A low-frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early-onset breast cancer (<60 years) and is associated with reduced DNA repair capacity.

Only a fraction of breast cancer (BC) cases can be yet explained by mutations in genes or genomic variants discovered in linkage, genome-wide association and sequencing studies. The known genes entailing medium or high risk for BC are strongly enriched for a function in DNA double strand repair. Thus, aiming at identifying low frequency variants conferring an intermediate risk, we here investigated 17 variants (MAF: 0.01-0.1) in 10 candidate genes involved in DNA repair or cell cycle control. In an exploration cohort of 437 cases and 1189 controls, we show the variant rs3810813 in the SLX4/FANCP gene to be significantly associated with both BC (≤60 years; OR = 2.6(1.6-3.9), p = 1.6E-05) and decreased DNA repair capacity (≤60 years; beta = 37.8(17.9-57.8), p = 5.3E-4). BC association was confirmed in a verification cohort (N = 2441). Both associations were absent from cases diagnosed >60 years and stronger the earlier the diagnosis. By imputation we show that rs3810813 tags a haplotype with 5 additional variants with the same allele frequency (R2 > 0.9), and a pattern of association very similar for both phenotypes (cases <60 years, p < 0.001, the Bonferroni threshold derived from unlinked variants in the region). In young cases (≤60 years) carrying the risk haplotype, micronucleus test results are predictive for BC (AUC > 0.9). Our findings propose a risk variant with high penetrance on the haplotype spanning SLX4/FANCP to be functionally associated to BC predisposition via decreased repair capacity and suggest this variant is carried by a fraction of these haplotypes that is enriched in early onset BC cases.

Treatment cost evaluation of extrauterine gravidity: a literature review of medical and surgical treatment costs.

BACKGROUND: The diagnosis of extrauterine pregnancy is possible very early giving the patient and doctors treatment options. As the risks and success rate of medical and surgical treatment are similar, the decision is increasingly influenced by cost-effectiveness. OBJECTIVE: The following article systematically reviews the known literature regarding cost, decision criteria and possible follow-up. METHODS: Literature review of extrauterine gravity in combination with cost in the online National Library of Medicine since 1.1.1997 following the PRISMA recommendations. RESULTS: Six articles were identified in which the cost of the laparoscopic versus medical treatment is reviewed. In five articles, the medical treatment was shown to be more cost effective and in the sixth article the costs were found to be equal. The cost saving varies between 18 and 88% depending on the consideration of direct and indirect costs. If indirect expenses are considered, the total sum increases with treatment failures. Failure rates are given as up to 27% depending on the type of failure (surgical or medical). These rates seem to be linked indirectly with the ß-HCG levels. Predictive parameters for the successful medical treatment are missing. CONCLUSIONS: The treatment of small extrauterine gravidities in haemodynamically stable patients (defined by HCG levels <1,500 IU/l) is medically successful and cost-effective. With HCG levels between 1,500 IU/l and 3,000 IU/l, the treatment costs are similar. HCG levels >5,000 IU/l favour the surgical treatment as being more cost-effective. A similar cut-off for the sonographic imaging is missing.

Should a drain be placed in early breast cancer surgery?

BACKGROUND: The current surgical debate has led to a reduction in the extent of surgery performed and thereby to a reduced occurrence of surgical trauma and, over the recent years, reduced seroma formation. This reduction in surgical procedures calls the need for a drain into question. METHOD: Using Google Scholar and the National Library of Medicine (PubMed), a literature review was performed on systematic reviews and meta-analyses regarding breast cancer surgery ± axillary dissection. Additionally, randomized trials for the time period after the last systematic review were included and evaluated according to the Jadad score. RESULTS: The search returned 5 systematic reviews, in which a total of 1,075 patients were included (537 cases and 538 controls). Since the last review, no prospective randomized trial meeting the inclusion criteria has been published. The current reviews conclude that insertion of a drain is associated with a longer hospital stay and reduced seroma formation. The data regarding wound infection and drain insertion is inconclusive. The omission of a drain is associated with early discharge, reduced postsurgical pain, and early mobilization, but also with an increase in outpatient seroma aspirations. CONCLUSION: The omission of a drain is possible in early breast cancer surgery (wide local excision and sentinel node biopsy) with adequate surgical techniques and instruments.

Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer.

