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Blomqvist, Carl
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Publications (10 of 46) Show all publications
Nilsson, G., Holmberg, L., Garmo, H., Duvernoy, O., Sjögren, I., Lagerqvist, B. & Blomqvist, C. (2012). Distribution of Coronary Artery Stenosis After Radiation for Breast Cancer. Journal of Clinical Oncology, 30(4), 380-386
Open this publication in new window or tab >>Distribution of Coronary Artery Stenosis After Radiation for Breast Cancer
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2012 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 4, p. 380-386Article in journal (Refereed) Published
Abstract [en]

PURPOSE

To study distribution of coronary artery stenosis among patients with breast cancer (BC) and to assess correlation between radiotherapy (RT) and location of stenosis.

PATIENTS AND METHODS

A Swedish BC cohort diagnosed from 1970 to 2003 was linked to registers of coronary angiography from 1990 to 2004, which yielded 199 patients. Stenoses of the coronary arteries were graded from 0 to 5, where 0 indicated a normal vessel and 5 indicated occlusion. Two hotspot areas for radiation were defined: proximal right coronary artery (prox RCA), mid and distal left anterior descending artery and distal diagonal (mdLAD + dD). RT regimens were categorized as high or low risk of irradiating the hotspot areas. Left breast/chest wall was considered high risk for mdLAD + dD; left internal mammary chain (IMC), high risk for prox RCA and mdLAD + dD from 1970 to 1995 and thereafter solely for mdLAD + dD; and right IMC, high risk for prox RCA. Other RT targets and no RT were considered low risk. Results were expressed in odds ratios (ORs) and 95% CIs.

RESULTS

For irradiated left- versus right-sided BC, the OR for grade 3 to 5 stenosis in mdLAD + dD was 4.38 (95% CI, 1.64 to 11.7), and for grade 4 to 5 stenosis, the OR was 7.22 (95% CI, 1.64 to 31.8). For high-risk RT versus low-risk or no RT, the OR for grade 3 to 5 stenosis in hotspot areas was 1.90 (95% CI, 1.11 to 3.24).

CONCLUSION

An increase of stenosis in mdLAD + dD in irradiated left-sided BC and an association between high-risk RT and stenosis in hotspot areas for radiation indicate a direct link between radiation and location of coronary stenoses.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-165741 (URN)10.1200/JCO.2011.34.5900 (DOI)000302620900016 ()22203772 (PubMedID)
Available from: 2012-01-09 Created: 2012-01-09 Last updated: 2017-12-08Bibliographically approved
Ghoussaini, M., Fletcher, O., Michailidou, K., Turnbull, C., Schmidt, M. K., Dicks, E., . . . Easton, D. F. (2012). Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nature Genetics, 44(3), 312-318
Open this publication in new window or tab >>Genome-wide association analysis identifies three new breast cancer susceptibility loci
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2012 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 3, p. 312-318Article in journal (Refereed) Published
Abstract [en]

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ~8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ~70,000 cases and ~68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10−35), 12q24 (rs1292011; P = 4.3 × 10−19) and 21q21 (rs2823093; P = 1.1 × 10−12). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-171132 (URN)10.1038/ng.1049 (DOI)22267197 (PubMedID)
Available from: 2012-03-15 Created: 2012-03-15 Last updated: 2017-12-07Bibliographically approved
Pierceall, W. E., Sprott, K. M., Heikkinen, T., Heikkila, P., Alaparthi, L., Aittomaki, K., . . . Blomqvist, C. (2012). Utilization of fluorescence in situ hybridization with cytokeratin discriminators in TOP2A assessment of chemotherapy-treated patients with breast cancer. Human Pathology, 43(9), 1363-1375
Open this publication in new window or tab >>Utilization of fluorescence in situ hybridization with cytokeratin discriminators in TOP2A assessment of chemotherapy-treated patients with breast cancer
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2012 (English)In: Human Pathology, ISSN 0046-8177, E-ISSN 1532-8392, Vol. 43, no 9, p. 1363-1375Article in journal (Refereed) Published
Abstract [en]

