Breast Neoplasms: Haglund C

Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brünner N, Chan DW, Babaian R, Bast RC, Dowell B, Esteva FJ, Haglund C, Harbeck N, Hayes DF, Holten-Andersen M, Klee GG, Lamerz R, Looijenga LH, Molina R, Nielsen HJ, Rittenhouse H, Semjonow A, Shih IeM, Sibley P, Sölétormos G, Stephan C, Sokoll L, Hoffman BR, Diamandis EP, Anonymous00039. · Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, Edinburgh, UK. · Clin Chem. · Pubmed #19042984 No free full text.

Abstract: BACKGROUND: Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. METHODS: Published reports relevant to use of tumor markers for 5 cancer sites--testicular, prostate, colorectal, breast, and ovarian--were critically reviewed. RESULTS: For testicular cancer, alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are recommended for diagnosis/case finding, staging, prognosis determination, recurrence detection, and therapy monitoring. alpha-Fetoprotein is also recommended for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign prostatic disease when total PSA is <10 microg/L. In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, postoperative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing may be used for screening asymptomatic adults 50 years or older. For breast cancer, estrogen and progesterone receptors are mandatory for predicting response to hormone therapy, human epidermal growth factor receptor-2 measurement is mandatory for predicting response to trastuzumab, and urokinase plasminogen activator/plasminogen activator inhibitor 1 may be used for determining prognosis in lymph node-negative patients. CA15-3/BR27-29 or carcinoembryonic antigen may be used for therapy monitoring in advanced disease. CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in postmenopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer. CONCLUSIONS: Implementation of these recommendations should encourage optimal use of tumor markers.

Linder N, Martelin E, Lundin M, Louhimo J, Nordling S, Haglund C, Lundin J. · Department of Oncology, Institute of Clinical Medicine, University of Helsinki, Haartmaninkatu 4, PO Box 105, 00029 Helsinki, Finland. · Eur J Cancer. · Pubmed #19112016 No free full text.

Abstract: Xanthine oxidoreductase (XOR) is a key enzyme in degradation of DNA and RNA, and has previously been shown to be decreased in aggressive breast and gastric cancer. In this study, XOR expression was assessed in tissue microarray specimens of 478 patients with colorectal cancer and related to clinical parameters. In addition, we performed in vitro studies of XOR activity, protein and mRNA in colon cancer cells (Caco-2). Results from the tissue expression analyses show that XOR was decreased in 62% and undetectable in 22% of the tumours as compared to normal tissue. Loss of XOR was associated with poor grade of differentiation (p=0.006) and advanced Dukes stage (p=0.03). In multivariate survival analysis, XOR was a prognostic factor (p=0.008), independent of Dukes stage, histological grade, age and tumour location. The in vitro analyses show that XOR is not measurable in undifferentiated Caco-2 cells, but appears and increases with differentiation. We conclude that XOR expression is associated with histological grade of differentiation and extent of disease in colorectal cancer, and it provides significant prognostic information independently of established factors.

Heinonen M, Fagerholm R, Aaltonen K, Kilpivaara O, Aittomäki K, Blomqvist C, Heikkilä P, Haglund C, Nevanlinna H, Ristimäki A. · Department of Pathology/HUSLAB and Haartman Institute, Helsinki University Central Hospital, Finland. · Clin Cancer Res. · Pubmed #18056170 links to  free full text

Abstract: 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-BRCA1/2 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-BRCA1/2 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.

Wickström M, Haglund C, Lindman H, Nygren P, Larsson R, Gullbo J. · Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University Hospital, Entrance 61, 4th floor, 75185 Uppsala, Sweden. · Invest New Drugs. · Pubmed #17922077 No free full text.