The Manchester scoring system (MSS) allows the calculation of the probability for the presence of mutations in BRCA1 or BRCA2 genes in families suspected of having hereditary breast and ovarian cancer. In 9,390 families, we determined the predictive performance of the MSS without (MSS-2004) and with (MSS-2009) consideration of pathology parameters. Moreover, we validated a recalibrated version of the MSS-2009 (MSS-recal). Families were included in the registry of the German Consortium for Hereditary Breast and Ovarian Cancer, using defined clinical criteria. Receiver operating characteristics (ROC) analysis was used to determine the predictive performance. The recalibrated model was developed using logistic regression analysis and tested using an independent random validation sample. The area under the ROC curves regarding a mutation in any of the two BRCA genes was 0.77 (95%CI 0.75-0.79) for MSS-2004, 0.80 (95%CI 0.78-0.82) for MSS-2009, and 0.82 (95%CI 0.80-0.83) for MSS-recal. Sensitivity at the 10% mutation probability cutoff was similar for all three models (MSS-2004 92.2%, MSS-2009 92.2%, and MSS-recal 90.3%), but specificity of MSS-recal (46.0%) was considerably higher than that of MSS-2004 (25.4%) and MSS-2009 (32.3%). In the MSS-recal model, almost all predictors of the original MSS were significantly predictive. However, the score values of some predictors, for example, high grade triple negative breast cancers, differed considerably from the originally proposed score values. The original MSS performed well in our sample of high risk families. The use of pathological parameters increased the predictive performance significantly. Recalibration improved the specificity considerably without losing much sensitivity.

The role of preoperative ultrasound evaluation of inguinal lymph nodes in patients with vulvar malignancy.

OBJECTIVES: Inguinal lymphadenectomy in vulvar malignancies is associated with significant morbidity, especially in patients over 70 years old. Under certain conditions, surgical guidelines recommend biopsy and evaluation of the sentinel node in early vulvar cancer. The purpose of our study is to evaluate ultrasonography as a predictor of inguinal lymph node involvement. METHODS: A retrospective study was performed with 60 patients who had vulvar malignancies (92% of which were squamous cell carcinomas) and who were treated at our hospital between 2002 and 2012. The patients ranged in age from 35 to 89 years, with a median age of 76 years. In total, 118 groin scans were retrospectively evaluated for sonographic evidence of lymph node involvement (i.e., absence of fatty hilum, irregular shape, cortical region diameter and vascularization pattern). The results were then compared with histopathologically confirmed lymph node status. RESULTS: Histopathologically confirmed lymph node status was available for 107 of the inguinal nodes examined by ultrasound, and lymph node metastases were found in 38 (35.5%) cases. The presence or absence of inguinal lymph node metastases was correctly identified by sonography in 92 (86.0%) of the scanned areas. Sensitivity was 76.3%, specificity was 91.3%, and positive and negative predictive values were 82.9% and 87.5%, respectively. CONCLUSIONS: Ultrasonography of the inguinal lymph nodes showed a relatively high sensitivity and specificity for predicting inguinal tumor metastases. However, our results indicate that surgical lymph node staging is still needed to precisely determine inguinal lymph node status in vulvar cancer, especially because a missed lymph node-metastasis is often fatal.

Ovarian cancer: in search of better marker systems based on DNA repair defects.

Ovarian cancer is the fifth most common female cancer in the Western world, and the deadliest gynecological malignancy. The overall poor prognosis for ovarian cancer patients is a consequence of aggressive biological behavior and a lack of adequate diagnostic tools for early detection. In fact, approximately 70% of all patients with epithelial ovarian cancer are diagnosed at advanced tumor stages. These facts highlight a significant clinical need for reliable and accurate detection methods for ovarian cancer, especially for patients at high risk. Because CA125 has not achieved satisfactory sensitivity and specificity in detecting ovarian cancer, numerous efforts, including those based on single and combined molecule detection and "omics" approaches, have been made to identify new biomarkers. Intriguingly, more than 10% of all ovarian cancer cases are of familial origin. BRCA1 and BRCA2 germline mutations are the most common genetic defects underlying hereditary ovarian cancer, which is why ovarian cancer risk assessment in developed countries, aside from pedigree analysis, relies on genetic testing of BRCA1 and BRCA2. Because not only BRCA1 and BRCA2 but also other susceptibility genes are tightly linked with ovarian cancer-specific DNA repair defects, another possible approach for defining susceptibility might be patient cell-based functional testing, a concept for which support came from a recent case-control study. This principle would be applicable to risk assessment and the prediction of responsiveness to conventional regimens involving platinum-based drugs and targeted therapies involving poly (ADP-ribose) polymerase (PARP) inhibitors.

