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Purpose: To prospectively determine whether there is a minimum number of cores required for histopathologic diagnosis of mammographically detected nonpalpable breast lesions with an add-on 14-gauge stereotactic core-needle biopsy device., Materials and Methods: The study was approved by the ethics committee of the hospital; informed consent was obtained. Biopsy was performed in 197 patients with 205 lesions (97 masses, 108 microcalcifications). The first sample (from the center) was collected in container A; second and third samples (2 mm from center), in container B; and additional samples, in container C. Malignancies, atypical ductal hyperplasia (ADH), and radial scars were excised. Benign lesions were followed up mammographically (mean, 24 months). Strict sensitivity and working sensitivity were calculated separately. Stereotactic biopsy with diagnosis of a nonmalignant lesion that, after surgery, proved to be malignant was considered false-negative when strict sensitivity was calculated. Stereotactic biopsy with diagnosis of ADH or radial scar was considered true-positive if the findings at surgery corresponded to the results at biopsy or indicated malignancy and was considered false-positive if the findings at surgery were benign when working sensitivity was calculated. Sensitivity, specificity, and overall accuracy of stereotactic biopsy were determined for masses and microcalcifications in all three containers by using surgical samples and findings at mammographic follow-up as reference. At chi2 analysis, P < .05 was considered to indicate significant difference., Results: Strict sensitivity of the first sample was 77% (66 of 86) (90% [35 of 39] for masses, 66% [31 of 47] for microcalcifications). Results of the first sample were false-negative significantly more often in microcalcifications (n = 16) than in masses (n = 4) (P = .010). Combined results of containers A and B (ie, three samples) yielded higher strict sensitivity than those with first sample alone (95% [37 of 39] for masses [P = .196], 91% [43 of 47] for microcalcifications [P < .001]). With multiple samples, strict and working sensitivity were both 100% (39 of 39) for masses and 91% (43 of 47) and 98% (46 of 47), respectively, for microcalcifications. Four false-negative diagnoses (ADH, three cases; lesion with discordant mammographic and stereotactic biopsy findings, one case) were microcalcifications., Conclusion: More than three samples are needed (a minimum number was not determined) for a histologic diagnosis of a mass lesion by using an add-on stereotactic biopsy device.

N-acetyltransferase 2 (NAT2) is a polymorphic enzyme participating in the metabolism of numerous pharmaceutical drugs and carcinogens found in tobacco smoke and diet. The NAT2 gene is highly polymorphic and several different allelic variants exist that determine the acetylator phenotype. In the course of our case-control study, we developed a new method based on fluorogenic allele-specific probes for analyzing the C282T and T341C polymorphisms of the NAT2 gene in 483 Finnish breast cancer patients and 482 healthy population controls. The slow NAT2 acetylation capacity-associated genotypes posed a somewhat increased overall breast cancer risk (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.01-1.73). This association was found to be confined to the advanced (stage III or IV) breast cancer (OR, 2.60; 95% CI, 1.29-5.24). When stratified by smoking habits, women who had smoked <5 pack-years and carried a NAT2 slow acetylator genotype were at a 2.6-fold (OR, 2.55; 95% CI, 1.01-6.48) risk of breast cancer. Moreover, women with the NAT2 slow acetylator genotype and low body mass index (BMI) (<25.4 kg/m2) were at somewhat increased risk of this malignancy (OR, 1.60; 95% CI, 1.07-2.39). Our results therefore suggest that NAT2 slow acetylator genotype may be an important modifier of environmentally induced breast cancer risk in Finnish women.

Introduction: It has been suggested that individuals with reduced DNA repair capacities might have increased susceptibility to environmentally induced cancer. In this study, we evaluated if polymorphisms in DNA repair genes XRCC1 (Arg280His, Arg399Gln) and XPD (Lys751Gln) modify individual breast cancer risk, with emphasis on tobacco smoking., Methods: The study population consisted of 483 incident breast cancer cases and 482 population controls of Finnish Caucasian origin. The genotypes were determined by PCR-RFLP-based methods. Odds ratio (OR) and confidence intervals (CIs) were calculated by unconditional logistic regression analyses., Results: No statistically significant overall effect in the breast cancer risk was seen for any of the studied polymorphisms. However, a significant increase in breast cancer risk was seen among ever smoking women if they carried at least one XRCC1-399 Gln allele (OR 2.33, 95% CI 1.30-4.19, pint 0.025) or XPD-751 Gln/Gln genotype (OR 2.52, 95% CI 1.27-5.03, pint 0.011) compared to smoking women not carrying these genotypes. The risks were found to be confined to women smoking at least five pack-years; the respective ORs were 4.14 (95% CI 1.66-10.3) and 4.41 (95% CI 1.62-12.0). Moreover, a significant trend of increasing risk with increasing number of the putative at-risk genotypes (p for trend 0.042) was seen. Women with at least two at-risk genotypes had an OR of 1.54 (95% CI 1.00-2.41) compared to women with no at-risk genotypes. Even higher estimates were seen for ever actively smoking women with at least two at-risk genotypes., Conclusion: Our results do not indicate a major role for XRCC1 and XPD polymorphisms in breast cancer susceptibility, but suggest that they may modify the risk especially among smoking women.