Abstract: OBJECTIVE: The dipeptide J1 acts as a prodrug of melphalan with a significant increased potency in vitro resulting from activation by cellular aminopeptidases. The current study was performed to evaluate the ex vivo profile of J1 using 176 primary tumor cell cultures from patients. In addition, the activity of J1 in combination with eight standard drugs, representing different mechanistic classes, was studied in nine different human tumor cell lines of different histopathological origin. METHODS: Ex vivo evaluation of tumor type selectivity, was performed using the established fluorometric microculture cytotoxicity assay (FMCA). Combinations between J1 and eight standard chemotherapeutic drugs were analyzed using the median-effect method. RESULTS: The prodrug J1 expressed approximately 50- to 100-fold higher potency but similar activity profile as that of its metabolite, melphalan. The difference was greater in some diagnoses (e.g. breast cancer, NHL and AML), and exceptionally high in some breast cancer samples with aggressive phenotypes. Combination analysis of J1 and standard chemotherapeutics yielded several potentially additive and synergistic interactions, most striking for etoposide with significant synergism in all studied cell lines. CONCLUSIONS: In conclusion, the ex vivo profile suggests that further evaluation of J1 as the alkylating agent in for example aggressive breast cancer might be of particular interest, preferentially in combination with DNA-topoisomerase II inhibitors like etoposide.

Railo M, Lundin J, Haglund C, von Smitten K, Nordling S. · Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland. · Tumour Biol. · Pubmed #17143016 No free full text.

Abstract: BACKGROUND: The aim of the present study was to evaluate a series of biomarkers with regard to long-term prognostic value in patients with T1 (< or =2 cm) node-negative breast cancer. METHOD: The prognostic value of Ki-67, p53, oestrogen receptor (ER) immunohistochemical labelling, flow-cytometric S phase fraction and ploidy was evaluated in 212 patients with pT1N0M0 breast cancer. The median follow-up time was 15.9 years (range 0.2-27.2 years). RESULTS: In an analysis of breast cancer-specific survival up to 5 years, high Ki-67 (> or =10%; p = 0.002), high p53 (> or =20%; p = 0.01), negative ER (<30%; p = 0.01) as well as aneuploidy of the tumour (p = 0.02) were significant prognostic factors. When the follow-up was extended to 10 years, only Ki-67 (p = 0.03) was significantly associated with outcome and beyond 15 years none of the studied markers provided significant prognostic information when analyzed separately. There was a weak but significant difference in long-term survival when patients with a combination of high Ki-67 (> or =10%), high SPF (>3%) and high p53 (> or =20%) were compared to patients with other combinations (p = 0.03). CONCLUSION: According to the results of our series, it seems that several prognostic markers which are associated with short-term survival (< or =5 years) in pT1N0M0 breast cancer may not be significant predictors of long-term (>15 years) breast cancer-specific survival.

Linder N, Haglund C, Lundin M, Nordling S, Ristimäki A, Kokkola A, Mrena J, Wiksten JP, Lundin J. · Developmental and Reproductive Biology and Hospital for Children and Adolescents, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. · J Clin Pathol. · Pubmed #16935971 No free full text.

Abstract: BACKGROUND: Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA and high-energy phosphates. About half of the patients with breast cancer have a decrease in XOR expression. Patients with breast cancer with unfavourable prognosis are independently identified by the loss of XOR. AIM: To assess the clinical relevance of XOR expression in gastric cancer. METHODS: XOR levels were studied by immunohistochemistry in tissue microarray specimens of 337 patients with gastric cancer and the relation between XOR expression and a series of clinicopathological variables, as well as disease-specific survival, was assessed. RESULTS: XOR was moderately decreased in 41% and was undetectable in another 14% of the tumours compared with the corresponding normal tissue. Decreased XOR was associated with advanced stage, deep tumour penetration, diffusely spread tumour location, positive lymph node status, large tumour size, non-curative disease, cellular aneuploidy, high S-phase fraction and high cyclooxygenase-2 expression, but not with p53 expression or Borrmann classification. Down regulation of XOR was associated with unfavourable outcome, and the cumulative 5-year gastric cancer-specific survival in patients with strong XOR expression was 47%, compared with 22% in those with moderate to negative expression (p<0.001). This was also true in patients with stage I-II (p = 0.01) and lymph node-negative (p = 0.02) disease, as well as in patients with smaller (< or =5 cm) tumours (p = 0.02). CONCLUSION: XOR expression in gastric cancer may be a new marker for a more aggressive gastric cancer biology, similar to that previously reported for breast cancer.

