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Purpose: To explore the ability of intraoperative specimen radiography (SR) to correctly identify positive margins in patients receiving breast conserving surgery (BCS). To assess whether the reoperation rate can be reduced by using this method., Methods: This retrospective study included 470 consecutive cases receiving BCS due to a primarily diagnosed breast cancer. SR was carried out in two planes, assessing the specimen regarding the presence of the lesion and its relation to all margins. If indicated, re-excision of selective orientations was advised. Under consideration of gross inspection and the SR-findings, it was up to the surgeon whether to perform re-resections. The recommendations for re-excision were, separately for each orientation, compared to the histopathological results, serving as gold standard., Results: Intraoperative SR was performed in 470 cases, thus 2820 margins were assessed. Of those, 2510 (89.0%) were negative and 310 (11.0%) positive. SR identified 2179 (77.3%) margins correctly as negative, whereas 331 (11.7%) clear margins were misjudged as positive. Of 310 infiltrated margins, SR identified 114 (4.0%) correctly, whereas 196 (7.0%) infiltrated margins were missed. This resulted in a sensitivity/specificity of 36.8%/86.8% and PPV/NPV of 25.6%/91.8%. Through targeted re-resections positive margins could be reduced by 31.0% [310 to 214 (7.6%)]. On case level, the rate of secondary procedures could be reduced by 37.0% [from 162 to 102 (21.7%)]., Conclusions: SR is a helpful tool to identify infiltrated margins and to reduce the rate of secondary surgeries by recommending targeted re-excisions of according orientations in order to obtain a final negative margin status.

Purpose: Non-invasive blood-based molecular markers have been investigated for cancer diagnosis and prognosis. Circulating free or cell-free DNA (cfDNA) variables have been shown to be putative markers in breast cancer prognosis., Methods: Here, we investigated the potential prognostic ability of cfDNA concentration and cfDNA integrity (cfDI) in a study cohort of 268 patients by quantitative PCR. We compared cfDNA concentration and cfDI at baseline and after one cycle of therapy in metastatic breast cancer (MBC) patients., Results: A significantly increased cfDI (P = 1.21E-7 for ALU and P = 1.87E-3 for LINE1) and decreased cfDNA concentration (P = 1.17E-3 for ALU and P = 1.60E-2 for LINE1) in both repetitive DNA elements after one cycle of therapy was observed. A multiple Cox regression model indicated that cfDI and cfDNA concentration can serve as independent prognostic markers in patients at baseline with HR (95% CI) of 0.70 (0.48-1.01) for ALU cfDI, 0.63 (0.44-0.92) for LINE1 cfDI, 2.44 (1.68-3.53) for ALU cfDNA concentration, and 2.12 (1.47-3.06) for LINE1 cfDNA concentration and after one cycle of therapy with HR (95% CI) of 0.59 (0.42-0.84) for ALU cfDI, 0.51 (0.36-0.74) for LINE1 cfDI, 1.59 (1.31-1.92) for ALU cfDNA concentration, and 1.30 (1.17-1.45) for LINE1 cfDNA concentration, respectively. By comparing integrated prediction error of different models, cfDNA variables were shown to improve the prognostic power of the CTC status., Conclusions: We hereby show that cfDNA variables, especially in combination with other markers, can serve as attractive prognostic markers for MBC patients at baseline and during the systematic therapy.

Unlabelled: Metastasis is the main cause of death in breast cancer patients. The development of reliable and cost-effective biomarker to evaluate the prognosis of metastatic breast cancer (MBC) patients is of great importance. S100P is a member of S100 family and has been proved to be associated with metastasis establishment., Methods: We investigated the plasma S100P levels in 60 healthy controls, 48 primary and 273 metastatic breast cancer patients. The MBC patients were followed-up for disease progression and death up to 3.5 years after recruitment. Radiographic response of MBC patients were also analyzed for investigation on treatment monitoring value of plasma S100P level. We found a robust association between high plasma S100P level (>7 ng/mL) and poor prognosis of metastatic breast cancer (MBC) patients (median progression-free survival time: 5.0 vs. 8.7 months, log-rank test p < 0.001; median overall survival time: 22.5 vs. 31.6 months, log-rank test p < 0.001). The plasma S100P level added additional prognostic relevance to the conventional prognostication model with clinicopathological factors and CTC enumeration. The plasma S100P level decreased significantly after treatment, while the reduction correlated with the radiographic response of the MBC patients. This finding indicates the value of plasma S100P in dynamic evaluation of treatment outcome. We hereby suggest plasma S100P level as a simple and cost-effective marker for the prognosis of metastatic breast cancer.