Breast cancer is the most common of cancers among women in industrialized countries. Many of breast cancer risk factors are known, but the majority of the genetic background is still unknown. Linkage disequilibrium-based association is a powerful tool for mapping disease genes and is suitable for mapping complex traits in founder populations. We report the results of a two-stage, autosome-wide scan for LD with breast cancer. Our aim was to identify genetic risk factors for sporadic breast cancer in an eastern Finnish population. Our case-control set is from the province of northern Savo in the late-settlement area of eastern Finland. This population is relatively young and genetically homogeneous. We used 435 autosomal microsatellite markers spaced by an average of 10 cM in a set of 49 breast cancer cases and 50 controls. In the first-stage scan, we found 21 markers in LD with breast cancer (Ps = 0.003-0.046, Fisher's exact test). In the second-stage scan with markers flanking 21 positive loci, four significant markers were found (Ps = 0.013-0.046, Fisher's exact test). Haplotype analysis using global score method with two, three, or four markers also revealed four positive marker combinations (simulated P for global score = 0.003-0.021). Our results suggest breast cancer-associated regions on 3p26, 11q23, and 22q13.1 in an eastern Finnish population.

Purpose: In the present study, we investigated the expression and prognostic value of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer as well as their relation to transcription factor activator protein (AP)-2 and HER2 oncogene. The role of invasion and metastasis-promoting MMPs and their potential regulators, AP-2 and HER2, is currently still unclear in breast cancer., Experimental Design: MMP-2 and MMP-9 expressions were analyzed immunohistochemically in a large prospective series of 421 breast cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University Hospital (Kuopio, Finland). The relation of MMP-2 and MMP-9 expressions to AP-2, HER2, clinicopathological data, and survival was investigated., Results: Both MMP-2 and MMP-9 were expressed in the cytoplasm of malignant and stromal cells. High expression of MMPs in carcinoma cells was related to small tumors (T1, stage I), whereas positive stromal expression of MMPs was associated with aggressive factors. High expression of MMP-2 and MMP-9 in carcinoma cells, but not in stromal cells, was related to high AP-2 expression. Positive stromal MMP-2 expression was associated with HER2 overexpression in the whole patient group and in the node-negative patient subgroup. Positive stromal MMP-9 expression was related to HER2 overexpression in estrogen receptor (ER)-positive disease. In the univariate survival analysis, positive stromal MMP-9 predicted shorter recurrence-free survival (RFS; P=0.0389) and breast cancer-related survival (BCRS; P=0.0081) in ER+ disease, especially in the subgroup of ER+ tumors of < or =2 cm in diameter (T1; P=0.0031 for RFS, and P=0.0089 for BCRS). High MMP-9 expression in cancer cells predicted longer RFS (P=0.0351) in the whole patient group. In the multivariate analysis of the whole patient group, the independent predictors of shorter RFS were reduced MMP-9 expression in carcinoma cells (P=0.0248), HER2 overexpression (P=0.0001), and advanced-stage disease (P=0.0002). Shorter BCRS was predicted by advanced-stage disease (P <0.0001)., Conclusions: Expression of MMP-2 and MMP-9 in breast cancer seems to be partly related to expression of AP-2 and HER2. Positive stromal MMP-9 expression predicts poor survival in the hormone-responsive small tumors, whereas MMP-9 expression in carcinoma cells favors survival. Evaluation of MMP-9 expression seems to add valuable information on breast cancer prognosis.

