Biomedical subjects

Pär-Ola Bendahl

Publications and source records attributed to Pär-Ola Bendahl.

At least 19 recordsLinked to original sources

PubMed2007

Cytogenetic characterization and gene expression profiling of the trastuzumab-resistant breast cancer cell line JIMT-1.

Resistance to the HER-2 targeting drug trastuzumab can be observed clinically, but the lack of suitable experimental models hampers studies of resistance mechanisms. We characterized a HER-2-positive carcinoma cell line (JIMT-1) derived from a 62-year-old breast cancer patient which was clinically resistant to trastuzumab. Multicolor fluorescence in situ hybridization revealed a complex hyperdiploid karyotype with numerous marker chromosomes and unbalanced translocations. Comparative genomic hybridization (CGH) revealed numerous regions of copy number aberration (CNA). Further analysis by array CGH identified 27 regions of CNA (16 amplified, 11 deleted). Thirty-eight percent of the genes in the amplified regions were overexpressed, compared to only 9% in regions of normal copy number ratios (CNR). Accordingly, 26% of the genes in the deleted regions were underexpressed, compared to 10% in regions of normal CNR. Most amplified and overexpressed genes were located on chromosome 1 as well as on 8q, 12q14.1, 17q11 approximately q21, and 20q13. In 17q11 approximately q21, we identified two separate amplicons, the HER-2 amplicon and a previously unreported amplicon at 17q21.31. Several aberrant genes are implicated in cancer development (e.g., JUN, CDK4, and SLUG protooncogenes, as well as the drug/hormone-metabolizing genes GSTM1 and CYP24). We conclude that cytogenetic and expression profiling of JIMT-1 revealed several new features that need further characterization and may shed light on trastuzumab resistance.

Animals↗

PubMed2006

Benefits from membership in cancer patient associations: relations to gender and involvement.

Cancer patient associations report a growing number of members and increasing possibilities to influence health care, but knowledge about the members' views on the benefit of involvement is scarce. We therefore investigated how members (n = 1742) of Swedish patient associations for breast cancer and prostate cancer rate the benefit of membership for their physical and psychological well-being and social adjustment to cancer. Using a scoring scale, 2/3 of the members reported that membership had benefit for psychological well-being, whereas half of the members reported benefit for physical well-being and social adjustment. Individuals who had been actively involved in board work and/or contact person activities within the associations reported significantly more benefit for all three parameters. Gender differences were observed with men, represented by individuals affected by prostate cancer, reporting greater benefit for all three parameters, although especially evident for psychological well-being. Individuals who obtained membership within two years of diagnosis reported greater benefit for psychological well-being and social adjustment compared to those who became members later. In conclusion, members in patient associations for cancer report benefit particularly for their psychological well-being and actively involved members and men affected by prostate cancer perceive the greatest benefit from membership.

Adaptation, Psychological↗

PubMed2005

Blood pharmacokinetics of various monoclonal antibodies labeled with a new trifunctional chelating reagent for simultaneous conjugation with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid and biotin before radiolabeling.

