| 1. |
- 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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| 2. |
- Linderholm, Barbro K., et al.
(författare)
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Vascular endothelial growth factor is a strong predictor of early distant recurrences in a prospective study of premenopausal women with lymph-node negative breast cancer
- 2008
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Ingår i: Breast. - : Elsevier BV. - 1532-3080 .- 0960-9776. ; 17:5, s. 484-491
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the prognostic significance of the pro-angiogenic cytokine vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), and S-phase fraction (SPF) for distant disease free survival (DDFS) in 219 premenopausal patients with node-negative breast cancer (NNBC). In univariate analysis significantly shorter DDFS was observed for patients with high VEGF (p = 0.006), high uPA (p = 0.001). and high SPF (p < 0.001). The prognostic significance of VEGF varied over time being very, strong for early relapses (0-2.25 years follow-up) (HR = 7.9: p = 0.006) while no difference was seen in the subsequent follow-up period (HR = 1.3: p = 0.62). In a series of bivariate analyses VEGF provided prognostic information during the whole observation period (0-72 months) in addition to age, tumor size, oestrogen receptor (ER), progesterone receptor (PgR), and uPA. Also this effect was more pronounced during the first follow-up period suggesting VEGF as a marker of early recurrences. (C) 2008 Elsevier Ltd. All rights reserved.
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| 3. |
- Berglund, Pontus, et al.
(författare)
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Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern
- 2008
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 61:2, s. 184-191
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours. Methods: Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections. Results: Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels. Conclusion: The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.
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| 4. |
- Jerevall, Piiha-Lotta, et al.
(författare)
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Exploring the two-gene ratio in breast cancer – independent roles for HOXB13 and IL17BR in prediction of clinical outcome
- 2008
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Ingår i: Breast Cancer Research and Treatment. - : Institutionen för klinisk och experimentell medicin. - 0167-6806 .- 1573-7217. ; 107:2, s. 225-234
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Tidskriftsartikel (refereegranskat)abstract
- Background: The two-gene expression ratio HOXB13:IL17BR has been proposed to predict the outcome of tamoxifen-treated breast cancer patients. We intended to examine whether this ratio can predict the benefit of 5 years vs. 2 years of tamoxifen treatment of postmenopausal patients. A further objective was to investigate any prognostic effects of the ratio in systemically untreated premenopausal patients. Based on the current knowledge of HOXB13 and IL17BR, we hypothesized that these genes may have individual prognostic or predictive power. Patients and methods: Expression of HOXB13 and IL17BR were quantified by real-time PCR in tumors from 264 randomized postmenopausal patients and 93 systemically untreated premenopausal patients. Results: A high HOXB13:IL17BR ratio was associated with aggressive tumor characteristics, as were low levels of IL17BR alone. The ratio and HOXB13 alone predicted recurrence-free survival after endocrine treatment, with a benefit of prolonged treatment in estrogen receptor-positive patients correlated to a low ratio (recurrence rate ratio: RR=0.39; p=0.030), or low expression of HOXB13 (RR=0.37; p=0.015). No difference in recurrence-free survival was seen for the high ratio or high HOXB13 subgroups. The predictive value of HOXB13 and HOXB13:IL17BR was significant in multivariate analysis. In the systemically untreated cohort, only IL17BR showed independent prognostic significance. Conclusion: We conclude that the ratio or HOXB13 alone can predict the benefit of endocrine therapy, with a high ratio or a high expression rendering patients less likely to respond. We have also shown that IL17BR might be an independent prognostic factor in breast cancer.
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| 5. |
- Niméus, Emma, et al.
(författare)
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Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy
- 2008
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionSome patients with breast cancer develop local recurrence after breast-conservation surgery despite postoperative radiotherapy, whereas others remain free of local recurrence even in the absence of radiotherapy. As clinical parameters are insufficient for identifying these two groups of patients, we investigated whether gene expression profiling would add further information.MethodsWe performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.ResultsWithin the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-).ConclusionA highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.
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| 6. |
- 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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| 7. |
- Liedberg, Fredrik, et al.
(författare)
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Tissue microarray based analysis of prognostic markers in invasive bladder cancer: Much effort to no avail?