Heinonen M, Bono P, Narko K, Chang SH, Lundin J, Joensuu H, Furneaux H, Hla T, Haglund C, Ristimäki A. · Department of Pathology, University of Helsinki, Helsinki, Finland. · Cancer Res. · Pubmed #15781626 links to  free full text

Abstract: HuR is a ubiquitously expressed mRNA-binding protein. Intracellular localization of HuR is predominantly nuclear, but it shuttles between the nucleus and the cytoplasm. In the cytoplasm it can stabilize certain transcripts. Because nucleocytoplasmic translocation of HuR is necessary for its activity, it was hypothesized that cytoplasmic HuR expression in cancer cells could be a prognostic marker. To test the significance of HuR in carcinogenesis of the breast, we have investigated HuR expression in a mouse mammary gland tumor model and from 133 invasive ductal breast carcinoma specimens. HuR expression was elevated in the cyclooxygenase-2 transgene-induced mouse mammary tumors, and its expression was predominantly cytoplasmic in the tumor cells. In the human carcinoma samples, high cytoplasmic immunoreactivity for HuR was found in 29% (38 of 133) of the cases. Cytoplasmic HuR expression associated with high grade (P = 0.0050) and tumor size over 2 cm (P = 0.0082). Five-year distant disease-free survival rate was 42% [95% confidence interval (95% CI), 26-58] in cytoplasm-high category and 84% (95% CI, 76-91) in cytoplasm-negative or -low category (P < 0.0001), and high cytoplasmic expression of HuR was an independent prognostic factor in a Cox multivariate model (relative risk 2.07; 95% CI, 1.05-4.07). Moreover, high cytoplasmic HuR immunopositivity was significantly associated with poor outcome in the subgroup of node-negative breast cancer in a univariate analysis (P < 0.0007). Our results show that high cytoplasmic HuR expression is associated with a poor histologic differentiation, large tumor size, and poor survival in ductal breast carcinoma. Thus, HuR is the first mRNA stability protein of which expression associates with poor outcome in breast cancer.

Sivula A, Talvensaari-Mattila A, Lundin J, Joensuu H, Haglund C, Ristimäki A, Turpeenniemi-Hujanen T. · Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland. · Breast Cancer Res Treat. · Pubmed #15754118 No free full text.

Abstract: Expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-2 (MMP-2) associates with reduced survival in human breast cancer. COX-2 may be directly involved with mammary carcinogenesis, since expression of COX-2 is sufficient for formation of breast tumors in transgenic mice, and COX-2 selective inhibitors can suppress tumorigenesis in rodent models of breast cancer. MMP-2 is an extracellular matrix degrading proteolytic enzyme that bas been linked to invasion and metastasis. A direct link between COX-2 and MMP-2 may exist, since inhibition of COX-2 activity can result in reduction of MMP-2 expression and activity. In this study we analyzed protein expression of COX-2 and MMP-2 in tissue array specimens of 278 invasive breast cancers by immunohistochemistry. Immunopositivity of these two markers was correlated with each other and with various clinicopathological parameters including survival. We found high COX-2 expression in 30% and high MMP-2 expression in 83% of the breast cancer specimens, and there was a positive association between the expression of these two factors (p = 0.003). It was especially evident that whenever COX-2 expression was high, MMP-2 expression was almost invariably high (95%). Furthermore, high expression of either COX-2 or MMP-2 associated with decreased disease specific survival when compared with the COX-2 or MPP-2 low group (p = 0.026 and p = 0.021, respectively). Taken together, our results indicate that expression of COX-2 protein is associated with expression of MMP-2 protein in human breast cancer and that both COX-2 and MMP-2 are markers of poor prognosis in breast cancer.

