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  • 1. Aaltonen, Kirsimari
    et al.
    Ahlin, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Salonen, Laura
    Fjällskog, Marie Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Heikkilä, Pävi
    Nevanlinna, Heli
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Reliability of cyclin A assessment on tissue microarrays in breast cancer compared to conventional histological slides2006In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 94, no 11, p. 1697-1702Article in journal (Refereed)
    Abstract [en]

    Cyclin A has in some studies been associated with poor breast cancer survival, although all studies have not confirmed this. Its prognostic significance in breast cancer needs evaluation in larger studies. Tissue microarray (TMA) technique allows a simultaneous analysis of large amount of tumours on a single microscopic slide. This makes a rapid screening of molecular markers in large amount of tumours possible. Because only a small tissue sample of each tumour is punched on an array, the question has arisen about the representativeness of TMA when studying markers that are expressed in only a small proportion of cells. For this reason, we wanted to compare cyclin A expression on TMA and on traditional large sections. Two breast cancer TMAs were constructed of 200 breast tumours diagnosed between 1997-1998. TMA slides and traditional large section slides of these 200 tumours were stained with cyclin A antibody and analysed by two independent readers. The reproducibility of the two readers' results was good or even very good, with kappa values 0.71-0.87. The agreement of TMA and large section results was good with kappa value 0.62-0.75. Cyclin A overexpression was significantly (P<0.001) associated with oestrogen receptor and progesterone receptor negativity and high grade both on TMA and large sections. Cyclin A overexpression was significantly associated with poor metastasis-free survival both on TMA and large sections. The relative risks for metastasis were similar on TMA and large sections. This study suggests that TMA technique could be useful to study histological correlations and prognostic significance of cyclin A on breast cancer on a large scale.

  • 2.
    Ahlin, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Aaltonen, Kirsimari
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nevanlinna, Heli
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ki67 and cyclin A as prognostic factors in early breast cancer: What are the optimal cut-off values?2007In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 51, no 4, p. 491-498Article in journal (Refereed)
    Abstract [en]

    AIMS: To find the optimal cut-off values for cyclin A and Ki67 in early breast cancer tumours and to evaluate their prognostic values. METHODS AND RESULTS: Tissue microarray (TMA) slides were constructed from 570 T1-4 N0-1 M0 breast cancer tumours. The TMA slides were stained for cyclin A and Ki67 using immunohistochemistry with commercial antibodies. To investigate the optimal cut-off values for cyclin A, Ki67 average and maximum values the material was split into two parts at cut-offs defined by dividing it into deciles. For each cut-off value the relative risk (RR) for metastasis-free survival (MFS) and overall survival (OS) was calculated comparing patients with high versus low cyclin A or Ki67 expression. When using a cut-off value around the seventh decile, cyclin A and Ki67 score correlated with the highest RR ratio for MFS in the chemotherapy-naïve subgroup. Among patients having received adjuvant chemotherapy, no statistically significant differences in MFS or OS were found. CONCLUSIONS: The optimal cut-off value for cyclin A average is 8% and for cyclin A maximum value 11%; for Ki67 the corresponding values are 15% and 22%. Additional studies are needed to verify these results.

  • 3. Ahlin, Cecilia
    et al.
    Fernö, Mårten
    Amini, Rose-Marie
    Karolinska universitetssjukhuset, Stockholm.
    Tolockiene, Egle
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bergh, Jonas
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ki-67 och cyklin A – prognostiska faktorer vid bröstcancer: Dags att införa proliferationsmarkörer i klinisk rutin2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 10, p. 672-675Article in journal (Refereed)
  • 4. Alvegård, T A
    et al.
    Bauer, H
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Rydholm, A
    Smeland, S
    The Scandinavian Sarcoma Group--background, organization and the SSG Register--the first 25 years.2004In: Acta Orthop Scand Suppl, ISSN 0300-8827, Vol. 75, no 311, p. 1-7Article in journal (Other scientific)
  • 5.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Aaltonen, Kirsimari
    Nevanlinna, Heli
    Carvalho, Ricardo
    Salonen, Laura
    Heikkilä, Päivi
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Mast cells and eosinophils in invasive breast carcinoma2007In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 7, p. 165-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Inflammatory cells in the tumour stroma has gained increasing interest recently. Thus, we aimed to study the frequency and prognostic impact of stromal mast cells and tumour infiltrating eosinophils in invasive breast carcinomas. METHODS: Tissue microarrays containing 234 cases of invasive breast cancer were prepared and analysed for the presence of stromal mast cells and eosinophils. Tumour infiltrating eosinophils were counted on hematoxylin-eosin slides. Immunostaining for tryptase was done and the total number of mast cells were counted and correlated to the proliferation marker Ki 67, positivity for estrogen and progesterone receptors, clinical parameters and clinical outcome. RESULTS: Stromal mast cells were found to correlate to low grade tumours and estrogen receptor positivity. There was a total lack of eosinophils in breast cancer tumours. CONCLUSION: A high number of mast cells in the tumours correlated to low-grade tumours and estrogen receptor positivity. Eosinophils are not tumour infiltrating in breast cancers.