Tumor biomarkers increasingly provide information for predicting outcomes with chemotherapeutic regimens (personalized medicine). Topo2A is a DNA helicase targeted by anthracyclines, cytotoxic therapeutics used in both adjuvant and palliative treatments of breast cancer. TOP2A gene amplification/deletion is implicated in response to anthracycline-based chemotherapy. We describe an approach for analyzing formalin-fixed, paraffin-embedded breast tumors on tissue microarrays with TOP2A fluorescence in situ hybridization coupled with cytokeratin immunofluorescence to target tumor cells. Stained tissue from patient specimens was imaged and analyzed using Metafer/Metacyte (Metasystems, Waltham, MA, USA), including customized image classifiers. TOP2A/CEN17 ratios of 2.0 or greater (amplified) and 0.8 or less (deleted) were observed for 10.0% and 6.1% of the patients, respectively. Patient outcomes for adjuvant chemotherapy (cyclophosphamide-epirubicin-fluorouracil, cyclophosphamide-methotrexate-fluorouracil, no chemotherapy) were evaluated. No statistical significance was achieved for clinical end points regarding TOP2A status in anthracycline-treated patients. However, patients with TOP2A aberrations receiving methotrexate-based therapy exhibited a significant decrease in 5-year distant disease-free survival and breast cancer-specific overall survival, especially for patients with TOP2A deletions (disease-free survival: hazard ratio, 5.31 [P = .001], and breast cancer-specific overall survival: hazard ratio, 6.45 [P ≤ .001]). No significant differences were seen in patients included in the no-chemotherapy group. Topo2A protein levels were assessed by immunohistochemistry with no correlative statistical relevance to immunofluorescence/fluorescence in situ hybridization-based prognosis for cyclophosphamide-epirubicin-fluorouracil or cyclophosphamide-methotrexate-fluorouracil groups. Interestingly, aberrant (under)expressing patients in the no-chemotherapy group exhibited better 5-year distant disease-free survival (hazard ratio, 0.39; P = .004), trending toward more favorable breast cancer-specific overall survival (hazard ratio, 0.61; P = .11). Our results indicate a strategy by which fluorescence in situ hybridization scoring targeted to cytokeratin-positive tumor cells may provide a tool for added precision and efficiency in TOP2A evaluation from tumor tissue.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-171135 (URN)10.1016/j.humpath.2011.08.018 (DOI)22204715 (PubMedID)
Available from: 2012-03-15 Created: 2012-03-15 Last updated: 2017-12-07Bibliographically approved
Peurala, H., Greco, D., Heikkinen, T., Kaur, S., Bartkova, J., Jamshidi, M., . . . Nevanlinna, H. (2011). MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer. PLoS ONE, 6(11), e26122
Open this publication in new window or tab >>MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, p. e26122-Article in journal (Refereed) Published
Abstract [en]

MiR-34a acts as a candidate tumour suppressor gene, and its expression is reduced in several cancer types. We aimed to study miR-34a expression in breast cancer and its correlation with tumour characteristics and clinical outcome, and regulatory links with other genes. We analysed miR-34a expression in 1,172 breast tumours on TMAs. 25% of the tumours showed high, 43% medium and 32% low expression of miR-34a. High miR-34a expression associated with poor prognostic factors for breast cancer: positive nodal status (p = 0.006), high tumour grade (p<0.0001), ER-negativity (p = 0.0002), HER2-positivity (p = 0.0002), high proliferation rate (p<0.0001), p53-positivity (p<0.0001), high cyclin E (p<0.0001) and γH2AX (p<0.0001). However, multivariate analysis adjusting for conventional prognostic factors indicated that high miR-34a expression in fact associated with a lower risk of recurrence or death from breast cancer (HR = 0.63, 95% CI = 0.41-0.96, p = 0.031). Gene expression analysis by differential miR-34a expression revealed an expression signature with an effect on both the 5-year and 10-year survival of the patients (p<0.001). Functional genomic analysis highlighted a novel regulatory role of the transcription factor MAZ, apart from the known control by p53, on the expression of miR-34a and a number of miR-34a targets. Our findings suggest that while miR-34a expression activation is a marker of aggressive breast tumour phenotype it exerts an independent effect for a lower risk of recurrence or death from breast cancer. We also present an expression signature of 190 genes associated with miR-34a expression. Our analysis for regulatory loops suggest that MAZ and p53 transcription factors co-operate in modulating miR-34a, as well as miR-34a targets involved in several cellular pathways. Taken together, these results suggest that the network of genes co-regulated with and targeted by miR-34a form a group of down-stream effectors that maybe of use in predicting clinical outcome, and that highlight novel regulatory mechanisms in breast cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-171138 (URN)10.1371/journal.pone.0026122 (DOI)22102859 (PubMedID)
Available from: 2012-03-15 Created: 2012-03-15 Last updated: 2017-12-07Bibliographically approved
Heikkinen, T., Greco, D., Pelttari, L. M., Tommiska, J., Vahteristo, P., Heikkilä, P., . . . Nevanlinna, H. (2011). Variants on the promoter region of PTEN affect breast cancer progression and patient survival. Breast Cancer Research, 13(6), R130
Open this publication in new window or tab >>Variants on the promoter region of PTEN affect breast cancer progression and patient survival
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2011 (English)In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 6, p. R130-Article in journal (Refereed) Published
Abstract [en]

