| 1. |
- 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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| 2. |
- Falck, Anna-Karin, et al.
(författare)
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Analysis of and prognostic information from disseminated tumour cells in bone marrow in primary breast cancer: a prospective observational study
- 2012
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Disseminated tumour cells (DTCs) in the bone marrow of patients with breast cancer have been identified as an independent predictor of poor prognosis in patients with non-metastatic disease. This prospective study aimed to evaluate the presence and prognostic value of DTCs in the bone marrow of female patients with primary breast cancer. Methods: Between 1999 and 2003, bone marrow aspirates were obtained from patients at the time of surgery for primary invasive breast cancer. DTCs in bone marrow were identified using monoclonal antibodies against cytokeratins for detection of epithelial cells. The detection of DTCs was related to clinical follow-up with distant disease-free survival (DDFS) and breast cancer-specific survival as endpoints. Bone marrow aspirates from adult healthy bone marrow donors were analysed separately. Results: DTCs were analysed in 401 patients, and cytokeratin-positive cells were found in 152 of these (38%). An immunofluorescence (IF) staining procedure was used in 327 patients, and immunocytochemistry (IC) was performed in 74 patients. The IF-based method resulted in 40% DTC-positive cases, whereas 30% were positive using IC (p = 0.11). The presence of DTCs in bone marrow was not significantly related to patient or tumour characteristics. The presence of DTCs was not a prognostic factor for DDFS (IF: hazards ratio [HR], 2.2; 95% confidence interval [CI], 0.63-2.2; p = 0.60; IC: HR, 0.84; 95% CI, 0.09-8.1; p = 0.88). Significant prognostic factors were lymph node metastases, oestrogen receptor positivity, Nottingham histological grade, and tumour size using Cox univariate analysis. The analyses were positive for epithelial cells in bone marrow from adult healthy donors in 19 (25%) samples. Conclusions: The detection of DTCs in bone marrow in primary breast cancer was previously shown to be a predictor of poor prognosis. We were not able to confirm these results in a prospective cohort including unselected patients before the standard procedure was established. Future studies with a standardised patient protocol and improved technique for isolating and detecting DTCs may reveal the clinical applications of DTC detection in patients with micrometastases in the bone marrow.
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| 3. |
- Isaksson, Sofi, et al.
(författare)
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CA 19-9 and CA 125 as potential predictors of disease recurrence in resectable lung adenocarcinoma
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Among patients who underwent primary surgery for non-small cell lung cancer (NSCLC), recurrent disease is frequent and cannot be accurately predicted solely from TNM stage and histopathological features. The aim of this study was to examine the association of tumor markers in pre-operative serum with recurrent disease. Material and methods Blood samples were collected prior to lung cancer surgery from 107 patients with stage I-III lung adenocarcinoma surgically treated at Lund University hospital, Lund, Sweden, between 2005 and 2011. The serum tumor markers Carcinoembryonic antigen (CEA), Neuron-specific enolase (NSE), Cancer antigen 125 (CA 125), Human epididymis protein 4 (HE4) and Carbohydrate antigen (CA 19-9) were analyzed retrospectively and clinical follow-up data were collected from patient charts. Forty (37%) patients were diagnosed with recurrent disease. Results Sixty-eight (64%) patients had at least one elevated tumor marker prior to surgery. In analysis of disease-free survival (DFS), CA 125 and/or CA 19-9 were significantly associated with recurrent disease adjusted to stage and adjuvant treatment (hazard ratio 2.8, 95% confidence interval 1.4-5.7, p = 0.006). Conclusion High pre-operative serum CA 19-9 and/or CA 125 might indicate an increased incidence of recurrent disease in resectable lung adenocarcinomas.
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| 4. |
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| 5. |
- Isaksson, Sofi, et al.
(författare)
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Detecting EGFR alterations in clinical specimens-pitfalls and necessities.