Context: Selection of systemic adjuvant therapies for women diagnosed as having breast cancer is based on risk estimations for cancer recurrence. In such estimations, tumors detected by mammography screening are considered to be associated with a similar risk of recurrence as tumors of similar size found by other methods., Objective: To compare the risk of recurrence and survival among women with cancerous tumors detected by mammography screening compared with other methods (outside of screening)., Design, Setting, and Patients: Retrospective study comparing clinical, histopathological, and biological features of cancerous tumors detected by mammography screening compared with tumors detected outside of screening. Women diagnosed as having breast cancer in 1991 or 1992 were identified from the Finnish Cancer Registry (n = 2842). The median follow-up time was 9.5 years. Cancer biological variables were analyzed from tumor tissue microarrays using immunohistochemistry or in situ hybridization and included ERBB2, TP53, and MK167 expression and ERBB2 amplification data., Main Outcome Measures: Univariate and multivariate analyses of potential risk factors for distant recurrence of breast cancer and 10-year survival., Results: Of the 1983 women with unilateral invasive breast cancer, data on tumor diameter were available for 1918 women. Women with cancerous tumors detected by mammography screening had better estimated 10-year distant disease-free survival than women with tumors found outside of screening (tumor size of < or =10 mm [n = 386] 92% vs 85% [P =.04]; 11-20 mm [n = 808] 88% vs 76% [P<.001]; 21-30 mm [n = 409] 86% vs 63% [P =.008]; >30 mm [n = 315] 68% vs 50% [P =.12], respectively). In a Cox multivariate model that included cancer biological factors, the relative hazard ratio for distant recurrence among women with tumors detected outside of screening (HR, 1.90; 95% confidence interval, 1.15-3.11) was significantly higher than among women with tumors detected by mammography screening (P =.01). Breast cancer diagnosis by mammography screening was an independent prognostic variable reducing the relative HR for distant recurrence. This effect was equal to or greater than the effect of 1-cm decrease in tumor diameter (HR, 1.20; 95% confidence interval, 1.10-1.31)., Conclusions: Cancerous tumors detected by mammography screening are associated with a better prognosis than tumors of similar size found outside of screening. The risk of distant metastases is overestimated for women diagnosed as having cancer by mammography screening unless the method of detection is taken into account in risk estimations.

The association between vitamin D receptor (VDR) gene polymorphisms and diseases such as breast cancer, prostate cancer and osteoporosis has been extensively investigated during recent years. To date, several polymorphisms have been found in the VDR gene. In this Finnish case-control study, comprising 483 breast cancer patients and 482 healthy population controls, we investigated the association between altered breast cancer risk and two polymorphisms in the 3' end of the gene detectable with ApaI and TaqI restriction enzymes. A statistically significant difference was observed in the ApaI genotype distribution between cases and controls. Women with the VDR variant a allele containing genotypes showed a decreased risk for breast cancer [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.54-0.98] compared to women with the AA genotype. This association was especially strong among women with a positive family history of breast cancer (OR 0.14, 95% CI 0.03-0.76). Moreover, there was a trend (P for trend = 0.0007) for decreased risk with increasing number of variant alleles. The lowest risk of breast cancer was seen for the women with the aa genotype (OR 0.03, 95% CI 0.003-0.31) compared to women with the AA genotype. A tendency of decreased risk of breast cancer was also observed for the TaqI T allele containing genotypes (Tt and TT) (OR 0.68, 95% CI 0.41-1.12), but because the distribution of Taql alleles in the controls missed the Hardy-Weinberg equilibrium (P = 0.01), we were unable to properly assess the potential impact of the TaqI polymorphism in breast cancer susceptibility. In conclusion, our results suggest that the VDR ApaI genotype may be an important modifier of individual breast cancer risk among Finnish women, especially if they have a positive family history of breast cancer.

