E2F1 copy number variations in germline and breast cancer: a retrospective study of 222 Italian women.

BACKGROUND: Breast cancer is the most common neoplasia among women in developed countries. The risk factors of breast cancer can be distinguished in modifiable and unmodifiable factors and, among the latter, genetic factors play a key role. Copy number variations (CNVs) are genetic variants that are classified as rare when present in less than 1% of the healthy population. Since rare CNVs are often cause of diseases, over the last years, their contribution in carcinogenesis has become a relevant matter of study. E2F1 is a transcriptional factor that plays an important role in regulating cell cycle and apoptosis. Its double and conflicting role is the reason why it acts both as oncogene and as tumour suppressor, depending on cell context. Since anomalies in expression or in number of copies of E2F1 have been related to several cancers, we aimed to study number of germline copies of E2F1 in women with breast cancer in order to better elucidate their contribution as predisposing factor to this tumour. METHODS: We performed, hence, a retrospective study on 222 Italian women with breast cancer recruited from October 2002 to December 2007. TaqMan CNV assay and Real-Time PCR were carried out to analyse, respectively, E2F1 CNV and E2F1 expression in the subjects of the study. Chi square test or Fisher's exact test and Student's t-test were used to calculate the frequency of CNVs and differences in continuous variables between groups, respectively. RESULTS: Intriguingly, we found that 10/222 (4.5%) women with breast cancer had more copies than controls (0/200, 0%), furthermore, the number of copies positively correlated with E2F1 gene expression in breast cancer tissue, suggesting that the constitutive gain of the gene could translate into an increased risk of genomic instability. Additionally, we found that altered E2F1 copies were present prevalently in the patients with contralateral breast cancer (20%) and all of them had a positive family history, both typically associated with hereditary cancer. CONCLUSIONS: Our findings suggest that copy number variations of E2F1 might be a susceptibility factor for breast cancer, however, further studies on large cohorts are to be performed in order to better delineate the phenotype linked to the gain of E2F1 copies.

Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis.

BACKGROUND: The contribution of BRCA germline mutational status to breast cancer patients' prognosis is unclear. We aimed to systematically review and perform meta-analysis of the available evidence of effects of BRCA germline mutations on multiple survival outcomes of breast cancer patients as a whole and in specific subgroups of interest, including those with triple negative breast cancer, those with Ashkenazi Jewish ancestry, and patients with stage I-III disease. METHODS: Sixty studies met all inclusion criteria and were considered for this meta-analysis. These studies involved 105,220 breast cancer patients, whose 3588 (3.4%) were BRCA mutations carriers. The associations between BRCA genes mutational status and overall survival (OS), breast cancer-specific survival (BCSS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) were evaluated using random-effect models. RESULTS: BRCA1 mutation carriers have worse OS than BRCA-negative/sporadic cases (hazard ratio, HR 1.30, 95% CI: 1.11-1.52) and worse BCSS than sporadic/BRCA-negative cases among patients with stage I-III breast cancer (HR 1.45, 95% CI: 1.01-2.07). BRCA2 mutation carriers have worse BCSS than sporadic/BRCA-negative cases (HR 1.29, 95% CI: 1.03-1.62), although they have similar OS. Among triple negative breast cancer, BRCA1/2 mutations carriers had better OS than BRCA-negative counterpart (HR 0.49, 95% CI: 0.26-0.92). Among Ashkenazi Jewish women, BRCA1/2 mutations carriers presented higher risk of death from breast cancer (HR 1.44, 95% CI: 1.05-1.97) and of distant metastases (HR 1.82, 95% CI: 1.05-3.16) than sporadic/BRCA-negative patients. CONCLUSION: Our results support the evaluation of BRCA mutational status in patients with high risk of harboring BRCA germline mutations to better define the prognosis of breast cancer in these patients.

Sentinel node biopsy performance after neoadjuvant chemotherapy in locally advanced breast cancer: A systematic review and meta-analysis.

The use of sentinel node biopsy (SNB) after neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer is debated. Our aim was to quantitatively review the available evidence on the performance of SNB after NAC in patients with locally advanced breast cancer. We performed a systematic review (by searching the PubMed, Cochrane and Scopus databases) and random effects meta-analysis to investigate on the feasibility and accuracy of SNB in these patients. The two outcomes of interest were the sentinel node identification rate (SIR) and the false negative rate (FNR). Sensitivity analysis and meta-regression were used to investigate the potential sources of between-study heterogeneity. We retrieved 72 eligible studies enrolling 7,451 patients. Upon meta-analysis, summary SIR resulted 89.6% [95% confidence interval (CI): 87.8-91.2; heterogeneity I(2): 76.9%], which poorly compares with the 95% SIR observed in some recent series of early breast cancer. The summary FNR resulted 14.2% (CI: 12.5-16.0; heterogeneity I(2): 29.1%), which was significantly higher than the 8-10% reference value. Considering an average post-NAC lymph node positivity rate of 50%, the downstaging due to false negative SNB would occur in 7/100 patients (with an excess error rate of 2-3/100 as compared to the early-stage setting). No plausible source of between-study heterogeneity was found. Based on the largest series of studies ever meta-analyzed, our findings highlight the limits of SNB performance in this population, where the impact of SNB on patient survival is still to be defined.

Role of resection margins in patients treated with breast conservation surgery.

BACKGROUND: After breast conservation therapy (BCT), margin status is routinely evaluated to select patients who need reexcision. The aim of this study was to investigate how margin status and other clinicopathologic factors correlate with the presence of residual tumor at reexcision. METHODS: A series of 431 breast cancer patients who underwent BCT followed by reexcision were considered because they had positive or close (< or =3 mm) margins. At univariate and multivariate analysis the frequency of residual tumor in the reexcision specimens was associated with the status and width of resection margins and with a series of other clinicopathologic factors. RESULTS: Of the 382 evaluable patients, 253 had positive and 129 close margins. Residual tumor was found at reexcision in 51.8% positive-margin patients and 34.1% close-margin patients (P = .001). In the latter group tumor-margin distance (range, 0.08 to 3 mm) was not associated with the incidence of residual tumor (P = .134). On univariate analysis age < or =45 years (P = .006), intraductal histotype (P = .005), size > 2 cm (P = .010), positive axillary nodes (P = .031), and timing of reexcision (P = .044) were significantly associated with a higher frequency of residual tumor. All these factors, except tumor size, maintained a significant predictive value on multivariate analysis. CONCLUSIONS: In the presence of positive margins, relevant residual disease cannot be ruled out and further surgery is indicated. Close margins do not mandate reexcision because they may indicate either that the tumor has been radically excised or the presence of residual foci of a multifocal tumor, which are usually effectively treated by radiotherapy.