  • 6.
    Carlsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sjöström, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Villman, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bengtsson, N. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ostenstad, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    HER2 expression in breast cancer primary tumours and corresponding metastases: Original data and literature review2004In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 90, no 12, p. 2344-2348Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate whether the HER2 expression in breast cancer is retained in metastases. The HER2 expression in primary tumours and the corresponding lymph node metastases were evaluated in parallel samples from 47 patients. The HercepTest was used for immunohistochemical analyses of HER2 overexpression in all cases. CISH/FISH was used for analysis of gene amplification in some cases. HER2 overexpression (HER2-scores 2+ or 3+) was found in 55% of both the primary tumours and of the lymph node metastases. There were only small changes in the HER2-scores; six from 1+ to 0 and one from 3+ to 2+ when the metastases were compared to the corresponding primary tumours. However, there were no cases with drastic changes in HER2 expression between the primary tumours and the corresponding lymph node metastases. The literature was reviewed for similar investigations, and it is concluded that breast cancer lymph node metastases generally overexpress HER2 to the same extent as the corresponding primary tumours. This also seems to be the case when distant metastases are considered. It has been noted that not all patients with HER2 overexpression respond to HER2-targeted Trastuzumab treatment. The stability in HER2 expression is encouraging for efforts to develop complementary forms of therapy, for example, therapy with radionuclide-labelled Trastuzumab.

  • 7. Eerola, Hannaleena
    et al.
    Pukkala, Eero
    Pyrhönen, Seppo
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sankila, Risto
    Nevanlinna, Heli
    Risk of cancer in BRCA1 and BRCA2 mutation-positive and -negative breast cancer families (Finland)2001In: Cancer Causes & Control, Vol. 12, p. 739-746Article in journal (Refereed)
  • 8. Ghoussaini, Maya
    et al.
    Fletcher, Olivia
    Michailidou, Kyriaki
    Turnbull, Clare
    Schmidt, Marjanka K
    Dicks, Ed
    Dennis, Joe
    Wang, Qin
    Humphreys, Manjeet K
    Luccarini, Craig
    Baynes, Caroline
    Conroy, Don
    Maranian, Melanie
    Ahmed, Shahana
    Driver, Kristy
    Johnson, Nichola
    Orr, Nicholas
    Dos Santos Silva, Isabel
    Waisfisz, Quinten
    Meijers-Heijboer, Hanne
    Uitterlinden, Andre G
    Rivadeneira, Fernando
    Hall, Per
    Czene, Kamila
    Irwanto, Astrid
    Liu, Jianjun
    Nevanlinna, Heli
    Aittomäki, Kristiina
    Blomqvist, Carl
    Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Meindl, Alfons
    Schmutzler, Rita K
    Müller-Myhsok, Bertram
    Lichtner, Peter
    Chang-Claude, Jenny
    Hein, Rebecca
    Nickels, Stefan
    Flesch-Janys, Dieter
    Tsimiklis, Helen
    Makalic, Enes
    Schmidt, Daniel
    Bui, Minh
    Hopper, John L
    Apicella, Carmel
    Park, Daniel J
    Southey, Melissa
    Hunter, David J
    Chanock, Stephen J
    Broeks, Annegien
    Verhoef, Senno
    Hogervorst, Frans B L
    Fasching, Peter A
    Lux, Michael P
    Beckmann, Matthias W
    Ekici, Arif B
    Sawyer, Elinor
    Tomlinson, Ian
    Kerin, Michael
    Marme, Frederik
    Schneeweiss, Andreas
    Sohn, Christof
    Burwinkel, Barbara
    Guénel, Pascal
    Truong, Thérèse
    Cordina-Duverger, Emilie
    Menegaux, Florence
    Bojesen, Stig E
    Nordestgaard, Børge G
    Nielsen, Sune F
    Flyger, Henrik
    Milne, Roger L
    Alonso, M Rosario
    González-Neira, Anna
    Benítez, Javier
    Anton-Culver, Hoda
    Ziogas, Argyrios
    Bernstein, Leslie
    Dur, Christina Clarke
    Brenner, Hermann
    Müller, Heiko
    Arndt, Volker
    Stegmaier, Christa
    Justenhoven, Christina
    Brauch, Hiltrud
    Brüning, Thomas
    Wang-Gohrke, Shan
    Eilber, Ursula
    Dörk, Thilo
    Schürmann, Peter
    Bremer, Michael
    Hillemanns, Peter
    Bogdanova, Natalia V
    Antonenkova, Natalia N
    Rogov, Yuri I
    Karstens, Johann H
    Bermisheva, Marina
    Prokofieva, Darya
    Khusnutdinova, Elza
    Lindblom, Annika
    Margolin, Sara
    Mannermaa, Arto
    Kataja, Vesa
    Kosma, Veli-Matti
    Hartikainen, Jaana M
    Lambrechts, Diether
    Yesilyurt, Betul T
    Floris, Giuseppe
    Leunen, Karin
    Manoukian, Siranoush
    Bonanni, Bernardo
    Fortuzzi, Stefano
    Peterlongo, Paolo
    Couch, Fergus J
    Wang, Xianshu
    Stevens, Kristen
    Lee, Adam
    Giles, Graham G
    Baglietto, Laura
    Severi, Gianluca
    McLean, Catriona
    Alnæs, Grethe Grenaker
    Kristensen, Vessela
    Børrensen-Dale, Anne-Lise
    John, Esther M
    Miron, Alexander
    Winqvist, Robert
    Pylkäs, Katri
    Jukkola-Vuorinen, Arja
    Kauppila, Saila
    Andrulis, Irene L
    Glendon, Gord
    Mulligan, Anna Marie
    Devilee, Peter
    van Asperen, Christie J
    Tollenaar, Rob A E M
    Seynaeve, Caroline
    Figueroa, Jonine D
    Garcia-Closas, Montserrat
    Brinton, Louise
    Lissowska, Jolanta
    Hooning, Maartje J
    Hollestelle, Antoinette
    Oldenburg, Rogier A
    van den Ouweland, Ans M W
    Cox, Angela
    Reed, Malcolm W R
    Shah, Mitul
    Jakubowska, Ania
    Lubinski, Jan
    Jaworska, Katarzyna
    Durda, Katarzyna
    Jones, Michael
    Schoemaker, Minouk
    Ashworth, Alan
    Swerdlow, Anthony
    Beesley, Jonathan
    Chen, Xiaoqing
    Muir, Kenneth R
    Lophatananon, Artitaya
    Rattanamongkongul, Suthee
    Chaiwerawattana, Arkom
    Kang, Daehee
    Yoo, Keun-Young
    Noh, Dong-Young
    Shen, Chen-Yang
    Yu, Jyh-Cherng
    Wu, Pei-Ei
    Hsiung, Chia-Ni
    Perkins, Annie
    Swann, Ruth
    Velentzis, Louiza
    Eccles, Diana M
    Tapper, Will J
    Gerty, Susan M
    Graham, Nikki J
    Ponder, Bruce A J
    Chenevix-Trench, Georgia
    Pharoah, Paul D P
    Lathrop, Mark
    Dunning, Alison M
    Rahman, Nazneen
    Peto, Julian
    Easton, Douglas F
    Genome-wide association analysis identifies three new breast cancer susceptibility loci2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 3, p. 312-318Article in journal (Refereed)
    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.

