| 1. |
- Brand, Judith S, et al.
(författare)
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Chemotherapy, genetic susceptibility, and risk of venous thromboembolism in breast cancer patients
- 2016
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Ingår i: Clinical Cancer Research. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1078-0432. ; 22:21, s. 5249-5255
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Venous thromboembolism (VTE) is highly heritable and a serious complication of cancer and its treatment. We examined the individual and joint effects of chemotherapy and genetic susceptibility on VTE risk in patients with breast cancer. Experimental design: A Swedish population-based study including 4,261 women diagnosed with primary invasive breast cancer between 2001 and 2008 in Stockholm, followed until 2012. Risk stratification by chemotherapy and genetic susceptibility [a polygenic risk score (PRS), including nine established VTE loci] was assessed using Kaplan-Meier and flexible parametric survival analyses, adjusting for patient, tumor, and treatment characteristics. Results: In total, 276 patients experienced a VTE event during a median follow-up of 7.6 years. Patients receiving chemotherapy [HR (95% CI) = 1.98; 1.40-2.80] and patients in the highest 5% of the PRS [HR (95% CI) = 1.90; 1.24-2.91] were at increased risk of developing VTE. Chemotherapy and PRS acted independently on VTE risk and the 1-year cumulative incidence in patients carrying both risk factors was 9.5% compared with 1.3% in patients not having these risk factors (P < 0.001). Stratified analyses by age showed that the risk-increasing effect of PRS was stronger in older patients (P interaction = 0.04), resulting in an excess risk among genetically susceptible patients receiving chemotherapy aged ≥ 60 years (1-year cumulative incidence = 25.0%). Conclusions: Risk stratification by chemotherapy and genetic susceptibility identifies patients with breast cancer at high VTE risk, who could potentially benefit from thromboprophylaxis. Our results further suggest that genetic testing is more informative in older patients with breast cancer.
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| 2. |
- Badn, Wiaam, et al.
(författare)
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Low-dose combretastatin A4 phosphate enhances the immune response of tumor hosts to experimental colon carcinoma
- 2006
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:15, s. 4714-4719
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Although there is a need to enhance the therapeutic efficiency in cancer by combining immunotherapeutic procedures with other therapy, combination with chemotherapy is complicated due to immunosuppressive effects of most chemotherapeutic drugs. The purpose of this investigation was to study whether combining tumor cell immunization with the vascular targeting drug combretastatin A4 phosphate (CA4P) would enhance tumor retardation and/or affect the antitumor immune response. Experimental Design: Rats with intrahepatic colon carcinoma were immunized weekly with IL-18/IFN gamma-transfected tumor cells, starting day 9, and were treated with a low-dose CA4P (2 mg/kg, 5 days a week starting day 7). The effect of CA4P was studied on tumor growth and on immune reactivity in vitro. Results: Rats with preexisting tumor, immunized and treated with low-dose CA4P, had a significantly retarded tumor growth compared with rats receiving CA4P or immunization alone. Splenocytes from rats treated with this combination had a significantly enhanced antitumor immune response compared with splenocytes from control rats. Exposure of nonadherent splenocytes to CA4P in vitro did not enhance their proliferation. However, 3-hour pretreatment of adherent splenocytes with 0.3 mu g/mL CA4P significantly enhanced proliferation and IFN gamma production of admixed nonadherent splenocytes, partly due to nitric oxide reduction. Combining the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester with CA4P and immunization further retarded tumor growth. Conclusion: Concomitant treatment of rats with progressively growing tumor with immunization and low-dose CA4P significantly enhances the therapeutic effect as compared with either treatment alone and results in an enhanced antitumor immune reactivity.
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| 3. |
- Bai, Yalai, et al.