PURPOSE: Knowledge of the blood pharmacokinetics of monoclonal antibodies is crucial in deciding the optimal time for starting the administration of a "clearing agent" or using a "clearing device." The primary purpose was to investigate whether the pharmacokinetics of various antibodies labeled with the same chelator and (111)In differed significantly after i.v. injection in immunocompetent rats. A new trifunctional chelator called "1033" containing a biotin and a radiometal chelation moiety is introduced, making it possible to use only one conjugation procedure for the antibody. EXPERIMENTAL DESIGN: Sixty-five non-tumor-bearing rats were included and divided into four groups (I-IV). The blood pharmacokinetics was investigated for rituximab, BR96, and trastuzumab labeled with 1033 and (111)In (I-III). The whole-body activity and activity uptake in muscle, liver, and kidney, which might explain differences in the early pharmacokinetics in blood, were also measured. hMN14 labeled with another chelator [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)], but with the same radionuclide ((111)In-biotin-DOTA-hMN14), was studied (IV). The blood pharmacokinetics from another 15 tumor-bearing rats was compared with those of non-tumor-bearing rats (III) by injection of (111)In-1033-BR96. RESULTS: No statistical difference was detected between the groups regarding the blood pharmacokinetics of rituximab, BR96, or trastuzumab. The pharmacokinetics and biodistribution of (111)In-biotin-DOTA-hMN14 exhibited a clear difference compared with others. There were no significant differences in the blood pharmacokinetics of (111)In-1033-BR96 between tumor-bearing rats and non-tumor-bearing rats. CONCLUSIONS: Different antibodies labeled with the trifunctional chelator 1033 and (111)In did not exhibit different blood pharmacokinetics, which means that the pharmacokinetics could be predicted irrespective of the IgG1 antibody chosen. A small tumor burden did not change the pharmacokinetics of the radioimmunoconjugates.

Animals↗

PubMed2005

Mapping of a novel ocular and cutaneous malignant melanoma susceptibility locus to chromosome 9q21.32.

An estimated 10% of all cutaneous malignant melanoma (CMM) cases are inherited, but the genetics of familial CMM are largely unknown. Ocular malignant melanoma (OMM), which is rare, may be associated with familial CMM. We performed a genome-wide scan of two Danish pedigrees with multiple cases of OMM (N = 10) and CMM (N = 3) and other malignancies (with no germline mutations in CDKN2A, CDK4, BRCA1, and BRCA2) to identify melanoma susceptibility genes. Results of parametric linkage analysis are presented as logarithm of the odds (LOD) scores, and all P values are two-sided. Peak two-point parametric LOD score of 2.2 (P = .0007) at D9S167 on chromosome 9q21 was observed. Targeted analysis of a third Danish family with OMM and CMM patients confirmed 9q21 linkage, providing a combined four-point parametric LOD score of 3.02 (nominal P = .00003 and genome-wide P = .086). Two families shared a common haplotype comprising three adjacent and highly polymorphic markers, limiting the region to less than 5 cM and 3 Mbp at 9q21.32. Expression of RASEF, a known gene in this region, was examined in tumor tissue from 10 sporadic CMM lesions and was found to be decreased in 70% of these tumors compared with RASEF expression in a human reference RNA pool from 10 different cell types and in 10 breast tumors.

Chromosome Mapping↗

PubMed2005

Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification.

Cyclins D1 and A2 are cell cycle regulators that also have the ability to interact with the estrogen receptor (ER) and consequently interfere with antiestrogen treatment in breast cancer. Experimental data support this concept, but the clinical relevance needs to be further established. In this study, we evaluated cyclin D1 and A2 protein expression by immunohistochemistry and cyclin D1 gene (CCND1) amplification by fluorescence in situ hybridization in 500 primary breast cancers arranged in tissue microarrays. Patients had been randomized to 2 years of adjuvant tamoxifen or no treatment with a median follow-up of 14 years, allowing for subgroup analysis of treatment response defined by cyclin status. We found that both cyclin D1 and A2 protein overexpression was associated with an impaired tamoxifen response, although not significant in multivariate interaction analyses, whereas tamoxifen-treated patients with CCND1-amplified tumors had a substantially increased risk for disease recurrence after tamoxifen treatment in univariate analyses [relative risk (RR), 2.22; 95% confidence interval (95% CI), 0.94-5.26; P = 0.06] in contrast to non-amplified tumors (RR, 0.39; 95% CI, 0.23-0.65; P < 0.0001). Consequently, a highly significant interaction between tamoxifen treatment and CCND1 amplification could be shown regarding both recurrence-free survival (RR, 6.38; 95% CI, 2.29-17.78; P < 0.001) and overall survival (RR, 5.34; 95% CI, 1.84-15.51; P = 0.002), suggesting an agonistic effect of tamoxifen in ER-positive tumors. In node-positive patients, the disparate outcome according to gene amplification status was even more accentuated. In summary, our data implicate that despite a significant correlation to cyclin D1 protein expression, amplification status of the CCND1 gene seems a strong independent predictor of tamoxifen response, and possibly agonism, in premenopausal breast cancer.