  • 9. Heikkinen, Tuomas
    et al.
    Greco, Dario
    Pelttari, Liisa M
    Tommiska, Johanna
    Vahteristo, Pia
    Heikkilä, Päivi
    Blomqvist, Carl
    Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
    Aittomäki, Kristiina
    Nevanlinna, Heli
    Variants on the promoter region of PTEN affect breast cancer progression and patient survival2011In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 13, no 6, p. R130-Article in journal (Refereed)
    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.

  • 10. Heinonen, Mira
    et al.
    Fagerholm, Rainer
    Aaltonen, Kirsimari
    Kilpivaara, Outi
    Aittomäki, Kristiina
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Heikkilä, Päivi
    Haglund, Caj
    Nevanlinna, Heli
    Ristimäki, Ari
    Prognostic role of HuR in hereditary breast cancer2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 23, p. 6959-6963Article in journal (Refereed)
    Abstract [en]

    Purpose: HuR is an mRNA-binding protein that enhances the stability of certain transcripts and can regulate their translation. Elevated cytoplasmic expression of HuR protein has been linked to carcinogenesis and is associated with reduced survival in breast, ovarian, and gastric adenocarcinomas. Experimental Design: Here, we have explored the relevance of HuR in familial breast cancer. Tumor samples were collected from patients with identified BRCA1 (n = 51) or BRCA2 (n = 47) mutations or familial non-BRCA1/2 cases (n = 525), and analyzed by immunohistochemistry. Results: Among familial non-BRCAI/2 breast cancer patients, cytoplasmic HuR protein expression was present in 39.4% of the cases and was associated with estrogen receptor negativity, progesterone receptor negativity, p53 positivity, high tumor grade, and ductal type of the tumor. In multivariate analysis, cytoplasmic HuR expression was an independent marker of reduced survival in the non-BRCAI/2 group along with tumor size >2 cm, lymph node metastasis, and high histologic grade. In patients with BRCA1 or BRCA2 mutations, cytoplasmic HuR expression was more frequent (62.7% for BRCA1 and 61.7% for BRCA2) than in the non-BRCA1/ 2 group, but in BRCA -mutated subgroups cytoplasmic HuR expression did not associate with survival. Conclusions: Our results show that HuR is an important prognostic factor in familial breast cancer patients and may contribute to carcinogenesis in this disease.

