosis in premenopausal breast cancer patients and it is an independent predictor of survival in patients with one to three positive lymph nodes. As all these patients received locoregional radiation therapy, CA IX may be associated with resistance to radiotherapy.
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| 5. |
- Dihge, Looket, et al.
(författare)
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Epidermal growth factor receptor (EGFR) and the estrogen receptor modulator amplified in breast cancer (AIB1) for predicting clinical outcome after adjuvant tamoxifen in breast cancer.
- 2008
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 109:2, s. 255-262
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Tidskriftsartikel (refereegranskat)abstract
- The epidermal growth factor receptor (EGFR) and the estrogen receptor (ER) modulator Amplified In Breast cancer-1 (AIB1) have been reported to be of importance for the prognosis of breast cancer patients. We have analyzed AIB1 and EGFR by immunohistochemistry in primary breast cancers (n = 297) arranged in a tissue microarray in order to predict outcome after adjuvant endocrine therapy with tamoxifen for two years. High expression of AIB1 was associated with DNA-nondiploidy, high S-phase fraction, HER2 amplification, and short term (≤2 years) distant disease-free survival (DDFS), independent of ER status. High expression of EGFR was strongly associated to ER negativity and also correlated with progesterone receptor negativity, high S-phase fraction, and inversely correlated with nodal metastases. In univariate analysis, high EGFR was associated with shorter DDFS (hazard ratio 2.1; P = 0.017), and reached borderline significance in a multivariate analysis, adjusting for ER, menopausal and lymph node status, tumor size, and HER2 (P = 0.057). In conclusion, both AIB1 and EGFR were associated to DDFS for breast cancer patients treated with two years of adjuvant tamoxifen; AIB1 with the development of early distant recurrences, indicating association between high AIB1 and resistance to tamoxifen during treatment, and EGFR with distant recurrences up to a follow up of five years.
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| 6. |
- Dolled-Filhart, Marisa, et al.
(författare)
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Classification of breast cancer using genetic algorithms and tissue microarrays
- 2006
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:21, s. 6459-6468
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: A multitude of breast cancer mRNA profiling studies has stratified breast cancer and defined gene sets that correlate with outcome. However, the number of genes used to predict patient outcome or define tumor subtypes by RNA expression studies is variable, nonoverlapping, and generally requires specialized technologies that are beyond those used in the routine pathology laboratory. It would be ideal if the familiarity and streamlined nature of immunohistochemistry could be combined with the rigorously quantitative and highly specific properties of nucleic acid-based analysis to predict patient outcome. EXPERIMENTAL DESIGN: We have used AQUA-based objective quantitative analysis of tissue microarrays toward the goal of discovery of a minimal number of markers with maximal prognostic or predictive value that can be applied to the conventional formalin-fixed, paraffin-embedded tissue section. RESULTS: The minimal discovered multiplexed set of tissue biomarkers was GATA3, NAT1, and estrogen receptor. Genetic algorithms were then applied after division of our cohort into a training set of 223 breast cancer patients to discover a prospectively applicable solution that can define a subset of patients with 5-year survival of 96%. This algorithm was then validated on an internal validation set (n=223, 5-year survival=95.8%) and further validated on an independent cohort from Sweden, which showed 5-year survival of 92.7% (n=149). CONCLUSIONS: With further validation, this test has both the familiarity and specificity for widespread use in management of breast cancer. More generally, this work illustrates the potential for multiplexed biomarker discovery on the tissue microarray platform.
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| 7. |
- Fernö, Mårten, et al.
(författare)
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Analys av HER2 i bröstcancer kvalitetssäkrad. Viktig behandlingsprediktiv och prognostisk faktor.
