| 1. |
- Haugen, Mads H., et al.
(författare)
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Protein signature predicts response to neoadjuvant treatment with chemotherapy and bevacizumab in HER2-negative breast cancers
- 2021
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Ingår i: JCO Precision Oncology. - 2473-4284. ; 5, s. 286-306
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Antiangiogenic therapy using bevacizumab has proven effective for a number of cancers; however, in breast cancer (BC), there is an unmet need to identify patients who benefit from such treatment. PATIENTS AND METHODS In the NeoAva phase II clinical trial, patients (N = 132) with large (= 25 mm) human epidermal growth factor receptor 2 (HER2)-negative primary tumors were randomly assigned 1:1 to treatment with neoadjuvant chemotherapy (CTx) alone or in combination with bevacizumab (Bev plus CTx). The ratio of the tumor size after relative to before treatment was calculated into a continuous response scale. Tumor biopsies taken prior to neoadjuvant treatment were analyzed by reverse-phase protein arrays (RPPA) for expression levels of 210 BC-relevant (phospho-) proteins. Lasso regression was used to derive a predictor of tumor shrinkage from the expression of selected proteins prior to treatment. RESULTS We identified a nine-protein signature score named vascular endothelial growth factor inhibition response predictor (ViRP) for use in the Bev plus CTx treatment arm able to predict with accuracy pathologic complete response (pCR) (area under the curve [AUC] = 0.85; 95% CI, 0.74 to 0.97) and low residual cancer burden (RCB 0/I) (AUC = 0.80; 95% CI, 0.68 to 0.93). The ViRP score was significantly lower in patients with pCR (P< .001) and in patients with low RCB (P<.001). The ViRP score was internally validated on mRNA data and the resultant surrogate mRNA ViRP score significantly separated the pCR patients (P = .016). Similarly, the mRNA ViRP score was validated (P < .001) in an independent phase II clinical trial (PROMIX). CONCLUSION Our ViRP score, integrating the expression of nine proteins and validated on mRNA data both internally and in an independent clinical trial, may be used to increase the likelihood of benefit from treatment with bevacizumab combined with chemotherapy in patients with HER2-negative BC.
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| 2. |
- Hedenfalk, Ingrid, et al.
(författare)
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Molecular classification of familial non-BRCA1/BRCA2 breast cancer
- 2003
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 100:5, s. 2532-2537
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Tidskriftsartikel (refereegranskat)abstract
- In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.
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| 3. |
- Kimbung, Siker, et al.
(författare)
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Assessment of early response biomarkers in relation to long-term survival in patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy plus bevacizumab : Results from the Phase II PROMIX trial
- 2018
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 142:3, s. 618-628
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Tidskriftsartikel (refereegranskat)abstract
- Pathologic complete response (pCR) is a predictor for favorable outcome after neoadjuvant treatment in early breast cancer. Modulation of gene expression may also provide early readouts of biological activity and prognosis, offering the possibility for timely response-guided treatment adjustment. The role of early transcriptional changes in predicting response to neoadjuvant chemotherapy plus bevacizumab was investigated. One-hundred-and-fifty patients with large, operable and locally advanced HER2-negative breast cancer received epirubicin and docetaxel, with the addition of bevacizumab. Patients underwent tumor biopsies at baseline, after Cycle 2 and at the time of surgery. The primary end point, pCR, and its relation with the secondary endpoints event-free survival (EFS), overall survival (OS) and gene expression profiles, are reported. The pCR rate was 13% (95% CI 8.6-20.2), with significantly more pCRs among triple-negative [28% (95% CI 14.8-45.4)] than among hormone receptor positive (HR+) tumors [9% (95% CI 4.6-16.3); (OR=3.9 [CI=1.5-10.3])]. pCR rates were not associated with EFS or OS. PAM50 subtypes significantly changed after Cycle 2 (p=0.03) and an index of absolute changes in PAM50 correlations between these time-points was associated with EFS [HR=0.62 (CI=0.3-1.1)]. In univariable analyses, signatures for angiogenesis, proliferation, estrogen receptor signaling, invasion and metastasis, and immune response, measured after Cycle 2, were associated with pCR in HR+ tumors. Evaluation of changes in molecular subtypes and other signatures early in the course of neoadjuvant treatment may be predictive of pCR and EFS. These factors may help guide further treatment and should be considered when designing neoadjuvant trials.