  • 11. Huusko, Pia
    et al.
    Juo, Suh-Hang Hank
    Gillanders, Elizabeth
    Sarantaus, Laura
    Kainu, Tommi
    Vahteristo, Pia
    Allinen, Minna
    Jones, MaryPat
    Rapakko, Katrin
    Eerola, Hannaleena
    Markey, Carol
    Vehmanen, Paula
    Gildea, Derek
    Freas-Lutz, Diane
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Leisti, Jaakko
    Blanco, Guillermo
    Puistola, Ulla
    Trent, Jeffrey
    Bailey-Wilson, Joan
    Winqvist, Robert
    Nevanlinna, Heli
    Kallioniemi, Olli-P
    Genome-wide scanning for linkage in Finnish breast cancer families.2004In: Eur J Hum Genet, ISSN 1018-4813, Vol. 12, no 2, p. 98-104Article in journal (Other scientific)
  • 12. Kilpivaara, Outi
    et al.
    Vahteristo, Pia
    Falck, Jacob
    Syrjäkoski, Kirsi
    Eerola, Hannaleena
    Easton, Douglas
    Bartkova, Jirina
    Lukas, Jiri
    Heikkilä, Päivi
    Aittomäki, Kristiina
    Holli, Kaija
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Kallioniemi, Olli-Pekka
    Bartek, Jiri
    Nevanlinna, Heli
    CHEK2 variant I157T may be associated with increased breast cancer risk.2004In: Int J Cancer, ISSN 0020-7136, Vol. 111, no 4, p. 543-7Article in journal (Other scientific)
  • 13. Kiuru, Maija
    et al.
    Lehtonen, Rainer
    Eerola, Hannaleena
    Aittomäki, Kristiina
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enh för onkologi.
    Nevanlinna, Heli
    Aaltonen, Lauri A
    Launonen, Virpi
    No germline FH mutations in familial breast cancer patients.2005In: Eur J Hum Genet, ISSN 1018-4813, Vol. 13, no 4, p. 506-9Article in journal (Other scientific)
  • 14. Lempiäinen, Anna
    et al.
    Hotakainen, Kristina
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Alfthan, Henrik
    Stenman, Ulf-Håkan
    Increased human chorionic gonadotropin due to hypogonadism after treatment of a testicular seminoma2007In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 53, no 8, p. 1560-1561Article in journal (Refereed)
  • 15. Leppä, Sirpa
    et al.
    Saarto, Tiina
    Vehmanen, Leena
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Elomaa, Inkeri
    A high serum matrix metalloproteinase-2 level is associated with an adverse prognosis in node-positive breast carcinoma.2004In: Clin Cancer Res, ISSN 1078-0432, Vol. 10, no 3, p. 1057-63Article in journal (Refereed)
  • 16.
    Lindman, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Åström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Villman, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bergh, Jonas
    Individually tailored toxicity-based 5-fluorouracil, epirubicin and cyclophosphamide (FEC) therapy of metastatic breast cancer2007In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 46, no 2, p. 165-171Article in journal (Refereed)
    Abstract [en]

    Chemotherapy dosing only based on body surface area (BSA) results in marked pharmacokinetic and toxicity variations, which may result in an inferior outcome for some patients. A toxicity-based dosing schedule for individually tailored treatment with granulocyte colony-stimulating factor (G-CSF) supported 5-fluorouracil (F), epirubicin (E) and cyclophosphamide (C) (dFEC) was developed and studied in patients with metastatic breast cancer with the purpose to determine its efficiency and toxicity. Twenty-six women, median age 48 years, were included and the individual E and C doses were tailored stepwise based on the recorded hematological toxicity. Twenty-one patients (81%; 95% confidence interval (CI), 66% to 96%) had an objective response, including six complete responses (23%; CI, 7%-39%). At median follow-up of 113 months, the median time to progression and median overall survival were 14 and 36 months, respectively. The delivered dose intensity was high but varied substantially between patients (ranges F 126-202, E 14.4-36.0, C 160-510 mg/m2/w). The dominating grade III/IV toxicity was nausea (12% of patients) and febrile neutropenia (31% of patients). The tailored and dose-escalated FEC was highly active and feasible in metastatic breast cancer and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.

  • 17.
    Lundgren, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Holmqvist, Marit
    Holmberg, Lars
    Blomqvist, Carl
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    High Expression of Cyclin E Increases the Risk for Breast Cancer Death by 2-3 Fold in Node Negative Breast Cancer Patients2009Conference paper (Other academic)
  • 18.
    Monazzam, Azita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Josephsson, Raymond
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Långström, Bengt
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Application of the multicellular tumour spheroid model to screen PET tracers for analysis of early response of chemotherapy in breast cancer2007In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 9, no 4, p. R45-Article in journal (Refereed)
    Abstract [en]

    Introduction

    Positron emission tomography (PET) is suggested for early monitoring of treatment response, assuming that effective anticancer treatment induces metabolic changes that precede morphology alterations and changes in growth. The aim of this study was to introduce multicellular tumour spheroids (MTS) to study the effect of anticancer drugs and suggest an appropriate PET tracer for further studies.

    Methods

    MTS of the breast cancer cell line MCF7 were exposed to doxorubicin, paclitaxel, docetaxel, tamoxifen or imatinib for 7 days for growth pattern studies and for 3 or 5 days for PET tracer studies. The effect on growth was computed using the semi-automated size determination method (SASDM). The effect on the uptake of PET tracers [18F]3'-deoxy-3'-fluorothymidine (FLT), [1-11C]acetate (ACE), [11C]choline (CHO), [11C]methionine (MET), and 2-[18F]fluoro-2-deoxyglucose (FDG) was calculated in form of uptake/viable volume of the MTS at the end of the drug exposures, and finally the uptake was related to effects on growth rate.

    Results

    The drugs paclitaxel, docetaxel and doxorubicin gave severe growth inhibition, which correlated well with inhibition of the FLT uptake. FLT had, compared with ACE, CHO, MET and FDG, higher sensitivity in monitoring the therapy effects.