Juuti A, Nordling S, Louhimo J, Lundin J, Haglund C. · Department of Surgery, Helsinki University Central Hospital, Helsinki, 00029 HUS, Finland. · J Clin Pathol. · Pubmed #15509674 links to  free full text

Abstract: BACKGROUND: Tenascin C is a large, hexameric, extracellular matrix protein that is present during embryonic development but essentially absent in adult tissues. It is involved in remodelling processes, such as wound healing and tumour development. Tissue expression of tenascin C correlates with prognosis in colorectal, cervical, and breast cancer and in carcinoma of the papilla of Vater. AIM: To study the expression of tenascin C in pancreatic cancer and to compare the staining results with the patients' clinicopathological data. MATERIAL AND METHODS: Formalin fixed, paraffin wax embedded specimens from 146 patients with pancreatic adenocarcinoma were stained with an anti-tenascin C monoclonal antibody. RESULTS: Tenascin C immunoreactivity was seen in most samples of pancreatic carcinoma: staining was weak in 72 (49%), moderate in 52 (36%), strong in 10 (7%), and negative in 12 (8%) samples. Tenascin C expression correlated with age (< or = 66 v >66 years) and poor differentiation (grades 1-2 v 3). There was no correlation between tenascin C expression and survival, clinical stage, tumour size, nodal status, distant metastasis, tumour location, or sex. CONCLUSION: Tenascin C expression was increased in most pancreatic carcinomas, but contrary to the results in other cancers, it is not a prognostic factor in pancreatic cancer.

Leivonen M, Lundin J, Nordling S, von Boguslawski K, Haglund C. · Department of Surgery, Peijas Hospital, Helsinki University Central Hospital, Vantaa, Finland. · Oncology. · Pubmed #15459490 No free full text.

Abstract: OBJECTIVE: Syndecan-1 is a cell surface heparan sulphate proteoglycan which participates in cell proliferation, cell migration and cell-matrix interactions. Epithelial syndecan-1 expression is reduced in several malignant tumours, but in breast and pancreatic cancer, increased expression has also been described. Loss of epithelial syndecan-1 has been associated with poor prognosis in some forms of cancer, but previous findings in breast cancer have been contradictory. The objective of this study was to evaluate the prognostic value of the immunohistochemical expression of syndecan-1 in a series of 200 patients with invasive breast cancer with a median follow-up of 17 years. METHODS: Formalin-fixed paraffin-embedded specimens were stained using a monoclonal antibody against syndecan-1. RESULTS: Syndecan-1 was expressed in the epithelium in 61% and in the stroma in 67% of the tumours. Epithelial syndecan-1 expression was associated with negative oestrogen receptor (ER) status (p < 0.01), and stromal syndecan-1 expression with positive ER status (p = 0.02). The breast cancer-specific 10-year overall survival for patients with epithelial syndecan-1 expression was 65%, compared with 82% for those with loss of epithelial expression (p = 0.02). Ten-year survival was 66% for those expressing stromal syndecan-1 and 83% for those lacking stromal expression (p = 0.15). Patients with both epithelial and stromal expression had a 10-year survival of only 56%, compared to 78% in patients with other expression pattern combinations (p < 0.002). In Cox multivariate analysis, only axillary involvement and tumour size were significant predictors of breast cancer-specific survival. CONCLUSION: Concomitant expression of syndecan-1 in both epithelium and stroma may be a predictor of unfavourable prognosis in breast cancer, and in contrast with previous studies, loss of epithelial syndecan-1 was associated with a more favourable prognosis.