Adult↗

PubMed2005

Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer.

PURPOSE: Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance. PATIENTS AND METHODS: Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors. RESULTS: VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER-positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor-positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status. CONCLUSION: Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor-positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.

Adult↗

PubMed2005

Improved prognostication in soft tissue sarcoma: independent information from vascular invasion, necrosis, growth pattern, and immunostaining using whole-tumor sections and tissue microarrays.

In 140 mixed primary soft tissue sarcomas with a median follow-up of 6 years, the prognostic importance of tumor size, tumor depth, grade, necrosis, vascular invasion, and peripheral growth pattern (pushing versus infiltrating) was evaluated on whole-tumor sections. Immunohistochemical expression of Ki-67, p53, cyclin A, bcl-2, beta-catenin, CD44, and P-glycoprotein was determined using tissue microarray from the peripheral growth zone. Local recurrences developed in 17% of the patients and correlated with necrosis, vascular invasion, and cyclin A expression. No local recurrence developed in tumors with a pushing growth pattern, regardless of tumor grade and depth. Metastasis developed in 39% of the patients. Vascular invasion was identified in 36% of the tumors and was the strongest prognostic factor for metastasis with a hazard ratio of 3.5. Growth pattern and tumor necrosis were also strong prognostic factors for metastasis, whereas malignancy grade, tumor size, and tumor depth did not have any independent prognostic value. Immunostaining showed independent prognostic information for Ki-67, beta-catenin, CD44, and P-glycoprotein. The results indicate that whole-tumor sections could facilitate identification of vascular invasion, necrosis, and peripheral growth pattern and that immunohistochemical profiling from the growth zone also provides independent prognostic information for metastasis in soft tissue sarcoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Immunohistochemical patterns in rectal cancer: application of tissue microarray with prognostic correlations.

We utilized the high-throughput tissue microarray method to characterize immunohistochemical expression patterns with correlations to prognosis in rectal cancer. Immunostaining for the markers Ki-67, Bcl-2, p53, EGFR, E-cadherin, beta-catenin, MLH1 and MSH2 was performed in 269 rectal cancers. Expression profiles were correlated to metastasis-free survival. Immunostaining revealed frequent upregulation and/or aberrant staining patterns for several of the markers, but Ki-67, p53, Bcl-2 and EGFR did not show any correlation to prognosis. However, reduced membranous staining for beta-catenin (p = 0.04), lack of cytoplasmic staining for beta-catenin (p = 0.04), reduced membranous staining for E-cadherin (p = 0.02) and lack of cytoplasmic staining for E-cadherin (p = 0.02) correlated with metastatic disease. Multivariate analysis including the factors Dukes' stage and tumor differentiation grade demonstrated increased risk of metastatic disease in tumors with lack of cytoplasmic staining for beta-catenin (HR = 3.1, p = 0.02), reduced membranous staining for beta-catenin (HR = 1.7, p = 0.06) and reduced membranous staining for E-cadherin (HR = 2.1, p = 0.06). Loss of MMR protein expression was confirmed to be a rare event in rectal cancer with loss of MLH1 staining in 3% and MSH2 in 1% of the tumors. The lack of prognostic information contributed by most of these markers suggests that single markers for prognosis may be of limited value in rectal cancer. However, altered expression of beta-catenin and E-cadherin correlated with metastatic disease, and these markers may have prognostic importance in rectal cancer.

Adenocarcinoma↗

PubMed2004

Expression profiling using tissue microarray in 211 malignant fibrous histiocytomas confirms the prognostic value of Ki-67.