    Conclusion

    SASDM provides an effective, user-friendly, time-saving and accurate method to record the growth pattern of the MTS, and also to calculate the effect of the drug on PET tracer uptake. This study demonstrate the use of MTS and SASDM in combination with PET tracers as a promising approach to probe and select PET tracer for treatment monitoring of anticancer drugs and that can hopefully be applied for optimisation in breast cancer treatment.

  • 19.
    Monazzma, Azita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Razifar, Pasha
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Qvarnström, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Josephsson, Raymond
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Långström, Bengt
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Multicellular Tumour Spheroid as a model for evaluation of [18F]FDG as biomarker for breast cancer treatment monitoring2006In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 6, p. 6-Article in journal (Refereed)
    Abstract [en]

    Background

    In order to explore a pre-clinical method to evaluate if [18F]FDG is valid for monitoring early response, we investigated the uptake of FDG in Multicellular tumour spheroids (MTS) without and with treatment with five routinely used chemotherapy agents in breast cancer.

    Methods

    The response to each anticancer treatment was evaluated by measurement of the [18F]FDG uptake and viable volume of the MTSs after 2 and 3 days of treatment.

    Results

    The effect of Paclitaxel and Docetaxel on [18F]FDG uptake per viable volume was more evident in BT474 (up to 55% decrease) than in MCF-7 (up to 25% decrease).

    Doxorubicin reduced the [18F]FDG uptake per viable volume more noticeable in MCF-7 (25%) than in BT474 MTSs.

    Tamoxifen reduced the [18F]FDG uptake per viable volume only in MCF-7 at the highest dose of 1 μM.

    No effect of Imatinib was observed.

    Conclusion

    MTS was shown to be appropriate to investigate the potential of FDG-PET for early breast cancer treatment monitoring; the treatment effect can be observed before any tumour size changes occur.

    The combination of PET radiotracers and image analysis in MTS provides a good model to evaluate the relationship between tumour volume and the uptake of metabolic tracer before and after chemotherapy. This feature could be used for screening and selecting PET-tracers for early assessment of treatment response.

    In addition, this new method gives a possibility to assess quickly, and in vitro, a good preclinical profile of existing and newly developed anti-cancer drugs.

  • 20.
    Nilsson, Greger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Duvernoy, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Sjögren, Iwar
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Distribution of Coronary Artery Stenosis After Radiation for Breast Cancer2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 4, p. 380-386Article in journal (Refereed)
    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.

  • 21.
    Nilsson, Greger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Terent, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Increased incidence of stroke in women with breast cancer2005In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 41, no 3, p. 423-429Article in journal (Refereed)
    Abstract [en]

    Meta-analyses have shown an excess of vascular deaths in women with breast cancer given radiotherapy (RT). In women with breast cancer, RT to the supraclavicular lymph nodes gives a substantial radiation dose to the proximal carotid artery. RT is known to increase the risk of carotid stenosis and ischaemic stroke in head and neck cancer. A study base of 25,171 women with breast cancer was defined. A linkage between the study base and the Hospital Discharge Register yielded 1766 women who were diagnosed with a stroke after a breast cancer. The observed number of strokes was compared with the expected number in the background population. The Relative Risk (RR) of stroke in the study group with breast cancer was 1.12 (95% Confidence Interval (CI)=1.07-1.17). The increased risk was confined to the subtype cerebral infarction, RR=1.12 (95% CI=1.05-1.19). A statistically significant increase in the risk of stroke was seen among women with a history of breast cancer. Whether this risk is associated with the breast cancer disease per se or related to any treatment requires further study.

  • 22. Nilsson-Ihrfelt, Elisabeth
    et al.
    Fjällskog, Marie-Louise
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Interfaculty Units, Centrum för klinisk forskning, Gävleborg. Enheten för onkologi.
    Ahlgren, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Edlund, Per
    Hansen, Jörgen
    Malmberg, Lena
    Villman, Kenneth
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Andersson, Gerhard
    Breast cancer on the Internet: the quality of Swedish breast cancer websites.2004In: Breast, ISSN 0960-9776, Vol. 13, no 5, p. 376-82Article in journal (Refereed)
  • 23. Nilsson-Ihrfelt, Elisabeth
    et al.
    Fjällskog, Marie-Louise
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enh för onkologi.
    Liss, Anders
    Department of Surgical Sciences.
    Jakobsson, Olafur
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enh för onkologi.
    Andersson, Gerhard
    Autobiographical memories in patients treated for breast cancer.2004In: J Psychosom Res, ISSN 0022-3999, Vol. 57, no 4, p. 363-6Article in journal (Other scientific)
  • 24. Niméus-Malmström, Emma
    et al.
    Koliadi, Anthoula
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ahlin, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Holmqvist, Marit
    Uppsala-Örebro Regional Oncologic Centre.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jirström, K.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Fernö, M.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort2010In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 127, no 4, p. 961-967Article in journal (Refereed)
    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.

