| 1. |
- Harbst, Katja, et al.
(författare)
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Molecular profiling reveals low- and high-grade forms of primary melanoma.
- 2012
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1557-3265. ; 18:15, s. 4026-4036
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Tidskriftsartikel (refereegranskat)abstract
- For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome.We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data.Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84-8.59), and overall (HR = 3.66; 95% CI, 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.
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| 2. |
- Kimbung, Siker, et al.
(författare)
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Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer
- 2016
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 22:1, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis. Experimental Design: A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n = 91) were subjected to whole-genome transcriptional profiling. Liver metastasis-selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis-selective genes in primary breast cancer was tested. Results: Liver relapse was associated with estrogen receptor (ER) expression (P = 0.002), luminal B subtype (P = 0.01), and was prognostic for an inferior postrelapse survival (P = 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by down-regulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis-selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P = 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P = 0.001) among luminal A tumors. Conclusions: Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer. (C)2015 AACR.
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| 3. |
- Sjöström, Martin, et al.
(författare)
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Comprehensive transcriptomic profiling identifies breast cancer patients who may be spared adjuvant systemic therapy.
- 2020
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 26:1, s. 171-182
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Tidskriftsartikel (refereegranskat)abstract
- There is currently no molecular signature in clinical use for adjuvant endocrine therapy omission in breast cancer. Given the unique trial design of SweBCG91-RT, where adjuvant endocrine and chemotherapy were largely unadministered, we sought to evaluate the potential of transcriptomic profiling for identifying patients who may be spared adjuvant endocrine therapy.We performed a whole transcriptome analysis of SweBCG91-RT, a randomized phase III trial of +/- radiotherapy after breast-conserving surgery for node-negative stage I-IIA breast cancer. 92% of patients were untreated by both adjuvant endocrine therapy and chemotherapy. We calculated 15 transcriptomic signatures from the literature and combined them into an Average Genomic Risk, which was further used to derive a novel 141-gene signature (MET141). All signatures were then independently examined in SweBCG91-RT, and in the publicly-available METABRIC cohort.In SweBCG91-RT, 454 patients were node-negative, post-menopausal and systemically untreated with ER-positive, HER2-negative cancers, which constitutes a low-risk subgroup and potential candidates for therapy omission. Most transcriptomic signatures were highly prognostic for distant metastasis, but considerable discordance was observed on the individual patient level. Within the MET141 low-risk subgroup (lowest 25th percentile of scores), 95% of patients were free of metastasis at 15 years even in the absence of adjuvant endocrine therapy. In a clinically low-risk subgroup of the METABRIC cohort not treated with systemic therapy, no breast cancer death occurred among the MET141 low-risk patients.Transcriptomic profiling identifies patients with an excellent outcome without any systemic adjuvant therapy in clinically low-risk patients of the SweBCG91-RT and METABRIC cohorts.
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| 4. |
- Stenmark Tullberg, Axel, et al.
(författare)
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Immune infiltrate in the primary tumor predicts effect of adjuvant radiotherapy in breast cancer; results from the randomized SweBCG91RT trial.
- 2021
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 27:3, s. 749-758
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-infiltrating immune cells play a key role in tumor progression. The purpose of this study was to analyze if the immune infiltrate predicts benefit from postoperative radiotherapy (RT) in a large randomized breast cancer RT trial.In the SweBCG91RT trial, patients with stage I and II breast cancer were randomized to breast conserving surgery (BCS) and postoperative RT or to BCS only and followed for a median time of 15.2 years. The primary tumor immune infiltrate was quantified through two independent methods; immunohistochemistry (IHC) and gene expression profiling. For IHC analyses, the absolute stromal area occupied by CD8+ T cells and FOXP3+ T cells, respectively, was used to define the immune infiltrate. For gene expression analyses, immune cells found to be prognostic in independent datasets were pooled into two groups consisting of antitumoral- and protumoral immune cells, respectively.An antitumoral immune response in the primary tumor was associated with a reduced risk of breast cancer recurrence and predicted less benefit from adjuvant RT. The interaction between RT and immune phenotype was significant for any recurrence in both the IHC and gene expression analyses (p=0.039 and p=0.035) and was also significant for IBTR in the gene expression analyses (p=0.025).Patients with an antitumoral immune infiltrate in the primary tumor have a reduced risk of any recurrence and may derive less benefit from adjuvant RT. These results may impact decisions regarding postoperative RT in early breast cancer.
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| 5. |
- Wahlin, Björn Engelbrekt, et al.