[Integrating the e-learning programme EGONE into the block of training in obstetrics and gynaecology]. / Integration des E-Learning-Programmes EGONE in das Blockpraktikum der Gynäkologie/Geburtshilfe.

OBJECTIVE: EGONE is an E-Learning Forum for Gynaecology, Obstetrics, Neonatology and Reproductive Endocrinology based on the Swiss Catalogue of Learning Objectives. For two semesters, students attending the gynaecology block at the Medical Faculty of the University of Ulm have been provided with licences to use EGONE. Students can work on a specially equipped computer and practise whenever they want. The aim of this study was to generate hypotheses as to which factors favour the use of EGONE and which didactic implications for the learning success the application of EGONE has. METHODS: During August 2009, 28 medical students in their 8th and 9th semester were interviewed after having completed their block of training in gynaecology. The instruments used included a questionnaire and a partially standardised interview. RESULTS: We found that the e-learning offering EGONE was basically met with a positive response from the medical students at the University of Ulm. Regarding the integration of EGONE, three problem areas were identified: shortage of equipment, lack of dependable access and functional, but not curricular integration. Students' suggestions for better integration of EGONE were related to two subject areas: establishing an assisted learning centre (e.g., PC pool with library) and developing curricular independence and relevance (e.g., specific application to patient cases, conducting seminars with EGONE). CONCLUSION: The integration of the e-learning programme EGONE presupposes a logical, didactic concept for the whole clinical block of training in gynaecology as well as dependable, sufficient infrastructure and technical equipment and providing didactic support to users.

The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study.

INTRODUCTION: While it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations. METHODS: A retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status. RESULTS: The cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95%CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95%CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95%CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families. CONCLUSIONS: Contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy.

The prostate cancer risk locus at 10q11 is associated with DNA repair capacity.

Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) that mildly predict prostate cancer risk. These SNPs are local tagging markers for causal gene alterations. Consideration of candidate genes in the tagged regions would be facilitated by additional information on the particular pathomechanisms which contribute to the observed risk increase. In this study we test for an association of prostate cancer tagging SNPs with alterations in DNA repair capacity, a phenotype that is frequently involved in cancer predisposition. DNA repair capacity was assessed on blood lymphocytes from 128 healthy probands after ionizing irradiation. We used the micronucleus (MN) assay to determine the cellular DNA double-strand break repair capacity and flow cytometry to measure damage induced mitotic delay (MD). Probands were genotyped for a panel of 14 SNPs, each representing an independent prostate cancer risk locus previously identified by GWAS. Associations between germline variants and DNA repair capacity were found for the SNPs rs1512268 (8p21), rs6983267 (8q24) and rs10993994 (10q11). The most significant finding was an association of homozygous rs10993994 T-allele carriers with a lower MN frequency (p=0.0003) and also a decreased MD index (p=0.0353). Cells with prostate cancer risk alleles at rs10993994 seem to cope more efficiently with DNA double strand breaks (less MN) in a shorter time (decreased MD index). This intriguing finding imposes concern about the accuracy of repair, with respect to the cancer risk that is mediated by T genotypes. To date, MSMB (microseminoprotein ß) is favored as the causal gene at the 10q11 risk locus, since it was the first candidate gene known to be expressionally altered by rs10993994. Based on the present observation, candidate genes from the contexts of DNA repair and apoptosis may be more promising targets for expression studies with respect to the rs10993994 genotype.

Medium-sized deletion in the BRCA1 gene: Limitations of Sanger sequencing and MLPA analyses.

We describe a family with a history of breast and ovarian cancer in which MLPA analysis of the BRCA1 gene pointed to a deletion including a part of exon 11. Further characterization confirmed a loss of 374 bp in a region completely covered by conventional sequencing which had not revealed the deletion. Because this alteration was only detected serendipitously with an MLPA probe, we calculated the probabilities of detecting medium-sized deletions in large exons by methods including initial PCR amplification. This showed that a considerable fraction of medium-sized deletions are undetectable by currently used standard methods of mutation analyses. We conclude that long, widely overlapping amplicons should be used to minimize the risk of missing medium-sized deletions. Alternatively, large exons could be completely covered by narrow-spaced MLPA probes.

The power of DNA double-strand break (DSB) repair testing to predict breast cancer susceptibility.