(författare)
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An Open Source, Automated Tumor Infiltrating Lymphocyte Algorithm for Prognosis in Triple-Negative Breast Cancer
- 2021
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 27:20, s. 5557-5565
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Although tumor infiltrating lymphocytes (TIL) assessment has been acknowledged to have both prognostic and predictive importance in triple negative breast cancer (TNBC), it is subject to inter and intra-observer variability that has prevented widespread adoption. Here we constructed a machine-learning based breast cancer TIL scoring approach and validated its prognostic potential in multiple TNBC cohorts. Experimental Design: Using the QuPath open source software, we built a neural-network classifier for tumor cells, lymphocytes, fibroblasts and “other” cells on hematoxylin-eosin (H&E) stained sections. We analyzed the classifier-derived TIL measurements with five unique constructed TIL variables. A retrospective collection of 171 TNBC cases was used as the discovery set to identify the optimal association of machine-read TIL variables with patient outcome. For validation we evaluated a retrospective collection of 749 TNBC patients comprised of four independent validation subsets. Results: We found that all five machine TIL variables had significant prognostic association with outcomes (p≤0.01 for all comparisons) but showed cell specific variation in validation sets. Cox regression analysis demonstrated that all five TIL variables were independently associated with improved overall survival after adjusting for clinicopathological factors including stage, age and histological grade (p≤0.003 for all analyses). Conclusions: Neural net driven cell classifier defined TIL variables were robust and independent prognostic factors in several independent validation cohorts of TNBC patients. These objective, open source TIL variables are freely available to download and can now be considered for testing in a prospective setting to assess clinical utility.
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| 4. |
- Bjarnadottir, Olöf, et al.
(författare)
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Global transcriptional changes following statin treatment in breast cancer.
- 2015
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 21:15, s. 3402-3411
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Tidskriftsartikel (refereegranskat)abstract
- Statins purportedly exert anti-tumoral effects, but the underlying mechanisms are currently not fully elucidated. The aim of this study was to explore potential statin-induced effects on global gene expression profiles in primary breast cancer.
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| 5. |
- Bjartell, Anders, et al.
(författare)
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Association of cysteine-rich secretory protein 3 and beta-microseminoprotein with outcome after radical prostatectomy
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:14, s. 4130-4138
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: It has been suggested that cysteine-rich secretory protein 3 (CRISP-3) and p-microseminoprotein (MSP) are associated with outcome in prostate cancer. We investigated whether these markers are related to biochemical recurrence and whether addition of the markers improves prediction of recurring disease. Experimental Design: Tissue microarrays of radical prostatectomy specimens were analyzed for CRISP-3 and MSP by immunohistochemistry. Associations between marker positivity and postprostatectomy biochemical recurrence [prostate-specific antigen (PSA) > 0.2 ng/mL with a confirmatory level] were evaluated by univariate and multivariable Cox proportional hazards regression. Multivariable analyses controlled for preoperative PSA and pathologic stage and grade. Results: Among 945 patients, 224 had recurrence. Median follow-up for survivors was 6.0 years. Patients positive for CRISP-3 had smaller recurrence-free probabilities, whereas MSP-positive patients had larger recurrence-free probabilities. On univariate analysis, the hazard ratio for patients positive versus negative for CRISP-3 was 1.53 (P =0.010) and for MSP was 0.63 (P = 0.004). On multivariable analysis, both CRISP-3 (P = 0.007) and MSP (P = 0.002) were associated with recurrence. The hazard ratio among CRISP-3-positive/MSP-negative patients compared with CRISP-3-negative/MSP-positive patients was 2.38. Adding CRISP-3 to a base model that included PSA and pathologic stage and grade did not enhance the prediction of recurrence, but adding MSP increased the concordance index minimally from 0.778 to 0.781. Conclusion: We report evidence that CRISP-3 and MSP are independent predictors of recurrence after radical prostatectomy for localized prostate cancer. However, addition of the markers does not importantly improve the performance of existing predictive models. Further research should aim to elucidate the functions of CRISP-3 and MSP in prostate cancer cells.
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| 6. |
- Bjartell, Anders
(författare)
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New Hope in Prostate Cancer Precision Medicine? miRNA Replacement and Epigenetics
- 2019
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 25:9, s. 2679-2681
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Tidskriftsartikel (refereegranskat)abstract
- SPINK1+/ETS- prostate cancer is an aggressive disease with poor clinical outcome. New data suggest a novel treatment by upregulating the expression of miR-338-5p/-421 through epigenetic modulation or by miRNA replacement. This is a new and interesting concept that warrants further exploration in clinical trials.See related article by Bhatia et al., p. 2755.