INTRODUTION:

The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer.

METHODS:

We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.

RESULTS:

All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.

CONCLUSIONS:

Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-171137 (URN)10.1186/bcr3076 (DOI)22171747 (PubMedID)
Available from: 2012-03-15 Created: 2012-03-15 Last updated: 2017-12-07Bibliographically approved
Niméus-Malmström, E., Koliadi, A., Ahlin, C., Holmqvist, M., Holmberg, L., Amini, R.-M., . . . Fjällskog, M.-L. (2010). Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort. International Journal of Cancer, 127(4), 961-967
Open this publication in new window or tab >>Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort
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2010 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 127, no 4, p. 961-967Article in journal (Refereed) Published
Abstract [en]

A large proportion of women with lymph node negative breast cancer treated with chemotherapy do not benefit from such treatment. Proliferation markers have been shown to recognize patients at high risk for recurrence. Ki67 has recently been included in the St Gallen guidelines. We investigated the prognostic importance of cyclin B1 in node negative breast cancer and included a study of reproducibility. In a population-based case-control study 190 women who died from breast cancer were defined as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size < 50 mm, no lymph node metastases, and no adjuvant chemotherapy. Tumor tissue was immunostained for cyclin B1. Two investigators evaluated the staining independently by counting approximately 100, 200, 500, and 1000 cells. Cyclin B1 was statistically significantly associated to breast cancer death, in both uni- and multivariate analyses (adjusted for tumor size, age, and endocrine therapy), with odds ratios 2-3 for both investigators. The agreement between the two investigators was good to very good, regardless of the number of counted cells (kappa values between 0.74 and 0.82).Cyclin B1 is a prognostic factor for breast cancer death in a population-based node negative patient cohort which can identify high-risk patients with a good to very good reproducibility. (c) 2009 UICC.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-113742 (URN)10.1002/ijc.25091 (DOI)000279971500023 ()19957331 (PubMedID)
Available from: 2010-02-03 Created: 2010-02-03 Last updated: 2017-12-12Bibliographically approved
Ahlin, C., Fernö, M., Amini, R.-M., Tolockiene, E., Blomqvist, C., Bergh, J. & Fjällskog, M.-L. (2010). Ki-67 och cyklin A – prognostiska faktorer vid bröstcancer: Dags att införa proliferationsmarkörer i klinisk rutin. Läkartidningen, 107(10), 672-675
Open this publication in new window or tab >>Ki-67 och cyklin A – prognostiska faktorer vid bröstcancer: Dags att införa proliferationsmarkörer i klinisk rutin
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2010 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 10, p. 672-675Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-159831 (URN)20402250 (PubMedID)
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2017-12-08Bibliographically approved
Lundgren, C., Holmqvist, M., Holmberg, L., Blomqvist, C. & Fjällskog, M.-L. (2009). High Expression of Cyclin E Increases the Risk for Breast Cancer Death by 2-3 Fold in Node Negative Breast Cancer Patients. Paper presented at 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, DEC 09-13, 2009.
Open this publication in new window or tab >>High Expression of Cyclin E Increases the Risk for Breast Cancer Death by 2-3 Fold in Node Negative Breast Cancer Patients
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2009 (English)Conference paper, Published paper (Other academic)
Keywords
Breast cancer, Cyclin E, proliferation
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-162879 (URN)10.1158/0008-5472.SABCS-09-3033 (DOI)
Conference
32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, DEC 09-13, 2009
Note
Abstract published in Cancer Res 2009;69(24 Suppl):Abstract nr 3033Available from: 2011-12-07 Created: 2011-12-05 Last updated: 2011-12-07Bibliographically approved
Tommiska, J., Bartkova, J., Heinonen, M., Hautala, L., Kilpivaara, O., Eerola, H., . . . Nevanlinna, H. (2008). The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. Oncogene, 27(17), 2501-6
Open this publication in new window or tab >>The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer
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2008 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, no 17, p. 2501-6Article in journal (Refereed) Published
Abstract [en]