- 2013
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Ingår i: Virchows Archiv: an international journal of pathology. - : Springer Science and Business Media LLC. - 1432-2307. ; 463:6, s. 755-764
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the epidermal growth factor receptor (EGFR) status in early stage lung cancer in Southern Sweden, a population for which there are no previous reports on the EGFR mutation frequency. Three hundred fifty small cell lung cancers, adenocarcinomas (AC), squamous cell carcinomas (SqCC), and large cell carcinomas were analyzed using a combination of techniques for the analysis of protein expression, gene copy numbers, and mutations. Immunohistochemical (IHC) staining with antibodies for the EGFR mutations L858R and del E746-A750 revealed intratumoral heterogeneity and several discrepant cases when compared to mutation-specific polymerase chain reaction (PCR)-based analysis. The frequencies of these two mutations, when considering IHC staining with mutation-specific antibodies in a cohort of 298 cases and subsequent confirmation by PCR, were 10 % in AC and <2 % in SqCC. Furthermore, screening by sequencing of EGFR in a cohort of 52 lung AC and squamous carcinomas demonstrated a more diverse mutation spectrum, not covered by the mutation-specific antibodies. High expression of total EGFR protein was correlated to high gene copy numbers but did not reflect the mutational status of the tumors. We believe that the mutation spectra in a Southern Swedish population is too diverse to be covered by the mutation-specific antibodies, and we also raise some other issues regarding the use of the mutation-specific antibodies, for example concerning heterogeneous expression of the mutated protein, optimal antibody dilution, and discrepancies between staining results and PCR.
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| 6. |
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| 7. |
- Isaksson, Sofi, et al.
(författare)
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Pre-operative plasma cell-free circulating tumor DNA and serum protein tumor markers as predictors of lung adenocarcinoma recurrence
- 2019
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Ingår i: Acta Oncologica. - 0284-186X. ; 58:8, s. 1079-1086
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lung cancer patients have a risk of recurrence even after curatively intended surgery. Cell-free circulating tumor DNA (ctDNA) and circulating tumor marker measurements are easily accessible through peripheral blood and could potentially identify patients with worse prognosis. The aim of this study was to examine ctDNA in pre-operative plasma and the role of tumor markers in pre-operative serum for their predictive potential on risk of tumor recurrence. Methods: Mutation analysis by 26-gene targeted sequencing was performed on 157 lung adenocarcinomas (ACs) from patients surgically treated at the Lund University Hospital 2005–2014. Of these, 58 tumors from patients in stages I–IIIA (34 stage I, 14 stage II and 10 stage III) with mutation(s) in EGFR, BRAF or KRAS were included. ctDNA from corresponding plasma (median 1.5 ml, range 1–1.6) was analyzed for one tumor-specific mutation in either of these three oncogenes using ultrasensitive IBSAFE droplet digital PCR (ddPCR). The tumor markers cancer antigen 125 (CA 125) and carbohydrate antigen 19-9 (CA 19-9) were analyzed in corresponding serum with electrochemiluminiscence immunoassay. Results: 6/7 patients with ctDNA and 19/51 without detected ctDNA were diagnosed with recurrence (log-rank test p =.001). 8/10 patients with positive serum tumor markers and 17/47 without tumor markers were diagnosed with recurrence (log-rank test, p =.0002). Fifteen patients had positive ctDNA and/or tumor markers, 12 of these had recurrence (log-rank test, p <.0001). Conclusion: A combination of tumor markers and ctDNA single mutation detection in low-volume pre-operative blood samples is a promising prognostic test. Prediction of recurrent disease in surgically treated early stage lung cancer can likely be further improved by using larger volumes of blood.
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| 8. |
- Salomonsson, Annette, et al.
(författare)
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Histological specificity of alterations and expression of KIT and KITLG in non-small cell lung carcinoma.
- 2013
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 52:11, s. 1088-1096
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of molecules within important oncogenetic pathways may have future implications for development of therapies and biomarkers in lung cancer. One such target is the tyrosine kinase receptor KIT (c-KIT). We evaluated alterations and expression of KIT and its ligand, KITLG (also known as SCF), in 72 clinical lung tumor specimens of different histologies. Gene copy number, mRNA expression levels, and protein expression were assayed using array-based comparative genomic hybridization, real-time quantitative reverse transcription PCR and immunohistochemistry, respectively. For validation, we investigated copy number alterations and mRNA expression in external microarray data sets of 1,600 and 555 primary lung tumors, respectively. Positivity for KIT staining was most common in large cell neuroendocrine carcinoma (LCNEC) which also showed the highest KIT mRNA expression levels whereas expression was lowest in squamous cell carcinoma (SqCC). KIT mRNA expression levels were higher in KIT immunopositive samples, but expression was not affected by KIT copy numbers. Copy number gains of KIT were significantly more frequent in SqCC compared with adenocarcinoma in our own series and in the 1,600-sample data set. Immunopositivity for both KIT and KITLG in the same tumor was rare except in LCNEC. Our results highlight an increased KIT mRNA expression and frequent KIT immunopositivity in LCNEC but point out a poor correlation between KIT copy numbers and expression in SqCC, perhaps reflecting the existence of a protective mechanism against KIT alterations in this subgroup. © 2013 Wiley Periodicals, Inc.
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