Background and Purpose: To measure local changes of collagen metabolism in irradiated breast skin and systemic changes in serum during and after radiotherapy and correlate these changes with skin thickness, erythema and palpable subcutaneous induration., Patients and Methods: Aminoterminal propeptides of type I and type III procollagens (PINP and PIIINP, respectively) were measured from skin suction blister fluid (SBF) in 21 breast cancer patients with breast conserving surgery and conventionally fractionated radiotherapy (RT) to a total dose of 50Gy. Suction blisters were induced in the operated and contralateral breast skin before RT, at 2.5 weeks, at the end of RT, and at 1, 4, 7, 12 and 24 months post-treatment. Blood samples for serum were taken simultaneously with SBF induction. Skin thickness of the suction blister sites was measured with a high-frequency ultrasound device. The investigated sites were scored for erythema at the end of RT and palpable subcutaneous induration at 1 and 2 years post-treatment., Results: In SBF the mean levels of PINP and PIIINP of the operated breast before RT were about 3-4 times higher than those in the contralateral breast due to the operation-related wound healing. The synthesis of PINP in irradiated breast after RT increased 7.7-fold (P < 0.001) 4 months post-irradiation. The PIIINP synthesis was at maximum at 1 month post-irradiation (P < 0.001). Both synthesis stayed elevated until 2 years. The level of PINP correlated significantly with the palpable skin induration at 1 and 2 years (P = 0.038 and P = 0.003, respectively). The skin thickness of the irradiated breast was highest at 4 months post-treatment and significantly elevated until 1 year. The skin thickness correlated with the PINP level until 7 months and with PIIINP between 4 and 18 months. The PINP/PIIINP ratio reached the maximum at 4 months and stayed elevated until 2 years. No change in mean serum level of PINP was found during or after RT., Conclusions: We demonstrated a maximum and elevated levels for PINP and PIIINP skin collagen metabolism determined from SBF during the 2 years' follow-up. Elevated levels of PINP and PIIINP correlated with the thickening of the skin and subcutaneous induration but not with erythema.

There is evidence that transforming growth factor (TGF)beta acts as a suppressor of tumor initiation but also as a promoter of tumor progression when the antiproliferative effect of the TGFbeta signaling pathway has been overridden by other oncogenic mutations. Several somatic mutations that disrupt the TGFbeta-SMAD signaling pathway have been reported in human breast tumors. We have examined the association between single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3987 patients and 3867 controls, median age approximately 50 years, and range 22-92 years. The promoter SNP, C-509T, and the T +29C signal-peptide SNP (encoding Leu10Pro) are in strong linkage disequilibrium. They are both significantly associated with increased incidence of invasive breast cancer in a recessive manner [odds ratios: (TT versus C-carrier), 1.25; 95% confidence intervals 1.06-1.48; P = 0.009 and (ProPro versus Leu-carrier), 1.21; 95% confidence intervals 1.05-1.37; P = 0.01]. The G-800A SNP was not significantly associated with incidence of breast cancer. The C-509T SNP is not contained within a known consensus sequence for a promoter regulatory element and therefore unlikely to affect TGFbeta1 expression, whereas the Leu10Pro signal peptide substitution potentially affects TGFbeta1 secretion. Transfections of HeLa cells with constructs encoding either the Pro or Leu forms of TGFbeta1 and driven by the cytomegalovirus promoter indicate that the signal peptide with Pro at residue 10 causes a 2.8-fold increase in secretion compared with the Leu form. These data indicate that the allele encoding Pro10 is associated with increased rates of TGFbeta1 secretion and with increased incidence of invasive breast cancer for the population samples described. It is estimated that 3% of all breast cancer cases may be attributable to Pro10 homozygosity.

Purpose: To assess the relative importance of 10 prognostic factors in pT1N0M0 breast cancer (< or =2 cm in diameter, node negative)., Experimental Design: Women diagnosed with breast cancer in Finland from 1991 to 1992 were identified from the files of the Finnish Cancer Registry, and individual clinicopathological data were collected from the hospital case records of women living in five regions comprising about one-half of the Finnish population. Of the women with minimum required information available (n = 2842), 852 had unilateral pT(1)N(0)M(0) cancer. The median follow-up time was 9.5 years, and only 5% had received systemic adjuvant therapy. Estrogen receptor (ER), progesterone receptor, erbB2, p53, and Ki-67 expression was determined from tumor tissue microarrays using immunohistochemistry, and the erbB2 (HER-2) amplification status was determined using chromogenic in situ hybridization., Results: Primary tumor size < or =5 mm and histological grade 1 were associated with 100 and 95% (95% confidence interval, 92-98%) 9-year distant disease-free survival, respectively, whereas strong erbB2 expression or the presence of >20% Ki-67-positive cells was associated with >20% risk. ER and progesterone receptor values obtained from the hospital case records or tumor microarrays showed weaker association with outcome than the erbB2 status. Small (< or =10 mm) erbB2-negative cancers were associated with >90% 9-year distant disease-free survival, irrespective of histological grade., Conclusions: Prognosis of pT(1)N(0)M(0) breast cancer is generally well defined by the histological grade and primary tumor size. The erbB2 status was superior to ER as a prognostic factor in these tumors.