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| 7. |
- Brennan, Donal J, et al.
(författare)
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Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer
- 2008
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 14:9, s. 2681-2689
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Survivin (BIRC5) is a promising tumor biomarker. Conflicting data exist on its prognostic effect in breast cancer. These data may at least be partly due to the manual interpretation of immunohistochemical staining, especially as survivin can be located in both the nucleus and cytoplasm. Quantitative determination of survivin expression using image analysis offers the opportunity to develop alternative scoring models for survivin immunohistochemistry. Here, we present such a model. Experimental Design: A breast cancer tissue microarray containing 102 tumors was stained with an anti-survivin antibody. Whole-slide scanning was used to capture high-resolution images. These images were analyzed using automated algorithms to quantify the staining. Results: Increased nuclear, but not cytoplasmic, survivin was associated with a reduced overall survival (OS; P = 0.038) and disease-specific survival (P = 0.0015). A high cytoplasmicto-nuclear ratio (CNR) of survivin was associated with improved OS (P = 0.005) and disease-specific survival (P = 0.05). Multivariate analysis revealed that the survivin CNR was an independent predictor of CIS (hazard ratio, 0.09; 95% confidence interval, 0.01-0.76; P = 0.027). A survivin CNR of >5 correlated positively with estrogen receptor (P = 0.019) and progesterone receptor (P = 0.033) levels, whereas it was negatively associated with Ki-67 expression (P = 0.04), p53 status (P = 0.005), and c-myc amplification (P = 0.016). Conclusion: Different prognostic information is supplied by nuclear and cytoplasmic survivin in breast cancer. Nuclear survivin is a poor prognostic marker in breast cancer. Moreover, CNR of survivin, as determined by image analysis, is an independent prognostic factor.
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| 8. |
- 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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| 9. |
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| 10. |
- Buddingh, Emilie P., et al.
(författare)
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Tumor-Infiltrating Macrophages Are Associated with Metastasis Suppression in High-Grade Osteosarcoma: A Rationale for Treatment with Macrophage Activating Agents
- 2011
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 17:8, s. 2110-2119
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: High-grade osteosarcoma is a malignant primary bone tumor with a peak incidence in adolescence. Overall survival (OS) of patients with resectable metastatic disease is approximately 20%. The exact mechanisms of development of metastases in osteosarcoma remain unclear. Most studies focus on tumor cells, but it is increasingly evident that stroma plays an important role in tumorigenesis and metastasis. We investigated the development of metastasis by studying tumor cells and their stromal context. Experimental Design: To identify gene signatures playing a role in metastasis, we carried out genome-wide gene expression profiling on prechemotherapy biopsies of patients who did (n = 34) and patients who did not (n = 19) develop metastases within 5 years. Immunohistochemistry (IHC) was performed on pretreatment biopsies from 2 additional cohorts (n = 63 and n = 16) and corresponding postchemotherapy resections and metastases. Results: A total of 118/132 differentially expressed genes were upregulated in patients without metastases. Remarkably, almost half of these upregulated genes had immunological functions, particularly related to macrophages. Macrophage-associated genes were expressed by infiltrating cells and not by osteosarcoma cells. Tumor-associated macrophages (TAM) were quantified with IHC and associated with significantly better overall survival (OS) in the additional patient cohorts. Osteosarcoma samples contained both M1-(CD14/HLA-DR alpha positive) and M2-type TAMs (CD14/CD163 positive and association with angiogenesis). Conclusions: In contrast to most other tumor types, TAMs are associated with reduced metastasis and improved survival in high-grade osteosarcoma. This study provides a biological rationale for the adjuvant treatment of high-grade osteosarcoma patients with macrophage activating agents, such as muramyl tripeptide. Clin Cancer Res; 17(8); 2110-9. (C) 2011 AACR.
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