Most presently known breast cancer susceptibility genes have been linked to DSB repair. To identify novel markers that may serve as indicators for breast cancer risk, we performed DSB repair analyses using a case-control design. Thus, we examined 35 women with defined familial history of breast and/or ovarian cancer (first case group), 175 patients with breast cancer (second case group), and 245 healthy women without previous cancer or family history of breast cancer (control group). We analyzed DSB repair in peripheral blood lymphocytes (PBLs) by a GFP-based test system using 3 pathway-specific substrates. We found increases of microhomology-mediated nonhomologous end joining (mmNHEJ) and nonconservative single-strand annealing (SSA) in women with familial risk vs. controls (P=0.0001-0.0022) and patients with breast cancer vs. controls (P=0.0004-0.0042). Young age (<50) at initial diagnosis of breast cancer, which could be indicative of genetic predisposition, was associated with elevated SSA using two different substrates, amounting to similar odds ratios (ORs=2.54-4.46, P=0.0059-0.0095) as for familial risk (ORs=2.61-4.05, P=0.0007-0.0045). These findings and supporting validation data underscore the great potential of detecting distinct DSB repair activities in PBLs as method to estimate breast cancer susceptibility beyond limitations of genotyping and to predict responsiveness to therapeutics targeting DSB repair-dysfunctional tumors.

Medium-sized deletion in the BRCA1 gene: limitations of Sanger sequencing and MLPA analyses

We describe a family with a history of breast and ovarian cancer in which MLPA analysis of the BRCA1 gene pointed to a deletion including a part of exon 11. Further characterization confirmed a loss of 374 bp in a region completely covered by conventional sequencing which had not revealed the deletion. Because this alteration was only detected serendipitously with an MLPA probe, we calculated the probabilities of detecting medium-sized deletions in large exons by methods including initial PCR amplification. This showed that a considerable fraction of medium-sized deletions are undetectable by currently used standard methods of mutation analyses. We conclude that long, widely overlapping amplicons should be used to minimize the risk of missing medium-sized deletions. Alternatively, large exons could be completely covered by narrow-spaced MLPA probes.

Heritability of baseline and induced micronucleus frequencies.

The scoring of micronuclei (MN) is widely used in biomonitoring and mutagenicity testing as a surrogate marker of chromosomal damage inflicted by clastogenic agents or by aneugens. Individual differences in the response to a mutagenic challenge are known from studies on cancer patients and carriers of mutations in DNA repair genes. However, it has not been studied to which extent genetic factors contribute to the observed variability of individual MN frequencies. Our aim was to quantify this heritable genetic component of both baseline and radiation-induced MN frequencies. We performed a twin study comprising 39 monozygotic (MZ) and 10 dizygotic (DZ) twin pairs. Due to the small number of DZ pairs, we had to recruit controls from which 38 age- and gender-matched random control pairs (CPs) were generated. For heritability estimates, we used biometrical modelling of additive genetic, common environmental, and unique environmental components (ACE model) of variance and direct comparison of variance between the sample groups. While heritability estimates from MZ to DZ comparisons produced inconclusive results, both estimation methods revealed a high degree of heritability (h(2)) for baseline MN frequency (h(2) = 0.68 and h(2) = 0.72) as well as for the induced frequency (h(2) = 0.68 and h(2) = 0.57) when MZ were compared to CP. The result was supported by the different intraclass correlation coefficients of MZ, DZ and CP for baseline (r = 0.63, r = 0.31 and r = 0.0, respectively) as well as for induced MN frequencies (r = 0.79, r = 0.74 and r = 0.0, respectively). This study clearly demonstrates that MN frequencies are determined by genetic factors to a major part. The strong reflection of the genetic background supports the idea that MN frequencies represent an intermediate phenotype between molecular DNA repair mechanisms and the cancer phenotype and affirms the approaches that are made to utilise them as predictors of, for example, cancer risk.

Does guideline-adherent therapy improve the outcome for early-onset breast cancer patients?