  • 25. Nyman, Heidi
    et al.
    Adde, Magdalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Karjalainen-Lindsberg, Marja-Liisa
    Taskinen, Minna
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Leppä, Sirpa
    Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy2007In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 109, no 11, p. 4930-4935Article in journal (Refereed)
    Abstract [en]

    Germinal center (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL) and can be used to stratify chemotherapy-treated patients into low- and high-risk groups. To determine how combination of rituximab with chemotherapy influences GC-associated clinical outcome, GC and non-GC phenotypes were identified immunohistochemically from samples of 90 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen (immunochemotherapy). One hundred and four patients previously treated with chemotherapy served as a control group. Consistent with previous studies, chemotherapy-treated patients with immunohistochemically defined GC phenotype displayed a significantly better overall (OS) and failure-free survival (FFS) than the non-GC group (OS, 70% vs 47%, P = .012; FFS, 59% vs 30%, P = .001). In contrast, immunohistochemically defined GC phenotype did not predict outcome in immunochemotherapy-treated patients (OS, 77% vs 76%, P = ns; FFS, 68% vs 63%, P = ns). In comparison, International Prognostic Index (IPI) could separate the high-risk patients from low- and intermediate-risk groups (OS, 84% vs 63%, P = .030; FFS, 79% vs 52%, P = .028). We conclude that rituximab in combination with chemotherapy seems to eliminate the prognostic value of immunohistochemically defined GC- and non-GC phenotypes in DLBCL.

  • 26. Peurala, Hanna
    et al.
    Greco, Dario
    Heikkinen, Tuomas
    Kaur, Sippy
    Bartkova, Jirina
    Jamshidi, Maral
    Aittomäki, Kristiina
    Heikkilä, Päivi
    Bartek, Jiri
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bützow, Ralf
    Nevanlinna, Heli
    MiR-34a expression has an effect for lower risk of metastasis and associates with expression patterns predicting clinical outcome in breast cancer2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, p. e26122-Article in journal (Refereed)
    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.

  • 27. Pierceall, William E
    et al.
    Sprott, Kam M
    Heikkinen, Tuomas
    Heikkila, Paivi
    Alaparthi, Lakshmi
    Aittomaki, Kristiina
    Al-Adhami, Mohammed
    Villegas-Bergazzi, Vivian
    Meyer, Jane L
    Kutok, Jeffery L
    Bartkova, Jirina
    Bartek, Jiri
    Nevanlinna, Heli
    Weaver, David T
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Utilization of fluorescence in situ hybridization with cytokeratin discriminators in TOP2A assessment of chemotherapy-treated patients with breast cancer2012In: Human Pathology, ISSN 0046-8177, E-ISSN 1532-8392, Vol. 43, no 9, p. 1363-1375Article in journal (Refereed)
    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.

  • 28. Poikonen, P
    et al.
    Sjostrom, J
    Amini, R-M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Villman, K
    Ahlgren, J
    Interfaculty Units, Centrum för klinisk forskning, Gävleborg.
    Blomqvist, C
    Department of Oncology, Radiology and Clinical Immunology.
    Cyclin A as a marker for prognosis and chemotherapy response in advanced breast cancer.2005In: Br J Cancer, ISSN 0007-0920, Vol. 93, no 5, p. 515-9Article in journal (Refereed)
  • 29. Poikonen, Paula
    et al.
    Sjöström, Johanna
    Klaar, Sigrid
    Nittby, Lena Tennvall
    Sigurdsson, Helgi
    Madsen, Ebbe Lindegaard
    Joensuu, Heikki
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enh för onkologi.
    Skin toxicity as a risk factor for major infections in breast cancer patients treated with docetaxel.2004In: Acta Oncol, ISSN 0284-186X, Vol. 43, no 2, p. 190-5Article in journal (Other scientific)
  • 30. Pylkäs, Katri
    et al.
    Tommiska, Johanna
    Syrjäkoski, Kirsi
    Kere, Juha
    Gatei, Magtouf
    Waddell, Nicola
    Allinen, Minna
    Karppinen, Sanna-Maria
    Rapakko, Katrin
    Kääriäinen, Helena
    Aittomäki, Kristiina
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Mustonen, Aki
    Holli, Kaija
    Khanna, Kum Kum
    Kallioniemi, Olli-Pekka
    Nevanlinna, Heli
    Winqvist, Robert
    Evaluation of the role of Finnish ataxia-telangiectasia mutations in hereditary predisposition to breast cancer.2006In: Carcinogenesis, ISSN 0143-3334Article in journal (Refereed)
  • 31. Saarilahti, Kauko
    et al.
    Arponen, Päivi
    Vaalavirta, Leila
    Tenhunen, Mikko
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Chemoradiotherapy of anal cancer is feasible in elderly patients: treatment results of mitomycin-5-FU combined with radiotherapy at Helsinki University Central Hospital 1992-2003.2006In: Acta Oncol, ISSN 0284-186X, Vol. 45, no 6, p. 736-42Article in journal (Refereed)
  • 32. Saarto, Tiina
    et al.
    Vehmanen, Leena
    Virkkunen, Pekka
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients.2004In: Acta Oncol, ISSN 0284-186X, Vol. 43, no 7, p. 650-6Article in journal (Other scientific)
  • 33. Schmidt, Marjanka K
    et al.
    Reincke, Scarlett
    Broeks, Annegien
    Braaf, Linde M
    Hogervorst, Frans B L
    Tollenaar, Rob A E M
    Johnson, Nichola
    Fletcher, Olivia
    Peto, Julian
    Tommiska, Johanna
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nevanlinna, Heli A
    Healey, Catherine S
    Dunning, Alison M
    Pharoah, Paul D P
    Easton, Douglas F
    Dörk, Thilo
    Van't Veer, Laura J
    Do MDM2 SNP309 and TP53 R72P interact in breast cancer susceptibility? A large pooled series from the breast cancer association consortium2007In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 19, p. 9584-9590Article in journal (Refereed)
    Abstract [en]