- 2008
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 105:32-33, s. 2181-2184
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Tidskriftsartikel (refereegranskat)abstract
- Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in 15-20% of all breast cancers, and is associated with an aggressive tumour type with impaired prognosis and a predictive marker for trastuzumab treatment. HER2 status can be determined by immunohistochemistry (IHC) at protein level and by fluorescence in situ hybridisation (FISH) analysing gene amplification, and it is recommended that it should be performed in all primary breast cancers. In a quality control study the reproducibility of HER2 status was assessed by distributing eleven breast tumours prepared on a tissue microarray to 25 pathology laboratories in Sweden in 2005 and 2006. The concordance between the laboratories indicated good reproducibility for IHC 2005 (kappa value 0.79) and very good reproducibility for 2006 (kappa value 0.86). The corresponding reproducibility for FISH was very good on both occasions (kappa value 0.92 and 0.96 respectively). A questionnaire indicated that 90% of all primary breast cancers diagnosed in Sweden in 2006 were tested for HER2 status. By way of summary, HER2 status is now implemented in clinical routine diagnostics in Sweden, and the present reproducibility study supports a high quality of testing.
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| 8. |
- Giltnane, Jennifer M., et al.
(författare)
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Quantitative measurement of epidermal growth factor receptor is a negative predictive factor for tamoxifen response in hormone receptor - Positive premenopausal breast cancer
- 2007
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 25:21, s. 3007-3014
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Although there is evidence for interaction between epidermal growth factor receptor ( EGFR) and estrogen receptor ( ER), it is still not clear how this affects response to endocrine therapies like tamoxifen. Here we assess the relationship between EGFR expression and tamoxifen response, with a new quantitative technology. Patients and Methods A tissue microarray was constructed from breast cancer from a cohort of 564 patients enrolled in a randomized clinical trial for adjuvant tamoxifen treatment in early breast cancer, with a median follow-up of 14 years. EGFR expression was measured using automated quantitative analysis, a fluorescence-based method for quantitative analysis of in situ protein expression. Results In ER-positive patients, tamoxifen-treated patients with low EGFR expression ( n = 113) showed a significant effect by 2 years of adjuvant tamoxifen ( P = .01), in contrast to no treatment effect in the EGFR-high group ( n = 73, P = .69). The untreated group showed 49% v 57% 10-year recurrence-free survival for EGFR low versus high ( P = .466) in the corresponding group of ER-positive patients. A significant beneficial effect of tamoxifen treatment was seen in the EGFR-low group ( hazard ratio [ HR] = 0.43 ( 95% CI, 0.22 to 0.84; P = .013) in contrast to no effect in the EGFR-high group ( HR = 1.14; 95% CI, 0.59 to 2.22; P = .7) by using a Cox model. Conclusion This study provides clinical evidence that confirms the basic work that has shown high EGFR can indicate resistance to tamoxifen. It suggests that careful measurement of EGFR protein expression might define a subset of low-stage patients that could benefit from an alternative therapy.
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| 9. |
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| 10. |
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| 11. |
- Jirström, Karin, et al.
(författare)
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Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification
- 2005
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 65:17, s. 8009-8016
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Tidskriftsartikel (refereegranskat)abstract
- Cyclins D1 and A2 are cell cycle regulators that also have the ability to interact with the estrogen receptor (ER) and consequently interfere with antiestrogen treatment in breast cancer. Experimental data support this concept, but the clinical relevance needs to be further established. In this study, we evaluated cyclin D1 and A2 protein expression by immunohistochemistry and cyclin D1 gene (CCND1) amplification by fluorescence in situ hybridization in 500 primary breast cancers arranged in tissue microarrays. Patients had been randomized to 2 years of adjuvant tamoxifen or no treatment with a median follow-up of 14 years, allowing for subgroup analysis of treatment response defined by cyclin status. We found that both cyclin D1 and A2 protein overexpression was associated with an impaired tamoxifen response, although not significant in multivariate interaction analyses, whereas tamoxifen-treated patients with CCND1-amplified tumors had a substantially increased risk for disease recurrence after tamoxifen treatment in univariate analyses [relative risk (RR), 2.22; 95% confidence interval (95% CI), 0.94-5.26; P = 0.06] in contrast to nonamplified tumors (RR, 0.39; 95% CI, 0.23-0.65; P < 0.0001). Consequently, a highly significant interaction between tamoxifen treatment and CCND1 amplification could be shown regarding both recurrence-free survival (RR, 6.38; 95% CI, 2.29-17.78; P < 0.001) and overall survival (RR, 5.34; 95% CI, 1.84-15.51; P = 0.002), suggesting an agonistic effect of tamoxifen in ER-positive tumors. In node-positive patients, the disparate outcome according to gene amplification status was even more accentuated. In summary, our data implicate that despite a significant correlation to cyclin D1 protein expression, amplification status of the CCND1 gene seems a strong independent predictor of tamoxifen response, and possibly agonism, in premenopausal breast cancer.
