| 31. |
- Gentile, Massimiliano, et al.
(författare)
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Deletion mapping of chromosome segment 11q24-q25, exhibiting extensive allelic loss in early onset breast cancer
- 2001
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Ingår i: International Journal of Cancer. - 0020-7136 .- 1097-0215. ; 92:2, s. 208-213
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Tidskriftsartikel (refereegranskat)abstract
- Frequent allelic deletions at chromosome 11q24-q25 have been described in both early and late onset breast cancers, suggesting the existence of a gene locus implicated in the initiation and/or progression of the disease. In the present study we fine mapped this region further by loss of heterozygosity (LOH) analysis in a population of early onset breast cancer cases (n = 102, 22 to 36 years old). Loss of chromosomal material was assessed for possible association with patient survival as well as Nottingham histologic grade (NHG). Additionally, we investigated the involvement of the 11q24-q25 locus in a group of familial breast cancer cases with no detectable BRCA1 or BRCA2 gene alterations (n = 32, ages 28 to 40 years). Among the consecutive patients, extensive LOH was observed for all markers at 11q24-q25, with frequencies ranging from 42% to 54%. Deletion at the D11S4125 marker was found to be associated with reduced survival (p = 0.026), whereas the adjacent D11S387 marker correlated with higher histologic grade (p = 0.042). In the familial cases, the most telomeric markers showed substantially lower proportions of LOH, ranging from 10% to 21%. Comparison of the two patient groups demonstrated that this difference in LOH frequency was statistically significant for the D11S4098, D11S968, D11S387 and D11S4125 markers (p = 0.020, p = 0.029, p = 0.0070 and p = 0.0030, respectively). We conclude that 11q25 may harbor a gene implicated in early onset breast cancer. Our data suggest that the most probable position for this locus is defined by the markers D11S387 and D11S4125 and furthermore that it may play a less significant role in familial breast cancer cases not linked to either of the BRCA genes.
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| 32. |
- Glodzik, Dominik, et al.
(författare)
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Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.
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| 33. |
- Hamdi, Yosr, et al.
(författare)
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Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3
- 2017
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 161:1, s. 117-134
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
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| 34. |
- Hatschek, T, et al.
(författare)
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Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial
- 2012
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Ingår i: Breast Cancer Research and Treatment. - New York, USA : Springer Verlag (Germany). - 0167-6806 .- 1573-7217. ; 131:3, s. 939-947
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Tidskriftsartikel (refereegranskat)abstract
- Anthracyclines and taxanes are active cytotoxic drugs in the treatment of early metastatic breast cancer. It is yet unclear whether addition of capecitabine to the combination of these drugs improves the treatment outcome. Patients with advanced breast cancer were randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin(A (R))) and paclitaxel (Taxol(A (R))) alone (ET) or in combination with capecitabine (Xeloda(A (R)), TEX). Starting doses for ET were epirubicin 75 mg/m(2) plus paclitaxel 175 mg/m(2), and for TEX epirubicin 75 mg/m(2), paclitaxel 155 mg/m(2), and capecitabine 825 mg/m(2) BID for 14 days. Subsequently, doses were tailored related to side effects. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL). 287 patients were randomized, 143 to ET and 144 to TEX. Median PFS was 10.8 months for patients treated with ET, and 12.4 months for those treated with TEX (HR 0.84, 95% CI 0.65-1.07, P = 0.16); median OS was 26.0 months for women in the ET versus 29.7 months in the TEX arm (HR 0.84, 95% CI 0.63-1.11, P = 0.22). OR was achieved in 44.8% (ET) and 54.2% (TEX), respectively (chi(2) 3.66, P = 0.16). TTF was significantly longer for patients treated with TEX, 6.0 months, versus 5.2 months following ET (HR 0.73, 95% CI 0.58-0.93, P = 0.009). Severe hematological side effects related to epirubicin and paclitaxel were evenly distributed between the treatment arms, mucositis, diarrhea, and Hand-Foot syndrome were significantly more frequent in the TEX arm. Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into clinically relevant improvement of the outcome.
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| 35. |
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| 36. |
- 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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| 37. |
- 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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| 38. |
- Isern, A E, et al.
(författare)
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Aesthetic outcome, patient satisfaction, and health-related quality of life in women at high risk undergoing prophylactic mastectomy and immediate breast reconstruction.