    Association studies in large series of breast cancer patients can be used to identify single-nucleotide polymorphisms (SNP) contributing to breast cancer susceptibility. Previous studies have suggested associations between variants in TP53 (R72P) and MDM2 (SNP309) and cancer risk. Data from molecular studies suggest a functional interaction between these genes. We therefore investigated the effect of TP53 R72P and MDM2 SNP309 on breast cancer risk and age at onset of breast cancer in a pooled series of 5,191 cases and 3,834 controls from the Breast Cancer Association Consortium (BCAC). Breast cancer risk was not found to be associated with the combined variant alleles [odds ratio (OR), 1.00; 95% confidence interval (95% CI), 0.81–1.23]. Estimated ORs were 1.01 (95% CI, 0.93–1.09) per MDM2 SNP309 allele and 0.98 (95% CI, 0.91–1.04) for TP53 R72P. Although we did find evidence for a 4-year earlier age at onset for carriers of both variant alleles in one of the breast cancer patient series of the BCAC (the German series), we were not able to confirm this effect in the pooled analysis. Even so, carriers of both variant alleles did not have different risk estimates for bilateral or estrogen receptor–positive breast cancer. In conclusion, in this large collaborative study, we did not find an association of MDM2 SNP309 and TP53 R72P, separately or in interaction, with breast cancer. This suggests that any effect of these two variants would be very small and possibly confined to subgroups that were not assessed in our present study.

  • 34. Svarvar, Catarina
    et al.
    Böhling, Tom
    Berlin, Örjan
    Gustafson, Pelle
    Folleras, Gunnar
    Bjerkehagen, Bodil
    Domanski, Henryk A
    Sundby Hall, Kirsten
    Tukiainen, Erkki
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Clinical course of nonvisceral soft tissue leiomyosarcoma in 225 patients from the Scandinavian Sarcoma Group2007In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 109, no 2, p. 282-291Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Leiomyosarcoma of nonvisceral soft tissues is an uncommon malignant tumor; thus, only small numbers of cases have been reported. This study was based on a large series of patients from the Scandinavian Sarcoma Group Register acquired during a 15-year period (from 1986 to 2001). Follow-up information was available for all patients. METHODS. The authors analyzed the clinical features of 225 patients with cutaneous, subcutaneous, or deep-seated leiomyosarcoma of the extremities, trunk wall, and superficial parts of the head and neck region to determine the natural course of the disease. Only patients who received their treatment at a specialist sarcoma center were included. Re-evaluation of histopathology was performed. RESULTS. The age of the patients (121 women and 104 men) ranged from 20 years to 98 years (median, 70 years), and the tumors ranged in size from 0.6 cm to 35 cm (median, 4.0 cm). Eighty-two percent of the tumors were classified as high grade. The median follow-up for survivors was 5.5 years. The local treatment was adequate in 154 of 206 patients (75%) who were without metastasis at presentation. At 10 years, 84% of the 206 patients with localized disease at presentation were free from local recurrence, 66% remained metastasis free, and 49% were alive. Multivariate analysis showed that higher malignancy grade (P = .006), larger tumor size (P =.003), and deeper tumor location (P =.002) were correlated significantly with decreased metastasis-free survival, inadequate local treatment was correlated with local recurrence (P =.007), and high malignancy grade was correlated with decreased overall survival (P =.007). CONCLUSIONS. The long-term prognosis for patients with subcutaneous and deep-seated soft tissue leiomyosarcoma remains poor despite the ability to achieve adequate local control through nonmutilating surgery with or without radiotherapy.

  • 35. Svarvar, Catarina
    et al.
    Larramendy, Marcelo L
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gentile, Massimiliano
    Koivisto-Korander, Riitta
    Leminen, Arto
    Bützow, Ralf
    Böhling, Tom
    Knuutila, Sakari
    Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis?2006In: Mod Pathol, ISSN 0893-3952, Vol. 19, no 8, p. 1068-82Article in journal (Refereed)
  • 36. Tommiska, J
    et al.
    Bartkova, J
    Heinonen, M
    Hautala, L
    Kilpivaara, O
    Eerola, H
    Aittomäki, K
    Hofstetter, B
    Lukas, J
    von Smitten, K
    Blomqvist, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Ristimäki, A
    Heikkilä, P
    Bartek, J
    Nevanlinna, H
    The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer2008In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, no 17, p. 2501-6Article in journal (Refereed)
    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.

  • 37. Tommiska, Johanna
    et al.
    Jansen, Laila
    Kilpivaara, Outi
    Edvardsen, Hege
    Kristensen, Vessela
    Tamminen, Anitta
    Aittomäki, Kristiina
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Börresen-Dale, Anne-Lise
    Nevanlinna, Heli
    ATM variants and cancer risk in breast cancer patients from Southern Finland2006In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 6, p. 209-Article in journal (Refereed)
    Abstract [en]

    Background: Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for breast cancer but the role for ATM genetic variants for breast cancer risk has remained unclear. Recently, a common ATM variant, ATMivs38 - 8T> C in cis with the ATMex39 5557G> A ( D1853N) variant, was suggested to associate with bilateral breast cancer among familial breast cancer patients from Northern Finland. We have here evaluated the 5557G> A and ivs38- 8T> C variants in an extensive case-control association analysis. We also aimed to investigate whether there are other ATM mutations or variants contributing to breast cancer risk in our population.