BACKGROUND AND OBJECTIVE: Guidelines for the treatment of early-onset breast cancer have been proposed in several countries, but to date, their impact on outcomes is unverified. The objective of this study was to evaluate the association between guideline-adherent versus nonadherent treatment and recurrence-free survival (RFS) and overall survival (OAS) in early-onset breast cancer patients. METHODS: A total of 1,778 patients were included in the study, of whom 111 were 35 years or younger and 1,667 were between 36 and 55 years. RFS and OAS were compared between the two groups, with respect to multiple parameters. All survival data were adjusted for tumor characteristics and analyzed with respect to guideline adherence according to the German Step 3 guidelines. RESULTS: Statistically significant differences between the two groups (<35 years, 36-55 years) were observed with regard to breast surgery (p = 0.002) and hormone therapy (p = 0.006). Both groups were treated identically in terms of guideline adherence concerning axillary dissection (p = 0.9), radiation therapy (p = 0.7) and chemotherapy (p = 0.556). Young breast cancer patients whose treatment adhered to guideline recommendations had increased RFS and OAS [RFS: p = 0.030, hazard ratio (HR) 2.95, 95% confidence interval (CI) 1.11-7.83; OAS: p < or = 0.001, HR 2.92, 95% CI 2.01-4.23]. CONCLUSION: Guideline-adherent treatment for early-onset breast cancer patients significantly improves OAS and RFS and should therefore be demanded for all patients.

Effects of guideline adherence in primary breast cancer--a 5-year multi-center cohort study of 3976 patients.

BACKGROUND: The aim of that study was to analyze the impact of German-S3-breast cancer guideline adherence on clinical outcomes. METHODS: A retrospective study analyzed 3976 patients first diagnosed with primary breast cancer according to an S3-guideline-based model that classified patients retrospectively into groups receiving "guideline-adherent and "guideline non-adherent" therapy. RESULTS: There was a significant association between treatment adherence and prolonged recurrence free and overall survival (p = 0.0001). The greater the number of violations in guideline adherence, the lower was overall survival (p = 0.0001). Advanced age at initial diagnosis was additionally associated with a reduction in guideline adherence. The percentage of guideline adherence for the therapeutic modalities BCT, mastectomy, axillary dissection and hormone therapy was greater than 80%. For chemotherapy, the percent of guideline adherence totaled 71.4%. CONCLUSION: Therapies dispensed in adherence with guidelines may improve recurrence-free survival and overall survival in patients with breast cancer.

Impact of guideline conformity on breast cancer therapy: results of a 13-year retrospective cohort study.

BACKGROUND: To date, few studies have investigated whether the implementation of national breast cancer guidelines fulfills the goal to optimize the national standard of care. Therefore, we aimed to evaluate retrospectively the guideline-related 13-year data on breast cancer patients treated at our institution. PATIENTS AND METHODS: In a retrospective cohort study, the records of a total of 2,231 patients with primary breast cancer treated during the period of 1992-2005 at the Department of Obstetrics and Gynecology, University of Ulm, Germany, were analyzed. Based on the German national Step 3 (S3) guideline, a model was created to classify groups according to therapy 'conforming' and 'non-conforming' to guideline recommendations. RESULTS: In 2005, 70.2% of all patients included received both surgical and systemic adjuvant therapies conforming to the guideline. Guideline-conforming treatment was accompanied with significant advantages in terms of recurrence-free survival (RFS) and overall survival (OAS) rates. CONCLUSIONS: It has to be demanded that breast cancer patients are treated in conformity with the S3 guidelines. The reasons for a treatment not conforming to the guidelines should be analyzed for the detection of barrier factors, in order to optimize adherence to the guidelines and therefore to prolong RFS and OAS.

Comparison of early onset breast cancer patients to older premenopausal breast cancer patients.

BACKGROUND: The objective of this study was to show differences between breast cancer patients < or =35 and >35 years with regard to tumor characteristics and to present the patient-relevant outcomes overall survival (OAS) and recurrence-free survival (RFS). METHODS: We analyzed data from 119 women aged 35 years or younger with breast cancer and compared multiple parameters against breast cancer patients between 36 and 55 (n = 1,097), all pre-menopausal. Data were adjusted for tumor characteristics and therapy. RESULTS: There was no statistically significant difference in tumor size, axillary lymph node involvement, and histological subtypes. On the contrary, grading lymphovascular invasion and receptor negativity showed statistically significant differences. Unadjusted hazard ratio are 2.11 (1.32-3.39) (OAS) and 1.92 (1.35-2.73) (RFS). Multi-adjusted hazard ratio are 2.97 (1.70-5.18) (OAS) and 2.11 (1.42-3.13) (RFS). CONCLUSIONS: In conclusion, young breast cancer patients still have a poor prognosis. Even after adjustment of the data, OAS and RFS showed a worse prognosis. Normal prognostic factors like tumor size, axillary lymph node involvement, and grading can therefore be not the explanation for the more aggressive disease progress within early onset breast cancer patients.

Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers.