Purpose: We proposed to investigate the expression and prognostic significance of activator protein 2 (AP-2) in breast cancer., Experimental Design: AP-2 was immunohistochemically analyzed in a prospective, consecutive series of 420 breast cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University Hospital, Kuopio, Finland. AP-2 expression was further compared with clinicopathological parameters and patients' survival., Results: Nuclear AP-2 expression was lower in carcinomas compared with normal ductal breast epithelium (P < 0.001). Nuclear expression was more often seen in lobular than in ductal or other carcinomas (P = 0.048). Cytoplasmic staining was present in 47% of the carcinomas. Low nuclear AP-2 expression level in carcinomas was associated with advanced stage (P = 0.002), axillary lymph node positivity (P = 0.012), poor differentiation (P = 0.001), and recurrences (P = 0.003). In univariate survival analyses, low nuclear AP-2 expression (P = 0.0028), advanced stage (P < 0.0001), lymph node metastases (P < 0.0001), and poor differentiation (P = 0.0498) predicted shorter recurrence-free survival (RFS). Low nuclear AP-2 staining and/or shift to cytoplasmic expression predicted shorter RFS (P = 0.0050) and breast cancer-related survival (BCRS; P = 0.0314) in univariate analyses. Cytoplasmic expression alone did not have prognostic value. In multivariate analysis, low nuclear AP-2 expression (P = 0.0292) and advanced stage (P = 0.0001) were independent predictors of shorter RFS; and stage (P < 0.0001) and ER-status (P = 0.0321) independently predicted BCRS. In the lymph-node positive patients, RFS was independently predicted by stage (P = 0.0110) and nuclear AP-2 status (P = 0.0151)., Conclusions: AP-2 seems to have a protective role in breast cancer. Low nuclear AP-2 expression was associated with disease progression and increased metastatic capability of the tumor. In addition, reduced nuclear AP-2 expression independently predicted elevated risk of recurrent disease in breast cancer.

The aim of this study was to evaluate the prognostic value of preoperative concentrations of the serum markers of type I collagen synthesis (PINP, PICP) and degradation (ICTP) in breast cancer. One hundred and eighty-four breast cancer patients without advanced disease were enrolled. Preoperative serum markers of type I collagen were assessed with specific radioimmunoassays. Elevated preoperative serum concentrations of ICTP (>4.9 microg/l) correlated statistically significantly with a poor prognosis for the breast cancer (P=0.0004) and shorter disease-free survival (P=0.02), and multivariate regression analysis likewise showed an elevated ICTP concentration (P=0.008), high grade (P=0.03) and high pathological stage (P=0.02) to be risk factors for poor survival. Sixty-five out of the 184 patients developed metastatic disease during the follow-up. The median follow-up time was 62 months (range 6-111 months). High ICTP (P=0.02) and large numbers of metastatic nodules (P=0.002) were prognostic factors for shorter disease-free survival in multivariate regression analysis. PINP and PICP had no significant prognostic value with respect to either overall or disease-free survival in this analysis. Our results indicate that preoperatively elevated serum ICTP is a prognostic factor in breast cancer, the measurement of which should improve the accuracy of predictions of the clinical outcome.

Our previous studies suggested that both COMT and GST genotypes might modify individual breast cancer risk. Here, we extended the studies to examine the potential combined effect of these genotypes in susceptibility to breast cancer. Our study population consisted of 483 Finnish breast cancer cases and 482 population control subjects. The odds ratios (ORs) and (95%) confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for known or suspected confounding factors. No significant increase in the overall breast cancer risk was seen for any combinations of the studied genotypes. However, a substantially increased risk of breast cancer was seen for women who had used hormone replacement therapy (HRT) and simultaneously carried the COMT-L allele containing genotypes and either the GSTP1 Ile/Ile genotype (OR 4.10, 95% CI 1.24-13.6) or the GSTT1 null genotype (OR 4.19, 95% CI 1.30-13.5). These associations appeared to be mainly attributable to long-term users of HRT; the respective ORs were 7.00 (95% CI 1.21-40.6) and 8.36 (95% CI 1.44-49.0) among the users of HRT of more than 30 months. In addition, the combination of COMT-L allele containing genotypes with the GSTM1 null genotype posed a remarkably increased risk (OR 9.10, 95% CI 1.84-45.0) of breast cancer in this study group. These results suggest that the use of HRT could substantially increase the risk of breast cancer among women with specific combinations of the at-risk genotypes of COMT and GST genes.