Ristimäki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J. · Department of Pathology, Molecular and Cancer Research Program, Helsinki University Central Hospital, P.O. Box 63 (Haartmaninkatu 8), FIN-00014 Helsinki, Finland. · Cancer Res. · Pubmed #11830510 links to  free full text

Abstract: Cyclooxygenase-2 (Cox-2) expression can induce mammary tumorigenesis in transgenic mice, and selective Cox-2 inhibitors are both chemopreventive and chemotherapeutic in rat models of breast cancer. We analyzed the expression of Cox-2 protein by immunohistochemistry in tissue array specimens of 1576 invasive breast cancers. Moderate to strong (elevated) expression of Cox-2 protein was observed in 37.4% of the tumors, and it was associated with unfavorable distant disease-free survival (P < 0.0001). Elevated Cox-2 expression was associated with a large tumor size, a high histological grade, a negative hormone receptor status, a high proliferation rate (identified by Ki-67), high p53 expression, and the presence of HER-2 oncogene amplification (P < 0.0001 for all comparisons), along with axillary node metastases and a ductal type of histology (P = 0.0001 and P = 0.0017, respectively). Interestingly, association with the unfavorable outcome was especially apparent in the subgroups defined by estrogen receptor positivity, low p53 expression, and no HER-2 amplification (P < 0.0001 for all comparisons). These results indicate that elevated Cox-2 expression is more common in breast cancers with poor prognostic characteristics and is associated with an unfavorable outcome. The present findings support efforts to initiate clinical trials on the efficacy of Cox-2 inhibitors in adjuvant treatment of breast cancer.

Leivonen M, Nordling S, Lundin J, von Boguslawski K, Haglund C. · Department of Surgery, Peijas Hospital, Vantaa, Finland. · Oncology. · Pubmed #11721177 No free full text.

Abstract: Sialyl-Tn (STn) is a carbohydrate antigen formed by the premature 2-6 sialylation of N-acetylgalactosamine. It belongs to a family of antigens widely expressed in carcinomas but only to a limited degree in normal tissue. The expression of STn has been associated with prognosis in different tumors. In this immunohistochemical study of 218 patients with invasive stage I-III breast cancer, STn was expressed in 39% of the tumors. High expression of STn correlated with estrogen and progesterone hormone receptor negativity (p = 0.0002 and p = 0.0003, respectively), and marginally with large tumor size (p = 0.04), high S-phase fraction (p = 0.04) and aneuploidy (p = 0.04), but not significantly with node status, grade or age. The patients had a median follow-up of 17 years. The breast-cancer-specific survival rate of patients with STn-negative cancers was higher than that of patients with cancers that expressed STn during the first 5 years of the follow-up (p = 0.013), but the difference between the groups decreased during the long-term follow-up. STn expression seems to be a marker for short-term, but not for long-term breast cancer outcome prediction.

Leivonen M, Nordling S, Lundin J, von Boguslawski K, Haglund C. · Department of Surgery, Peijas Hospital, Vantaa, Finland. · Breast Cancer Res Treat. · Pubmed #11518462 No free full text.

Abstract: New prognostic and predictive factors are needed to adjust more appropriate therapy for individual patients after operation. p27 is a cell cycle regulator, and a low tissue expression of this protein has been shown to correlate with poor prognosis in colorectal, lung, gastric, prostate, and breast cancer. In this study on 197 breast cancer patients with a median follow-up of 17 years, the prognostic value of immunohistochemical p27 expression was evaluated. After 5 years of follow-up patients with a p27 expression in less than 50% of the tumor cells had a significantly lower survival rate than those with an expression above this level (p = 0.01). However, after longer follow-up the difference decreased and was no longer significant at 7 years (p = 0.1) or when the entire follow-up period was examined (p=0.67). Tests for associations showed that a low p27 expression correlated with a high histologic grade, a high S-phase fraction (SPF), an advanced TNM stage and negative hormone receptor status. In conclusion: Tissue expression of p27 is a significant predictor of 5-year, but not of 10- or 15-year breast cancer specific survival.