PURPOSE: To estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families and to determine predictive risk factors. PATIENTS AND METHODS: A retrospective, multicenter, cohort study was performed from 1996 until 2008 and comprised 2,020 women with unilateral breast cancer (index patients, n = 978; relatives, n = 1.42) from 978 families who had a BRCA1 or BRCA2 mutation. Cox regression analysis was applied to assess the association of age at first breast cancer with time from first to contralateral breast cancer, stratified by the affected BRCA gene. RESULTS: The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 47.4% (95% CI, 38.8% to 56.0%) for patients from families with BRCA1 or BRCA2 mutations. Members of families with BRCA1 mutations had a 1.6-fold (95% CI, 1.2-fold to 2.3-fold) higher risk of contralateral breast cancer than members of families with BRCA2 mutations. Younger age at first breast cancer was associated with a significantly higher risk of contralateral breast cancer in patients with BRCA1 mutation, and a trend was observed in patients with BRCA2 mutation. After 25 years, 62.9% (95% CI, 50.4% to 75.4%) of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer developed contralateral breast cancer, compared with only 19.6% (95% CI, 5.3% to 33.9%) of those who were older than 50 years of age at first breast cancer. CONCLUSION: Contralateral breast cancer risk depends on age at first breast cancer and on the affected BRCA gene, and this risk should be considered in treatment planning.

Increased radiosensitivity as an indicator of genes conferring breast cancer susceptibility.

PURPOSE: This paper briefly summarizes the research on increased radiosensitivity in breast cancer patients measured by the micronucleus test (MNT) and its association to genetic variants in DNA repair genes. More preliminary data are presented on the distribution of chromosomes and chromosome fragments in micronuclei (MN) in order to gain more information on clastogenic and aneugenic effects and better understand the phenotype of increased radiosensitivity. MATERIAL AND METHODS: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. In four patients with high MN frequency (three cancer patients, one control) and four probands with low MN frequency, the presence of chromosome fragments or whole chromosomes in MN was determined by fluorescence in situ hybridization analysis for chromosomes 1, 7, and 17. RESULTS: An increased MN frequency in breast cancer patients compared to controls has consistently been reported with high significance. Higher MN frequencies were observed in 20-50% of breast cancer patients. Chromosomal fragments of chromosome 17, but not of chromosomes 1 and 7 were more frequent in the probands with high MN frequency than in those with low frequency (p = 0.045). CONCLUSION: The MNT detects a cellular phenotype common to a portion of sporadic breast cancer patients. This phenotype is very likely to be genetically determined. For the genetic dissection of breast cancer susceptibility this phenotype may turn out to be more efficient than breast cancer itself. Additional parameters which can be measured simultaneously with the MN frequency may be able to further enhance its usefulness.

On the difference of micronucleus frequencies in peripheral blood lymphocytes between breast cancer patients and controls.

Sporadic breast cancer patients as well as mutation carriers of the BRCA genes have a reduced DNA repair capacity compared to controls when assessed by the G0 micronucleus test (G(0)MNT) or by induced chromosomal aberrations. Since the individual MN frequencies vary widely and overlap between cases and controls it remained unclear which percentage of the cases should be considered to exhibit an increased radiosensitivity. We performed a similar case-control study and found a highly significant difference (P < 0.0001) between all breast cancer cases (N = 91) and female controls (N = 96) using descriptive statistics and ANOVA with adjustment for age. This difference also holds for baseline MN frequencies (P = 0.0006) and for subgroups of the patients similar to those without treatment (P < 0.0001). These results were confirmed in a second sample acquired at a different hospital. Since we are dealing in this analysis with two predefined groups (patients and controls), we calculated odds ratios (ORs) in order to assess the discriminative power of the G0 MNT. These amounted to OR = 4.9 (P < 0.0001) for MN frequencies obtained by visual counting and ranged from OR = 11 (P < 0.0011) to OR = 22 (P < 0.0001) using automated counting. In order to overcome the problem of choosing a cut-off point inherent in ORs, receiver operating characteristic curves were calculated, which visualize specificity and sensitivity over the entire range of values and which characterize the discriminative power of a test by the area under the curve (AUC) (visual counting, baseline: AUC = 0.67; induced AUC = 0.75; automated counting: AUC > 0.88; evaluation sample: AUC > 0.73). We conclude that the G0 MNT may be a useful tool to substitute the phenotype breast cancer in association and linkage studies and that it may be possible to develop a test useful in the diagnosis or risk assessment for breast cancer.