- 2008
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Ingår i: Journal of Plastic, Reconstructive and Aesthetic Surgery. - : Elsevier BV. - 1878-0539 .- 1748-6815. ; 61:10, s. 1177-1187
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Tidskriftsartikel (refereegranskat)abstract
- Prophylactic mastectomy is an effective risk-reducing option in women with hereditary increased risk of breast cancer. It may be combined with immediate reconstruction, with the intention of improving aesthetic outcome and health-related quality of life. Sixty-one women underwent prophylactic mastectomy and immediate breast reconstruction in Malmö, Sweden, between 1995 and 2003. Forty women underwent bilateral prophylactic mastectomy and immediate reconstruction. Ten of these had a previous breast cancer diagnosis. Twenty-one women underwent contralateral prophylactic mastectomy and immediate reconstruction after a previous breast cancer. Fifty-four of the women (89%) were evaluated clinically for aesthetic results and complications. Patient satisfaction and quality of life were evaluated with one study-specific and two standardised health-related questionnaires administered at time of clinical follow-up. Median follow-up time was 42 months (range 7–99 months). The position of the reconstructed breasts was judged as satisfactory in 77% of breasts. Symmetry in relation to the midline was adequate in 89% of breasts. A capsular contracture grade III according to Baker and indentation tonometry was observed in 1% of breasts (1/104). The complication rate was 18% (7% early and 11% late). Secondary corrections were carried out in 11% of breasts. The study-specific questionnaire revealed a high degree of satisfaction. No woman regretted the procedure, and all women would have chosen the same type of surgery again. An age-stratified comparison of Swedish women using the Short Form 36 Health Survey Questionnaire (SF-36) questionnaire was carried out for this study. The study population scores were high, suggesting that prophylactic mastectomy and immediate reconstruction on both physical and psychological issues in this retrospective study had no negative effect. Also, the Hospital Anxiety and Depression Scale (HAD) questionnaire did not suggest any increased anxiety or depression among the patients. Prophylactic mastectomy and immediate breast reconstruction in women at risk of hereditary breast cancer may be carried out with a satisfactory aesthetic outcome and an acceptable rate of complications comparable to those in other studies, and does not in itself seem to be associated with a decreased quality of life.
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| 39. |
- Isern, A E, et al.
(författare)
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Histopathological findings and follow-up after prophylactic mastectomy and immediate breast reconstruction in 100 women from families with hereditary breast cancer.
- 2008
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Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 1532-2157 .- 0748-7983. ; 34, s. 1148-1154
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To survey the histopathological abnormalities in breasts of women who have undergone risk reducing mastectomy and to evaluate the effect of this measure on future breast cancer development. PATIENTS/METHODS: Between August 1995 and October 2006 100 consecutive women with a hereditary increased risk of breast cancer underwent prophylactic mastectomy (PM) at Malmö University Hospital. Fifty of the 100 women had no previous breast cancer. Fifty were BRCA1 or BRCA2 mutation carriers. All breast specimens have been examined histopathologically according to a prospective protocol. Follow-up data was collected from medical records and data in the Regional Cancer Registry. RESULTS: In the PM specimens abnormal lesions were found in 18 women (three with invasive cancers, eight in situ cancers and seven atypical hyperplasia). In previously healthy women lesions were more frequent after the age of 40 than among younger women (p=0.03). BRCA mutation carriers were more likely to present with ADH (atypical ductal hyperplasia)/ALH (atypical lobular hyperplasia) compared to the non-carriers/untested cases (p=0.01). After a median follow-up of 52 months (range 1-136 months) none of the women have developed breast cancer in the area of the prophylactically removed breast. CONCLUSIONS: Prevalent atypical or malignant lesions are relatively a common finding in PM specimens in asymptomatic women with hereditary increased risk of breast cancer. Such findings were significantly more common above age 40 in women without previous breast cancer. The risk of newly formed breast cancer after PM is small. The clinical importance of detecting a premalignant or preinvasive lesion in the breast at PM is still unclear.
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| 40. |
- Isern, A E, et al.
(författare)
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Risk of recurrence following delayed large flap reconstruction after mastectomy for breast cancer.
- 2011
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Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 98, s. 659-666
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of this retrospective matched cohort study was to evaluate the rate of recurrence among women with delayed large flap breast reconstruction after mastectomy for breast cancer. The recurrence rate among women treated at a single hospital was compared with that in an individually matched control group of women with breast cancer who did not have reconstruction after mastectomy. METHODS: Between 1982 and 2001, 125 women with previous invasive breast carcinoma underwent delayed large flap breast reconstruction with pedicled musculocutaneous or microvascular flaps (a median of 32 months after mastectomy). They were matched individually with 182 women with breast cancer who had a mastectomy but did not undergo breast reconstruction. Matching criteria were year of diagnosis, age at diagnosis and treating hospital. Medical records were evaluated until October 2007. Histopathological specimens for all included women were re-evaluated. The endpoint was locoregional or distant breast cancer recurrence. The risk of recurrent disease was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. RESULTS: Median follow-up for the entire cohort was 146 months. The reconstruction group had a 2·08 (95 per cent confidence interval 1·07 to 4·06) times higher risk of recurrent disease than the mastectomy only group. CONCLUSION: Women with breast cancer who had delayed reconstruction with a large flap in this study had a higher risk of recurrent disease than those with mastectomy alone. Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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