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| 4. |
- Kimbung, Siker, et al.
(författare)
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Clinical and molecular complexity of breast cancer metastases.
- 2015
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 35, s. 85-95
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Forskningsöversikt (refereegranskat)abstract
- Clinical oncology is advancing toward a more personalized treatment orientation, making the need to understand the biology of metastasis increasingly acute. Dissecting the complex molecular, genetic and clinical phenotypes underlying the processes involved in the development of metastatic disease, which remains the principal cause of cancer-related deaths, could lead to the identification of more effective prognostication and targeted approaches to prevent and treat metastases. The past decade has witnessed significant progress in the field of cancer metastasis research. Clinical and technological milestones have been reached which have tremendously enriched our understanding of the complex pathways undertaken by primary tumors to progress into lethal metastases and how some of these processes might be amenable to therapy. The aim of this review article is to highlight the recent advances toward unraveling the clinical and molecular complexity of breast cancer metastases. We focus on genes mediating breast cancer metastases and organ-specific tropism, and discuss gene signatures for prediction of metastatic disease. The challenges of translating this information into clinically applicable tools for improving the prognostication of the metastatic potential of a primary breast tumor, as well as for therapeutic interventions against latent and active metastatic disease are addressed.
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| 5. |
- Kimbung, Siker, et al.
(författare)
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Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition.
- 2012
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 319:2, s. 232-241
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Tidskriftsartikel (refereegranskat)abstract
- Although pre-clinical and clinical studies on PARP1 inhibitors, alone and in combination with DNA-damaging agents, show promising results, further ways to improve and broaden the scope of application of this therapeutic approach are warranted. To this end, we have investigated the possibility of improving the response of BRCA1 mutant breast cancer cells to PARP1 inhibition by co-targeting the PI3K pathway. Human breast cancer cell lines with or without the expression of BRCA1 and/or PTEN were treated with PARP1 and PI3K inhibitors as single agents and in combination. PARP1 inhibition induced DNA damage conferring a G2/M arrest and decrease in viability, paralleled by the induction of apoptosis. PI3K inhibition alone caused a G1 arrest and decreased cell growth. Most importantly, sequential combination of PARP and PI3K inhibitors interacted synergistically to significantly decrease growth compared to PARP inhibition alone. Global transcriptional profiling revealed that this decrease in growth was associated with down-regulation of macromolecule biosynthesis and the induction of apoptosis. Taken together, these results suggest an improved treatment strategy for BRCA1-mutant and possibly also triple-negative breast cancers with similar molecular defects.
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| 6. |
- 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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| 7. |
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| 8. |
- Matikas, Alexios, et al.
(författare)
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Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer
- 2018
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression (GE) signatures and Tumor Infiltrating Lymphocytes (TIL) enumeration are predictive for response to neoadjuvant chemotherapy in HR- and in HER2+ breast cancer, but data are conflicting in HR+/HER2- disease. This study aimed to explore their predictive value in this subset, measured both at baseline and after short exposure to chemotherapy. Specifically, the PROMIX phase 2 trial enrolled patients with locally advanced HER2- BC to receive six cycles of epirubicin and docetaxel, plus bevacizumab during cycles 3-6. Patients underwent tumor biopsies at baseline and after cycle 2 for GE profiling and enumeration of TIL, FOXP3+ T-cells and CD163+ macrophages. An immune related gene module and the quantification of the immune infiltrate were analyzed for association with pathologic complete response (pCR), decrease in tumor size and disease-free survival (DFS). Of the 150 patients enrolled in PROMIX, 113 were HR+/HER2-. Baseline GE and immune cell enumeration data were available from 71 patients, while data after 2 cycles of chemotherapy were available from 41. At baseline, only GE was statistically significantly associated with higher pCR rates (OR 2.29, 95% CI 1.05 - 5.38, p = 0.037) and decrease in tumor size (r = 0.25, p = 0.047). In contrast, longitudinal data indicate that both GE (r = 0.54, p<0.001) and TIL abundance (p = 0.009) are stronger predictors for the reduction of tumor size, while low FOXP3+ was statistically significantly associated with an improved DFS (p = 0.027). In conclusion, GE analysis, TIL and FOXP3+ enumeration after short-term exposure to chemotherapy carry important predictive information in HR+/HER2- breast cancer at the neoadjuvant setting.