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| 12. |
- Jirström, Karin, et al.
(författare)
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Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial
- 2005
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 58:11, s. 1135-1142
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Tidskriftsartikel (refereegranskat)abstract
- Background: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment.Aims: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer.Materials/methods: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression.Results: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly.Conclusions: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.
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| 13. |
- Jögi, Annika, et al.
(författare)
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Nuclear expression of the RNA-binding protein RBM3 is associated with an improved clinical outcome in breast cancer
- 2009
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 22:12, s. 1564-1574
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Tidskriftsartikel (refereegranskat)abstract
- Single-strand RNA-binding proteins (RBPs) are involved in many aspects of RNA metabolism and in the regulation of gene transcription. The RBP RBM3 was recently suggested to be a proto-oncogene in colorectal cancer; however, such a role has not been corroborated by previous studies in the colon or other tumor types, and the prognostic implications of tumor-specific RBM3 expression remain unclear. Mono-specific antibodies against RBM3 were generated. Antibody specificity was confirmed using siRNA gene silencing, western blotting and immunohistochemistry on a panel of breast cancer cell lines. Using tissue microarrays and IHC, RBM3 protein expression was examined in 48 normal tissues and in 20 common cancers. Additional analysis in two independent breast cancer cohorts (n = 1016) with long-term follow-up was also carried out. RBM3 was upregulated in cancer compared to normal tissues. The nuclear expression of RBM3 in breast cancer was associated with low grade (P<0.001), small tumors (P<0.001), estrogen receptor (ER) positivity (P<0.001) and Ki-67 negativity (P<0.001) in both the breast cancer cohorts. An increased nuclear expression of RBM3 was associated with a prolonged overall and recurrence-free survival. The prognostic value was particularly pronounced in hormone receptor-positive tumors and remained significant in multivariate interaction analysis after controlling for tamoxifen treatment (HR: 0.49, 95% CI: 0.30-0.79, P = 0.004). These data strongly indicate that nuclear RBM3 is an independent favorable prognostic factor in breast cancer, and seems to have a specific role in ER-positive tumors. Modern Pathology (2009) 22, 1564-1574; doi:10.1038/modpathol.2009.124; published online 4 September 2009
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| 14. |
- Kronblad, Åsa, et al.
(författare)
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Hypoxia inducible factor-1alpha is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response.
- 2006
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 118:10, s. 2609-2616
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia is common in many solid tumours, including breast cancer. Hypoxia triggers the expression of hypoxia inducible factor-1 alpha (HIF-1 alpha), and HIF-1 alpha has been associated with an impaired prognosis in breast cancer and down-regulation of the oestrogen receptor (ER), potentially affecting the treatment efficiency of antioestrogens. The role of HIF-1 alpha regarding prognostic and treatment predictive information in breast cancer has not been established and we therefore analyzed HIF-1 alpha using immunohistochemistry in a cohort of 377 premenopausal stage II breast cancers arranged in a tissue microarray. The patients were included in a randomized trial with either 2 years of tamoxifen or no adjuvant treatment. The tamoxifen treatment effect could be studied in subgroups of breast cancer and pure prognostic information could be scrutinized for untreated control patients. HIF-1 alpha was scored as positive in 24% of the tumours and correlated positively to tumour size, Nottingham histological grade (NHG), Ki-67, Her2 and cyclin E expression and negatively to lymph node status, cyclin D1, ER and PR (progesterone receptor) expression. Surprisingly, there was no difference in tamoxifen response for patients with high or low HIF-1 alpha expressing tumours. In lymph node-positive patients as well as NHG 1/2 tumours, high HIF-1 alpha protein expression was significantly associated with an impaired recurrence-free survival (p = 0.014, 0.0.18). When analyzing the subgroup of NHG 1/2 tumours, a high HIF-1 alpha expression was the only independent significant prognostic marker in multivariate analysis, including standard prognostic markers, suggesting that HIF-1a might be a useful prognostic marker in this subgroup of breast cancer, with a rather good but diverse prognosis. (c) 2005 Wiley-Liss, Inc.