The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P=0.0003) and BRCA2 (30%; P=0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P=0.0002), progesterone receptor (PR) negative (P=0.004) and were of higher grade (P=0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P=0.0006) and p53 was overabundant (47%; P<0.0000000001) among the difficult-to-treat ER/PR/ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.

Keywords
DNA damage response, triple-negative breast cancer, BRCA1/BRCA2 familial cancer, ATM defects, genetic instability
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-17438 (URN)10.1038/sj.onc.1210885 (DOI)000254844900015 ()17982490 (PubMedID)
Available from: 2008-06-24 Created: 2008-06-24 Last updated: 2017-12-08Bibliographically approved
Villman, K., Öhd, J. F., Lidbrink, E., Malmberg, L., Lindh, B., Blomqvist, C., . . . Ahlgren, J. (2007). A phase II study of epirubicin, cisplatin and capecitabine as neoadjuvant chemotherapy in locally advanced or inflammatory breast cancer. European Journal of Cancer, 43(7), 1153-1160
Open this publication in new window or tab >>A phase II study of epirubicin, cisplatin and capecitabine as neoadjuvant chemotherapy in locally advanced or inflammatory breast cancer
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2007 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 43, no 7, p. 1153-1160Article in journal (Refereed) Published
Abstract [en]

Aim: To assess the efficacy and safety of epirubicin, capecitabine and cisplatin (EXC) combination therapy in locally advanced breast cancer (LABC) and investigate the predictive value of selected biomarkers. Methods: Newly diagnosed LABC patients received four 3-weekly cycles of neoadjuvant EXC (epirubicin 60 mg/m2 day 1; capecitabine 1000 mg/m2 bid, days 1-14; cisplatin 60 mg/m2day 1) and two cycles of post-operative EXC. Results: Eight (17%) of 48 patients had inflammatory breast cancer. Overall response rate was 74% (95% CI: 59-86%), including complete responses in 13% (95% CI: 5-26%). Nine (22%; 95% CI: 11-38%) of 41 patients undergoing surgery achieved pathologic complete response (pCR), giving a pCR rate of 19% (95% CI: 9-33%) in the intent-to-treat population. Haematological toxicity was manageable. The most problematic toxicities were chemotherapy-induced nausea/vomiting and hypercoagulative disorders. None of the biomarkers investigated, including HER2, predicted response. Conclusion: EXC showed high efficacy in LABC, with high clinical response and pCR rate. Nausea and vomiting were unexpectedly frequent, and more aggressive prophylaxis and management of these side effects is recommended in future studies of this combination.

Keywords
Epirubicin, Cisplatin, Capecitabine, Breast cancer, Neoadjuvant, Phase II, Clinical trial, Biomarker, Pathologic complete response
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-95414 (URN)10.1016/j.ejca.2007.02.002 (DOI)000246605100015 ()17398088 (PubMedID)
Available from: 2007-02-02 Created: 2007-02-02 Last updated: 2017-12-14Bibliographically approved
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