The tissue microarray technology is a high-throughput technique that allows studies of multiple markers in large tumor materials. We performed immunohistochemical profiling using tissue microarray and immunostaining for Ki-67, p53, bcl-2, CD44, cyclin A and Pgp in a series of 211 malignant fibrous histiocytomas (MFHs) with correlation to prognosis. Tissue from 50 local recurrences and 20 metastases was available for comparison with the primary tumors. In univariate analysis, Ki-67 was the only immunohistochemical marker significantly correlated with metastasis with a hazard ratio of 1.9. Multivariate analysis, with tumor size, depth, necrosis, vascular invasion, mitotic rate and Ki-67 expression, revealed an independent prognostic value of tumor size and Ki-67. Local recurrences did not differ from the corresponding primary tumors, whereas metastases showed a trend for upregulation of cyclin A and Pgp. In this large series of MFHs, a tumor size greater than 8 cm and a Ki-67 index of more than 20% were strong and independent prognostic factors for metastasis. In contrast, p53, bcl-2, CD44, cyclin A and Pgp, which have previously been suggested as prognostic factors in soft tissue sarcomas, did not show such correlations. Hence, we suggest that proliferation, as measured by Ki-67 index, should be considered as a prognostic marker in clinical management of pleomorphic soft tissue sarcomas.

Adult↗

PubMed2004

Amplification of the cyclin D1 gene is associated with tumour subsite, DNA non-diploidy and high S-phase fraction in squamous cell carcinoma of the head and neck.

Amplification of CCND1 (cyclin D1 gene) in squamous cell carcinoma of the head and neck (SCCHN) is correlated to poor prognosis. The purpose of this study was to investigate whether CCND1 amplification is related to different subsites and also to DNA ploidy status and S-phase fraction (SPF). Biopsies from 67 patients with SCCHN were analysed for CCND1 amplification by fluorescence in situ hybridisation (FISH) and for ploidy status and SPF by flow cytometry (FCM). Twenty-one of 67 tumours (31%) showed CCND1 amplification and the frequencies differed significantly between different subsites (p = 0.01). Tumours from hypopharynx, larynx and oropharynx showed higher rates of amplification as compared to tumours from oral cavity and epipharynx. CCND1 amplification was also associated to DNA non-diploidy and high SPF (p = 0.002 and p = 0.002, respectively). In conclusion, the rate of CCND1 amplification differed between different subsites in SCCHN and was also associated to a more aggressive tumour phenotype, as defined by DNA non-diploidy and high SPF.

Adult↗

PubMed2003

Patterns of chromosomal imbalances defines subgroups of breast cancer with distinct clinical features and prognosis. A study of 305 tumors by comparative genomic hybridization.

Chromosomal copy number aberrations (CNAs) are common in breast cancer and involve genomic regions in a frequency and combination, suggesting distinct routes of tumor development. We studied chromosomal gains (+) and losses (-) by comparative genomic hybridization from a series of 305 unselected primary invasive breast cancers. CNAs were observed in >90% of the tumors and involved all chromosomal arms in various frequencies, the most common being +1q (55%), +8q (41%), +16p (40%), +17q (28%), -13q (27%), -16q (22%), +20q (19%), -8p (18%), and +11q (16%). Eighteen pairs of CNAs were revealed as significantly associated using Fisher's exact test with Bonferroni correction, the most common pairs being -8p/+8q, +17q/+20q, and -4q/-13q. To study more complex relationships between individual CNAs, principal component analysis and distance-based tree modeling were performed independently. Three distinct patterns of CNAs were observed. Group A was defined by +1q, +16p, and -16q, group B by +11q, +20q, +17q, and -13q, and group C by -8p and +8q. Group A was correlated to positive estrogen receptor and progesterone receptor (PgR) status (P < 0.001 and P < 0.05, respectively). Groups B and C were correlated to DNA nondiploidy (P < 0.001 and P < 0.05), high histological grade and lymph node positivity (P < 0.05), and group B also to high proliferation rate, large primary tumor size (P < 0.001), and negative PgR status (P < 0.05). Patients with aberrations in group A only had a significantly higher breast cancer survival rate than all other patients. The worst survival was seen for patients with aberrations in group C only along with the patients displaying aberrations from all CNA pattern groups (ABC). The 5-year survival rates vary from 96% in group A to 56% in group C. These correlations were independent of node status, tumor size, and PgR status in a multivariate analysis. We conclude that patterns of copy number gains and losses define breast tumors with distinct clinicopathological features and patient prognosis.