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| 9. |
- Morgan, G, et al.
(författare)
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Abstract P3-02-02: Concordance between immunohistochemical and gene-expression based subtyping of early breast cancer using core needle biopsies and surgical specimens - experices from SCAN-B
- 2018
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Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
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Konferensbidrag (refereegranskat)abstract
- Introduction: Preoperative chemotherapy in early breast cancer increases the rate of breast preservation and provides prognostic information. Treatment decisions in these cases rely on biomarker assessments and subtyping from tissue acquired through core needle biopsies. Tumor heterogeneity and representativity are pit-falls when limited tissue is available. Biomarker expression may change considerably as a result of preoperative chemotherapy, and in a subset of cases a complete pathological response at time of surgery may even preclude any further assessment. Therefore, the reliability and reproducibility of biomarkers in base-line core biopsies are of utmost importance for patients treated with preoperative chemotherapy.Material and Methods: In an ongoing population-based study of early breast cancer, the SCAN-B (NCT02306096), patients were identified for whom an ultra-sound guided core needle biopsy was analyzed for biomarkers during primary clinical work-up and the patient was offered primary surgery as initial treatment. Clinical biomarker profiles including immunohistochemical (IHC) determinations of ER, PgR, HER2 and Ki67 were translated to subtypes according to modified St Gallen criteria (2013) and compared with paired samples from surgical specimens. In addition, tumor specimens for biomolecule extraction and RNA sequencing were collected fresh in RNAlater.Results: IHC data was available from 51 paired samples. The subtype distribution in core needle biopsies was DCIS in 1 case (2 %), LCIS in 1 case (2 %) Luminal A-like in 16 cases (31 %), Luminal B-like (HER2 negative) in 26 cases (51 %), Luminal B-HER2-like (HER2 positive) in 4 cases (8 %), HER2-positive (non-luminal) in 1 case (2 %) and triple negative (ductal) breast cancer in 2 cases (4 %). The subtype distribution in surgical specimens was DCIS in 0 case (0 %), LCIS in 1 case (2 %) Luminal A-like in 18 cases (35 %), Luminal B-like (HER2negative) in 23 cases (45 %), Luminal B--like (HER2 positive) in 6 cases (12 %), HER2-positive (non-luminal) in 1 case (2 %) and triple negative (ductal) breast cancer in 2 cases (4 %). Notably, 5/16 cases classified as Luminal A-like in the core needle biopsy were reclassified as Luminal B-like (HER2-negative) in the surgical specimen, whereas 9/26 cases classified as Luminal B-like (HER2-negative) in the core needle biopsy were reclassified as either Luminal A-like (7 cases) or Luminal B-like (HER2 positive) (2 cases) in the surgical specimen. In all instances, except one, transition between Luminal A-like and Luminal B-like was due to recorded Ki67 expression. One case that was classified as a DCIS in the core needle was reclassified as Luminal B-like (HER2 negative) at time of surgery.Discussion: In this limited material, discordance between evaluations regarding Luminal A-like and Luminal B-like was considerable. Especially the misclassification of primary HER2-positive breast cancer needs further evaluation. These findings may be caused by tumor heterogeneity, and highlight the risk of both over- and under-treatment upon biomarker assessment from core needle biopsies. Data from gene expression based subtype classifications will be presented during the meeting.
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| 10. |
- Palazon, Asis, et al.
(författare)
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An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression
- 2017
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 32:5, s. 5-683
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Tidskriftsartikel (refereegranskat)abstract
- Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity. Palazon et al. demonstrate the importance of the HIF-1α/VEGF-A axis in tumor immunity. HIF-1α, but not HIF-2α, drives CD8+ T cell glycolytic metabolism, migration, and effector function, while the HIF-1α transcriptional target VEGF-A contributes to tumor vascularization.
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