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| 15. |
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| 16. |
- Larsson, Anna-Maria, et al.
(författare)
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Erythropoietin Receptor Expression and Correlation to Tamoxifen Response and Prognosis in Breast Cancer.
- 2009
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 15:17, s. 5552-5559
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The main function of erythropoietin (EPO) is to stimulate erythropoiesis. EPO receptors (EPOR) are expressed in other cell types, including tumor cells, suggesting that the EPO/EPOR pathway governs additional cellular processes besides erythropoiesis. Recombinant EPO (rhEPO) is frequently given to anemic cancer patients, although data on clinical outcome are conflicting. In an attempt to understand these clinical data, we analyzed EPO and EPOR expression in breast cancer and evaluated EPOR as a putative prognostic and predictive marker in breast cancer patients treated with tamoxifen. EXPERIMENTAL DESIGN: EPO mRNA/protein and EPOR mRNA were quantified by PCR and ELISA, respectively. Tissue microarrays containing 500 breast tumors from premenopausal women randomized to tamoxifen or no adjuvant treatment were evaluated for EPOR expression by immunohistochemistry. Predictive and prognostic information was evaluated using Kaplan-Meier curves and log-rank tests to estimate recurrence-free survival (RFS). RESULTS: EPO and EPOR were expressed in cultured cells, and breast tumor specimens expressed EPOR at varying levels. Tamoxifen treatment significantly increased RFS in patients with estrogen receptor-positive/progesterone receptor-positive (ER(+)/PR(+)) tumors with low EPOR expression (P = 0.001) but had no effect on RFS in patients with tumors with high EPOR expression (P = 0.98). In the untreated cohort, RFS was significantly improved for patients with ER(+) tumors with high EPOR expression. CONCLUSION: EPOR is abundantly expressed in breast cancer specimens. The fact that high expression of EPOR is related to an impaired tamoxifen response in ER(+)/PR(+) tumors and to improved survival in untreated patients suggests that EPOR expression in breast cancer affects tumor behavior. (Clin Cancer Res 2009;15(17):5552-9).
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| 17. |
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| 18. |
- Rydén, Lisa, et al.
(författare)
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Determination of sentinel lymph node (SLN) status in primary breast cancer by prospective use of immunohistochemistry increases the rate of micrometastases and isolated tumour cells: Analysis of 174 patients after SLN biopsy.
- 2007
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Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 1532-2157 .- 0748-7983. ; 33:1, s. 33-38
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The objective of the present study was to evaluate the prospective use of immunohistochemistry (IHC) for histopathological diagnosis of sentinel lymph node(s) (SLN) in primary breast cancer using stage migration and non-SLN metastases as endpoints in relation to metastatic involvement. Method: Serial sectioning and prospective use of IHC were applied to SLN examination in addition to routine haematoxylin-eosin staining in 174 consecutive patients with unifocal T1-T2 breast cancer included in a National Sentinel Node Study. Axillary lymph node dissection (ALND) was performed in all cases with macrometastases, micrometastases and isolated tumour cells (ITC). Results: The SLN was found in 173/174 patients and a metastatic foci was found in 50 patients including 28/50 with macrometastases, 16/ 50 with micrometastases and 6/50 with ITC. IHC detected 3/16 of the micrometastases and 4/6 of ITC. Stage migration from NO to N1mi was encountered in 3/132 patients by use of IHC. Non-SLN metastases were noted in 15/28 of patients with macrometastases and in 3/16 of patients with micrometastases, whereas no patient with ITC had additional metastases (p = 0.007). Conclusion: The prospective use of lHC and serial sectioning for histopathological diagnosis of SLNs increased the detection rate of N1mi and ITC, but only 3/132 patients were stage-migrated by use of IHC. Patients with ITC did not have any risk of non-SLN metastases, supporting that ALND can safely be omitted in this group of patients. (C) 2006 Elsevier Ltd. All fights reserved.