    Methods: Two common ATM variants, 5557G> A and ivs38- 8T> C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls.

    Results: Neither of the two common variants, 5557G> A and ivs38- 8T> C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls.

    Conclusion: Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G> A or ivs38- 8T> C variant with increased breast cancer risk or with bilateral breast cancer.

  • 38. Tommiska, Johanna
    et al.
    Seal, Sheila
    Renwick, Anthony
    Barfoot, Rita
    Baskcomb, Linda
    Jayatilake, Hiran
    Bartkova, Jirina
    Tallila, Jonna
    Kaare, Milja
    Tamminen, Anitta
    Heikkilä, Päivi
    Evans, D Gareth
    Eccles, Diana
    Aittomäki, Kristiina
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bartek, Jiri
    Stratton, Michael R
    Nevanlinna, Heli
    Rahman, Nazneen
    Evaluation of RAD50 in familial breast cancer predisposition.2006In: Int J Cancer, ISSN 0020-7136, Vol. 118, no 11, p. 2911-6Article in journal (Refereed)
  • 39. Tynninen, O
    et al.
    Sjostrom, J
    von Boguslawski, K
    Bengtsson, NO
    Heikkila, R
    Malmstrom, P
    Ostenstad, B
    Wist, E
    Valvere, V
    Saksela, E
    Paavonen, T
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tumour microvessel density as predictor of chemotherapy response in breastcancer patients2002In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 86, p. 1905-1908Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate the predictive value of intratumoural microvessel density in breast cancer. We studied immunohistochemically primary tumours of 104 patients with metastasised breast cancer who took part in a randomised multicentre trial comparing docetaxel to sequential methotrexate and 5-fluorouracil. Vessels were highlighted with factor VIII staining and counted microscopically. Microvessel density was compared with clinical response to chemotherapy and patient survival. The microvessel density of the primary tumour was not significantly associated with patient's response to chemotherapy, time to progression or overall survival in the whole patient population or in the docetaxel or methotrexate and 5-fluorouracil groups. However, disease-free survival was longer in patients with low microvessel density (P=0.01). These findings suggest that microvessel density of the primary tumour cannot be used as a predictive marker for chemotherapy response in advanced breast cancer.

  • 40. Vahteristo, Pia
    et al.
    Syrjäkoski, Kirsi
    Heikkinen, Tuomas
    Eerola, Hannaleena
    Aittomäki, Kristiina
    von Smitten, Karl
    Holli, Kaija
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kallioniemi, Olli-Pekka
    Nevanlinna, Heli
    BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition.2006In: Eur J Hum Genet, ISSN 1018-4813, Vol. 14, no 2, p. 167-72Article in journal (Refereed)
  • 41. Vahteristo, Pia
    et al.
    Yliannala, Kristiina
    Tamminen, Anitta
    Eerola, Hannaleena
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nevanlinna, Heli
    BACH1 Ser919Pro variant and breast cancer risk.2006In: BMC Cancer, ISSN 1471-2407, Vol. 6, p. 19-Article in journal (Refereed)
  • 42. Vehmanen, L
    et al.
    Saarto, T
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Taskinen, M-R
    Elomaa, I
    Tamoxifen treatment reverses the adverse effects of chemotherapy-induced ovarian failure on serum lipids.2004In: Br J Cancer, ISSN 0007-0920, Vol. 91, no 3, p. 476-81Article in journal (Other scientific)
  • 43. Vehmanen, Leena
    et al.
    Elomaa, Inkeri
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Saarto, Tiina
    Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status.2006In: J Clin Oncol, ISSN 1527-7755, Vol. 24, no 4, p. 675-80Article in journal (Refereed)
  • 44. Vehmanen, Leena
    et al.
    Saarto, Tiina
    Risteli, Juha
    Risteli, Leila
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enh för onkologi.
    Elomaa, Inkeri
    Short-term intermittent intravenous clodronate in the prevention of bone loss related to chemotherapy-induced ovarian failure.2004In: Breast Cancer Res Treat, ISSN 0167-6806, Vol. 87, no 2, p. 181-8Article in journal (Other scientific)
  • 45. Villman, Kenneth
    et al.
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, Rolf
    Department of Medical Sciences.
    Nygren, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Predictive value of in vitro assessment of cytotoxic drug activity in advanced breast cancer.2005In: Anticancer Drugs, ISSN 0959-4973, Vol. 16, no 6, p. 609-15Article in journal (Refereed)
  • 46.
    Villman, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Öhd, John F.
    Lidbrink, Elisabet
    Malmberg, Lena
    Lindh, Birgitta
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bergh, Jonas
    Bergström, Daniel
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    A phase II study of epirubicin, cisplatin and capecitabine as neoadjuvant chemotherapy in locally advanced or inflammatory breast cancer2007In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 43, no 7, p. 1153-1160Article in journal (Refereed)
    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.

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