Adult↗

PubMed2003

High tumor tissue concentration of urokinase plasminogen activator receptor is associated with good prognosis in patients with ovarian cancer.

The urokinase plasminogen activator (uPA) system is involved in tumor growth and metastasis. We assayed the components of the uPA system in homogenates of 64 primary epithelial ovarian tumors and 5 metastases and evaluated the association of these parameters to prognosis in the 51 malignant cases. The levels of uPA, PAI-2 and the uPA:PAI-1 complex increased with progressive loss of histological differentiation (p(trend) <0.001, <0.05 and <0.001). The level of PAI-1 was higher in poorly than in well/moderately differentiated tumors (p = 0.03). The content of uPAR was lower in benign tumors as compared to borderline malignancies (p = 0.002), invasive primary tumors (p < 0.001), and metastases (p = 0.002). Surprisingly, the level of uPAR was lower in poorly differentiated as compared to both borderline (p = 0.01) and well differentiated malignant tumors (p = 0.005). Also, the level of uPAR was lower in advanced as compared to early stages of the disease (p(trend) = 0.002). The median follow-up time for patients was 5.8 years. High tumor tissue levels of uPAR were associated with longer postoperative survival (HR = 0.4, 95% CI = 0.2-0.8, p = 0.01). In contrast, shorter survival was evident in patients with high tumor levels of uPA from 2 years on after operation (HR = 4.6, 95% CI = 1.2-17, p = 0.02). High tPA levels tended to be associated with shorter overall survival after 2 years (HR = 2.9, 95% 95% CI = 0.9-9.8, p = 0.08). Although high tumor tissue content of uPAR was associated with a less aggressive phenotype characterized by well differentiated histology and longer survival, low content of uPAR in the poorly differentiated tumors and metastases presumably results from increased elimination of uPAR.

Adenocarcinoma, Clear Cell↗

PubMed2003

Improved DNA flow cytometric, DNA ploidy, and S-phase reproducibility between 15 laboratories in analysis of breast cancer using generalized guidelines.

BACKGROUND: Lack of generalized guidelines for DNA flow cytometric analysis (FCM) may be the main reason for its limited use in the clinical management of breast cancer. METHODS: After an initial interlaboratory reproducibility study (Round I), we concluded that it was the evaluation of the DNA histograms rather than the technical performance of the analysis that was the main reason for discordant results between laboratories. Guidelines for the interpretation of DNA histograms were therefore drawn up. We present here data from a new reproducibility study (Round II) using these guidelines. RESULTS: For 10 laboratories also participating in Round I, use of the guidelines increased the concordance in DNA ploidy status from 89% to 100% for the 46 samples used in both rounds. The concordance rate for SPF also increased; mean r(s)-value increased from 0.81 to 0.88, and mean kappa value (lower two-thirds versus upper third versus not reported) increased from 0.55 to 0.71. Five new laboratories, participating only in Round II, also agreed with the 10 original laboratories regarding DNA ploidy status. With the inclusion of all 15 laboratories, we obtained a mean r(s)-value of 0.81 and a mean kappa value of 0.72 for SPF. CONCLUSIONS: Generalized guidelines for DNA FCM increase interlaboratory agreement, which is highly important in clinical routines and in multicenter studies. Furthermore, inexperienced FCM laboratories using generalized guidelines can produce and interpret DNA FCM data equally as well as experienced laboratories.