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| 19. |
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| 20. |
- Rydén, Lisa, et al.
(författare)
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HER2 status in hormone receptor positive premenopausal primary breast cancer adds prognostic, but not tamoxifen treatment predictive, information
- 2008
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 109:2, s. 351-357
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOverexpression of human epidermal growth factor receptor 2 (HER2) or amplification of its gene is a prognostic factor in primary breast cancer and a predictor for tamoxifen treatment efficacy in oestrogen receptor (ER) positive disease. In the present study we explored a defined cohort of breast cancer patients included in a randomised trial in order to assess prognostic and tamoxifen treatment information yielded by HER2 status.MethodsPremenopausal breast cancer patients with stage II tumours (n = 564) were included and allocated to 2 years of adjuvant tamoxifen treatment versus no adjuvant treatment. ER, progesterone receptor (PR) status and HER2 status was determined by immunohistochemistry using a tissue microarray. HER2 amplification was analysed by fluorescent in situ hybridisation and tumours being amplified and/or HER2 3+ were considered HER2+. HER2 status was evaluable in 83% of the patients and 12.6% were HER2+. In untreated patients, HER2 was a negative prognostic factor in ER+ patients, HR 2.95; 95% CI: 1.61–5.38, p < 0.001, but not in ER- patients, HR 0.67; 95% CI: 0.28–1.61, p = 0.4, and a significant interaction between the two markers was found, p < 0.01. HER2 status was not related to tamoxifen treatment efficacy in ER+ patients (term of interaction p = 0.95). When stratifying for PR status, similar results were achieved.DiscussionHER2+ and ER+ breast cancer constituted a subgroup of tumours with poor prognosis in premenopausal breast cancer, whereas no treatment interaction was found between HER2 status and tamoxifen in ER+ tumours. The poor prognosis in HER2+ and ER+ patients may interfere with the interpretation of HER2 data in non-randomised trials of adjuvant tamoxifen.
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| 21. |
- Rydén, Lisa, et al.
(författare)
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Reproducibility of human epidermal growth factor receptor 2 analysis in primary breast cancer: a national survey performed at pathology departments in Sweden.
- 2009
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Ingår i: Acta oncologica (Stockholm, Sweden). - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 48:6, s. 860-6
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Tidskriftsartikel (refereegranskat)abstract
- HER2 is a treatment predictive factor for the effect of trastuzumab and associated with poor prognosis in breast cancer. The analysis of HER2 must be performed with good quality, with regard to both the immunohistochemical (IHC) and in situ hybridization (ISH) analysis.A tissue microarray (TMA) including 11 breast cancer samples was sent twice (once in 2005 and again in 2006) to 24 pathology departments in Sweden. A questionnaire was also sent to the departments in 2006.With IHC, all departments reported the same results (0/1+ vs. 2+ vs. 3 + ) for three (2005) and six samples (2006). The mean kappa-value increased from 0.67 to 0.77, indicating a good reproducibility at both occasions. With fluorescence-ISH (FISH), the 11 departments using this technique reported the same results (amplified vs. normal) for nine (2005) and ten samples (2006). The mean kappa-value showed very good reproducibility both 2005 and 2006 (0.92 and 0.96, respectively). Based on the answers from the participating departments, the questionnaire revealed that 31% of primary breast cancer diagnosed in 2006 (n = 5 043) were 2 + /3+. FISH analysis of 2+ confirmed 12% of the samples to be amplified. The corresponding figure for 3 + was 90%. In total, 14.3% of the samples were HER2 positive (2+ and amplified, or 3 + ).The results obtained in this study indicate that the reproducibility for HER2 analysis is good (IHC) and very good (FISH) between the pathology departments in Sweden using TMA-based tumor samples. In 2006, 14.3% of invasive breast cancers were HER2 positive.