- 2008
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Ingår i: Urologic Oncology. - : Elsevier BV. - 1873-2496. ; 26:1, s. 17-24
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate altered protein expression with tissue microarray methodology for 15 different markers with potential prognostic significance in invasive bladder cancer. MATERIALS AND METHODS: Invasive tumor was sampled with the tissue-arraying instrument in 133 consecutive patients who underwent radical cystectomy, and at least 3, 0.6-mm tissue cores were obtained. With immunohistochemistry, the expressions of TP53, RB1, CDKN1A (p21), MKI67 (Ki67), PTGS2 (Cox-2), CTNNA1 (alpha-catenin), CTNNB1 (beta-catenin), AKT, PTEN, RHOA, RHOC, STAT1, VEGFC, EGFR, and ERBB2 (HER2) were quantified, and correlations were made with tumor grade, pathologic stage, lymph node status, and disease-specific survival. RESULTS: Decreased immunohistochemical expression of CTNNA1 and of PTEN correlated with higher pathologic tumor stages (P = 0.01 and P = 0.01, respectively), whereas increased AKT1 and ERBB2 correlated with lower pathologic tumor stages (P = 0.01 and P = 0.03, respectively). Increased RHOA expression was more common in grade 3 than in grade 2 tumors (P = 0.016). There were no other correlations among the 15 factors studied and pathologic stage, lymph node status, or tumor grade. No association was found between bladder cancer death and altered marker status for any of the markers studied. CONCLUSIONS: Currently, there are reasons to have a skeptical attitude toward the value of tissue microarray based immunohistochemistry as a method for evaluating prognostic markers in invasive bladder cancer. In this study, 15 antibodies were tested but were found to be of little clinical value. Whether this negative finding is related to the group of patients or factors studied, or the methodology is unclear.
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| 8. |
- Brommesson, Sara, et al.
(författare)
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Tiling array-CGH for the assessment of genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs.
- 2008
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Ingår i: BMC Clinical Pathology. - : Springer Science and Business Media LLC. - 1472-6890. ; 8:July 10
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Today, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. In this respect, high resolution genomic profiling may provide a more reliable approach than conventional histopathological and tumor biological factors. METHODS: 32 K tiling microarray-based comparative genomic hybridization (aCGH) was used to explore the genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs, and was compared with histopathological and tumor biological parameters. RESULTS: Based on global copy number profiles and unsupervised hierarchical clustering, five of ten (p = 1.9 x 10-5) unilateral tumor pairs displayed similar genomic profiles within the pair, while only one of eight bilateral tumor pairs (p = 0.29) displayed pair-wise genomic similarities. DNA index, histological type and presence of vessel invasion correlated with the genomic analyses. CONCLUSION: Synchronous unilateral tumor pairs are often genomically similar, while synchronous bilateral tumors most often represent individual primary tumors. However, two independent unilateral primary tumors can develop synchronously and contralateral tumor spread can occur. The presence of an intraductal component is not informative when establishing the independence of two tumors, while vessel invasion, the presence of which was found in clustering tumor pairs but not in tumor pairs that did not cluster together, supports the clustering outcome. Our data suggest that genomically similar unilateral tumor pairs may represent a more aggressive disease that requires the addition of more severe treatment modalities, and underscores the importance of evaluating the clonality of multiple tumors for optimal patient management. In summary, our findings demonstrate the importance of evaluating the properties of both tumors in order to determine the most optimal patient management.
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| 9. |
- Carlsson, Anders, et al.
(författare)
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Serum proteome profiling of metastatic breast cancer using recombinant antibody microarrays.
- 2008
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 44:3, s. 472-480
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Tidskriftsartikel (refereegranskat)abstract
- The driving force behind oncoproteomics is to identify biomarker signatures associated with a particular malignancy. Here, we have for the first time used large-scale recombinant scFv antibody microarrays in an attempt to classify metastatic breast cancer versus healthy controls, based on differential protein expression profiling of whole serum samples. Using this multiplexed and miniaturised assay set-up providing pM range sensitivities, breast cancer could be classified with a specificity and sensitivity of 85% based on 129 serum analytes. However, by adopting a condensed 11 analyte biomarker signature, composed of nine non-redundant serum proteins, we were able to distinguish cancer versus healthy serum proteomes with a 95% sensitivity and specificity, respectively. When a subgroup of patients, not receiving anti-inflammatory drugs, was analysed, a novel eight analyte biomarker signature with a further improved predictive power was indicated. In a longer perspective, antibody microarray analysis could provide a tool for the development of improved diagnostics and intensified biomarker discovery for breast cancer patients.
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| 10. |
- 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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