Breast Neoplasms↗

PubMed2003

Low-dose hormone therapy and carbohydrate metabolism.

OBJECTIVE: To evaluate the influence by two low doses of oral continuous-combined formulations of 17 beta-estradiol (E(2)) and norethisterone acetate (NETA) on carbohydrate metabolism in healthy postmenopausal women. DESIGN: A double-blind, randomized, placebo-controlled trial. SETTING: Volunteers at a university hospital. SUBJECT: One hundred twenty healthy postmenopausal women. INTERVENTION(S): One hundred twenty women were randomized to three treatment arms: (1) E(2) 1 mg/NETA 0.25 mg group (n = 40); (2) E(2) 1 mg/NETA 0.5 mg group (n = 40); (3) placebo group (n = 40). A total of 102 women completed 12 months of treatment. An oral glucose tolerance test (OGTT) was performed at baseline and at 3, 6, and 12 months. MAIN OUTCOME MEASURE(S): Fasting glucose, fasting insulin, total area under the curve (AUC) and insulin/glucose index during OGTT. RESULT(S): Fasting levels of glucose and insulin declined significantly in the E(2)/NETA 0.5 mg group. At OGTT, the total AUC for insulin declined in both active arms. The curve for glucose increased significantly in the E(2)/NETA 0.25 mg group. A lower insulin/glucose index was observed during OGTT in both active regimens when compared with placebo. In the active treatment groups, a significant reduction of fasting glucose and/or fasting insulin was encountered in women with higher basal fasting levels (fasting glucose >4.2 mmol/L or log-fasting insulin >0.87). CONCLUSION(S): Oral low-dose E(2) 1 mg/NETA 0.5 mg regimen did not impair carbohydrate metabolism, but seemed to improve insulin sensitivity in healthy postmenopausal women.

Blood Glucose↗

PubMed2003

High preoperative plasma concentration of tissue plasminogen activator (tPA) is an independent marker for shorter overall survival in patients with ovarian cancer.

OBJECTIVE: The objective was to evaluate the preoperative blood concentration of tissue plasminogen activator (tPA) as a discriminator between malignant and benign ovarian tumors, and as a potential marker of postoperative prognosis in patients with ovarian cancer. METHODS AND MATERIAL: The concentration of tPA was assayed with ELISA (Imulyse Biopool) in preoperative plasma samples obtained from 111 patients with adnexal lesions. Tumors were classified as benign (n = 25), borderline malignant (n = 11), well-differentiated (G1, n = 22), moderately differentiated (G2, n = 11), and poorly differentiated malignant (G3, n = 42). The median follow-up time of patients with malignant tumors was 5.6 years (range 2.1-13.2 years) and 37 patients died during the follow-up period. RESULTS: Patients with moderately and poorly differentiated tumors had higher levels of plasma tPA compared to those with well-differentiated tumors (P = 0.004 and P = 0.005). No significant differences in the plasma tPA levels were observed between patients with benign, borderline, and well-differentiated tumors. The tPA levels were not different between stages nor within stage Ia-c. In a multivariate Cox proportional hazards model including stage, grade, age, and plasma tPA dichotomized at the median (> or =9 vs <9 ng/mL), high levels of tPA were significantly associated with shorter survival: HR = 4.4 (95% CI 2.0-9.8, P = 0.0003). In the univariate analyze high levels of tPA showed HR = 4.5 (95% CI 2.1-9.6, P = 0.0003). CONCLUSIONS: High concentration of plasma tPA was an independent marker for poor prognosis in patients with ovarian cancer in our study. Plasma tPA did, however, not discriminate between benign and malignant adnexal lesions.

Adult↗

PubMed2003

A prospective study of different types of hormone replacement therapy use and the risk of subsequent breast cancer: the women's health in the Lund area (WHILA) study (Sweden).