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| 22. |
- Rydén, Lisa, et al.
(författare)
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Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer
- 2005
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 23:21, s. 4695-4704
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance.Patients and Methods Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors.Results VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER–positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor–positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status.Conclusion Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor–positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.
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| 23. |
- Rydén, Lisa, et al.
(författare)
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Tumor-specific VEGF-A and VEGFR2 in postmenopausal breast cancer patients with long-term follow-up : Implication of a link between VEGF pathway and tamoxifen response
- 2005
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Ingår i: Breast Cancer Research and Treatment. - The Hague : Nijhoff. - 0167-6806 .- 1573-7217. ; 89:2, s. 135-143
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor (VEGF-A) is considered a prognostic indicator for clinical outcome in breast cancer. Conflicting results nevertheless exist and there is a need for larger studies including untreated patients in order to clarify the importance of tumor-specific VEGF-A regarding prognosis as well as potential links to predictive treatment information. VEGF-A and its receptor, vascular endothelial growth receptor 2 (VEGFR2), were therefore analyzed by immunohistochemistry in postmenopausal breast cancers enrolled in a clinical trial where patients were randomized to adjuvant tamoxifen treatment (n=124) for 2 years or no treatment (n=127) with a median follow-up of 18 years. The tumors were arranged in a tumor tissue microarray system enabling parallell analysis of the angiogenic factors and hormone receptor status. Tumor-specific expression of VEGFR2 correlated strongly with expression of VEGF-A and progesterone receptor (PR) negativity, whereas VEGF-A was not associated with hormone receptor status. Among patients with estrogen receptor (ER) positive (fraction > 10%) tumors, there was a statistically significant tamoxifen response in VEGF-A negative tumors at both 10-year and 18-year disease-free survival (DFS), contrasting to VEGF-A positive tumors who had no beneficial effect of tamoxifen. A treatment-interaction variable indicated a marked difference in tamoxifen response depending on VEGFA-status in terms of DFS at 10 and 18 years of follow-up, p=0.046 and p=0.039, respectively. VEGFR2 status did not yield significant predicitve information for tamoxifen response in patients with ER fraction > 10%, whereas in patients with ER fraction > 90% both VEGF-A and VEGFR2 status were associated with tamoxifen treatment effect.
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| 24. |
- Rydén, Lisa, et al.
(författare)
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Two years of adjuvant tamoxifen in premenopausal patients with breast cancer : a randomised, controlled trial with long-term follow-up
- 2005
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 41:2, s. 256-264
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Tidskriftsartikel (refereegranskat)abstract
- Adjuvant tamoxifen treatment increases recurrence-free survival (RFS) and overall survival (OS) in early breast cancer, although in premenopausal patients the number of studies comparing tamoxifen vs no treatment are limited. We report herein the effect on RFS of adjuvant tamoxifen treatment in a multicentre trial of premenopausal patients with stage II breast cancer patients randomised between 1986 and 1991 to 2 years of tamoxifen treatment (n = 276) or no treatment (n = 288). The receptor status of the tumour was known for 541 (96%) of the patients included. Tamoxifen treatment significantly increased RFS in patients with hormone receptor-positive (oestrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+)) tumours (Relative Risk (RR) 0.65; 95% Confidence Interval (CI): 0.48–0.89, P = 0.006), and the beneficial effect of tamoxifen was extended to patients with indicators of poor prognosis, such as young age and nodal-positivity. PR status was a significant predictor of response to tamoxifen in multivariate models with testing of interactions of hormone receptor status and adjuvant therapy.
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| 25. |
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