(författare)
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T Cells in Tumors and Blood Predict Outcome in Follicular Lymphoma Treated with Rituximab
- 2011
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 17:12, s. 4136-4144
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: T cells influence outcome in follicular lymphoma, but their contributions seem to be modified by therapy. Their impact in patients receiving rituximab without chemotherapy is unknown. EXPERIMENTAL DESIGN: Using flow cytometry, we evaluated the T cells in tumors and/or blood in a total of 250 follicular lymphoma patients included in two Nordic Lymphoma Group randomized trials that compared single rituximab with IFN-α2a-rituximab combinations. RESULTS: In univariate analysis, higher levels of CD3(+), CD4(+), and CD8(+) T cells in both tumors and blood correlated with superior treatment responses, and in multivariate analysis, tumor-CD3(+) (P = 0.011) and blood-CD4(+) (P = 0.029) cells were independent. CD4(+) cells were favorable regardless of treatment arm, but CD8(+) cells were favorable only in patients treated with single rituximab, because IFN-α2a improved responses especially in patients with low CD8(+) cell levels. Higher levels of blood-CD3(+) (P = 0.003) and blood-CD4(+) (P = 0.046) cells predicted longer overall survival, and higher levels of blood-CD8(+) cells longer times to next treatment (P = 0.046). CONCLUSIONS: We conclude that therapeutic effects of rituximab are augmented by tumor-associated T cells for rapid responses and by systemic T cells for sustained responses. CD4(+) and CD8(+) cells are both favorable in patients treated with rituximab. IFN-α2a abrogates the negative impact of few CD8(+) cells.
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| 6. |
- Ambros, Inge M, et al.
(författare)
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A multilocus technique for risk evaluation of patients with neuroblastoma.
- 2011
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 17:4, s. 792-804
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Tidskriftsartikel (refereegranskat)abstract
- Precise and comprehensive analysis of neuroblastoma genetics is essential for accurate risk evaluation and only pangenomic/multilocus approaches fulfill the present-day requirements. We present the establishment and validation of the PCR-based multiplex ligation-dependent probe amplification (MLPA) technique for neuroblastoma.
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| 7. |
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| 8. |
- Bundred, Nigel J, et al.
(författare)
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Cyclooxygenase-2 inhibition does not improve the reduction in ductal carcinoma in situ proliferation with aromatase inhibitor therapy: results of the ERISAC randomized placebo-controlled trial.
- 2010
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 16:5, s. 1605-12
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Tidskriftsartikel (refereegranskat)abstract
- Tamoxifen reduces risk of recurrence after breast conservation surgery for ductal carcinoma in situ (DCIS), but no data exists on the effectiveness of aromatase inhibitors for DCIS. Cyclooxygenase-2 (COX-2) is overexpressed in DCIS, representing another potential therapeutic target. The aim of the study was to determine the effect of aromatase and/or COX-2 inhibition on epithelial proliferation and apoptosis in a presurgical study of estrogen receptor (ER)-positive DCIS. Methods: Postmenopausal women with ER-positive DCIS diagnosed by core biopsy were randomized to a 2 x 2 design of either 14 days of exemestane or placebo and celecoxib, or placebo immediately before surgery. Paired baseline and end point biopsies were analyzed for proliferation (Ki67), apoptosis, human epidermal growth factor receptor 2 (HER2), COX-2, and progesterone receptor (PR) expression by immunohistochemistry. The primary end point was a decrease in Ki67 between diagnosis and surgical excision.
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| 9. |
- De Brouwer, Sara, et al.
(författare)
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Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.
- 2010
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 16:17, s. 4353-62
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Tidskriftsartikel (refereegranskat)abstract
- Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression.
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| 10. |
- Fouladiun, Marita, 1963, et al.
(författare)
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Daily physical-rest activities in relation to nutritional state, metabolism, and quality of life in cancer patients with progressive cachexia.
- 2007
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Ingår i: Clinical cancer research. - 1078-0432. ; 13:21, s. 6379-85
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate daily physical-rest activities in cancer patients losing weight in relation to disease progression. EXPERIMENTAL DESIGN: Physical activity-rest rhythms were measured (ActiGraph, armband sensor from BodyMedia) in relation to body composition (dual-energy X-ray absorptiometry), energy metabolism, exercise capacity (walking test), and self-scored quality of life (SF-36, Hospital Anxiety and Depression Scale) in weight-losing outpatients with systemic cancer (71 +/- 2 years, n = 53). Well-nourished, age-matched, and previously hospitalized non-cancer patients served as controls (74 +/- 4 years, n = 8). Middle-aged healthy individuals were used as reference subjects (49 +/- 5 years, n = 23). RESULTS: Quality of life was globally reduced in patients with cancer (P < 0.01), accompanied by significantly reduced spontaneous physical activity during both weekdays and weekends compared with reference subjects (P < 0.01). Spontaneous physical activity declined over time during follow-up in patients with cancer (P < 0.05). However, overall physical activity and the extent of sleep and bed-rest activities did not differ between patients with cancer and age-matched non-cancer patients. Spontaneous physical activity correlated weakly with maximum exercise capacity in univariate analysis (r = 0.41, P < 0.01). Multivariate analysis showed that spontaneous physical activity was related to weight loss, blood hemoglobin concentration, C-reactive protein, and to subjectively scored items of physical functioning and bodily pain (SF-36; P < 0.05-0.004). Anxiety and depression were not related to spontaneous physical activity. Patient survival was predicted only by weight loss and serum albumin levels (P < 0.01), although there was no such prediction for spontaneous physical activity. CONCLUSIONS: Daily physical-rest activities represent variables which probably reflect complex mental physiologic and metabolic interactions. Thus, activity-rest monitoring provides a new dimension in the evaluation of medical and drug interventions during palliative treatment of patients with cancer.
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