OBJECTIVES: Reports suggest that combined estrogen plus progestin hormone replacement therapy (HRT) confers a higher breast cancer risk than estrogen alone. We aimed to establish whether breast cancer risk depends on the type of HRT formula. METHODS: The cohort consisted of 6586 women, aged 50-64 years, from the Lund area, Sweden, with no reported breast cancer upon inclusion. We obtained information such as HRT use through a questionnaire between December 1995 and February 2000. New breast cancers were identified through the South Swedish tumor registry. RESULTS: Between inclusion and December 2001, 101 women developed breast cancer. Only ever use of the continuous combined estrogen plus progestin (CCEP) formula differed between cases and controls (45.2% versus 23.5%; p = 0.000001). Compared with never users, exclusive CCEP users had the highest age-adjusted hazard ratio HR 3.3 (95% CI: 1.9-5.6; p < 0.001), followed by users of CCEP in addition to other HRT formulas HR 2.8 (95% CI: 1.4-5.5; p = 0.003). No significant increase was seen in women who exclusively used other HRT formulas. CONCLUSION: Women who used CCEP had over three times the risk of developing breast cancer compared with never users and twice the risk compared with users of other types of HRT.

Breast Neoplasms↗

PubMed2003

Estrogen and progesterone receptor assay in paraffin-embedded breast cancer--reproducibility of assessment.

Immunohistochemical (IHC) assays are routinely used for determining the estrogen receptor (ER) and progesterone receptor (PgR) status of women with breast cancer. The present knowledge of reproducibility of the subjective IHC assessment is limited. The purpose of this study was to evaluate the interobserver reproducibility in IHC assessment of 127 (ER) and 126 (PgR) cases of primary breast cancer. The slides were independently re-assessed by 22 pathologists from nine hospitals. A simple assessment protocol was used with a cut-off value > 10% stained nuclei, regardless of staining intensity. The concordance was high, with a kappa value of 0.78 for ER and 0.72 for PgR. Since some of the 22 pathologists considered one or several sections to be inevaluable, the evaluation comprised three groups (< or = 10% vs. > 10% vs. not evaluated). Although the percentage of positive cases varied among the 22 pathologists (ER: 57%-79%; PgR: 41%-66%), the overall concordance was good for both ER and PgR (kappa = 0.78 and 0.72, respectively). A further improvement in concordance should be possible to achieve through training.

Breast Neoplasms↗

PubMed2003

Comparison of immunohistochemical and biochemical assay of steroid receptors in primary breast cancer--clinical associations and reasons for discrepancies.

Estrogen (ER) and progesterone receptor (PgR) status was analysed in paraffin-embedded breast cancer material with immunohistochemical (IHC) technique and compared with corresponding analyses in cytosols (CYT). ER showed the same status (positive/negative) with both methods in 88% of the samples (352/402). The concordance was also high for PgR status (81% [321/394]). Besides values near cut-off, heterogeneity in the distribution of receptor positive and negative nuclei within a tumour sample was the main reason for discordances. Histological type, presence of sclerosis, necrosis and non-invasive cells, and technical artefacts seem to be of only limited importance for explaining discordances All patients have been treated with adjuvant tamoxifen for two years. The two subgroups, which were ER(CYT)+/ ER(IHC) + or ER(CYT)-/ER(IHC) +, both had a significantly better progression-free survival (PFS; median follow-up: almost 6 years) than the ER(CYT)-/ER(IHC)- group (p < 0.001 and p = 0.007, respectively). The remaining group, ER(CYT)+/ER(IHC)-, had an intermediate PFS. For PgR, the associations with PFS were weaker, with significantly better PFS than the PgR(CYT)-/PgR(IHC)- group being found only for the PgR(CYT) +/PgR(IHC)- group (p = 0.03).

Breast Neoplasms↗