Breast cancer (BC) is the leading cancer among women worldwide and in 5-10 % of cases is of hereditary origin, mainly due to BRCA1/2 mutations. Therefore, the German Consortium for Familial Breast and Ovarian Cancer (HBOC) with its 15 specialized academic centers offers families at high risk for familial/hereditary cancer a multimodal breast cancer surveillance program (MBCS) with regular breast MRI, mammography, ultrasound, and palpation. So far, we know a lot about the psychological effects of genetic testing, but we know little about risk-correlated adherence to MBCS or prophylactic surgery over time. The aim of this study was to investigate counselees' adherence to recommendations for MBCS in order to adjust the care supply and define predictors for incompliance. All counselees, who attended HBOC consultation at the University Hospital Heidelberg between July 01, 2009 and July 01, 2011 were eligible to participate. A tripartite questionnaire containing sociodemographic information, psychological parameters, behavioral questions, and medical data collection from the German consortium were used. A high participation rate was achieved among the study population, with 72 % returning the questionnaire. This study showed a rate of 59 % of full-adherers to the MBCS. Significant predictors for partial or full adherence were having children (p = 0.0221), younger daughters (p = 0.01795), a higher awareness of the topic HBOC (p = 0.01795, p < 0.0001), a higher perceived breast cancer risk (p < 0.0001), and worries (p = 0.0008)/impairment (p = 0.0257) by it. Although the current data suggest a good adherence of MBCS, prospective studies are needed to understand counselees' needs to further improve surveillance programs and adherence to them. Adherence to the breast cancer surveillance program for women at risk for familial breast and ovarian cancer versus overscreening-a monocenter study in Germany.

The prediction of unfavorable long-term esthetic outcome (AO) is important for patient consultation. We aimed to analyze variables characterizing the improvement and impairment of AO over time after breast-conserving surgery. A subgroup of a prospective, monocenter cohort study was analyzed to evaluate the results of the BCCT.core software (Breast Cancer Conservative Treatment.cosmetic results) which was used to objectively assess the AO before (n = 356), shortly after (n = 294) and in median 3 years after surgery (n = 356). We analyzed potential influencing factors (such as body mass index, (y)pT-stage, weight of resected specimen, etc.) on the AO using logistic regression analyses (n = 256). Finally, we tried to characterize groups of patients with improving or impaired AO over time (n = 294). Predictors for an unfavorable AO were an axillary lymphadenectomy (OR = 4.05), a tumor in the 12 o'clock position (OR = 2.22), a tumor stage larger or equal to (y)pT2 stage (OR = 2.11), and a surgical specimen weight >75 g (OR = 2.71). Patients with lower specimen weight were more likely to improve in the long-term follow-up (p = 0.018), whereas patients with a higher (y)pT-stage tended to become impaired with time. Although overall AO decreased over time, nearly half of the patients with an unfavorable AO shortly after surgery improved in the long-term follow-up. Predictors of unfavorable AO can be used in patient consultation preoperatively to prepare them for the postsurgical period and/or to recommend surgical alternatives (e.g., more complex oncoplastic techniques). Knowledge of improvement and impairment may help patients and physicians in the postsurgical consultation setting.

Circulating or cell-free DNA (cfDNA) has been evaluated as a biomarker in many cancers including breast cancer. In particular, integrity of cfDNA has been shown to be altered in cancers. We have estimated the biomarker potential of cfDNA in primary (PBC) and metastatic breast cancer (MBC). cfDNA integrity (cfDI) and concentration were determined in plasma of 383 individuals, including 82 PBC and 201 MBC cases, as well as 100 healthy controls, by measuring ALU and LINE1 repetitive DNA elements using quantitative PCR. The MBC patient group was further sub-divided into patients with detectable circulating tumour cells (CTCpos-MBC, n = 100) and those without (CTCneg-MBC, n = 101). A hierarchical decrease in cfDI and increase in cfDNA concentration from healthy controls to PBC and further onto MBC patients were observed. Investigation of cfDNA in media of cell lines was in concordance with these results. Combination of cfDI and cfDNA concentration could differentiate PBC cases from controls (area under the curve, AUC = 0.75), MBC cases from controls (AUC = 0.81 for CTCneg-MBC, AUC = 0.93 for CTCpos-MBC), and CTCneg-MBC from CTCpos-MBC cases (AUC = 0.83). cfDI additionally demonstrated a positive correlation to progression-free (HR of 0.46 for ALU, P = 0.0025) and overall survival (HR of 0.15 for ALU and 0.20 for LINE1, P < 0.0001) in MBC, and had lower prediction error than CTC status. Our findings show that reduced cfDI and increased cfDNA concentration can serve as diagnostic markers for PBC and MBC, and cfDI as a prognostic marker for MBC, thereby making them attractive candidates for blood-based multi-marker assays.

Variants of uncertain clinical significance (VUS) in the high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2 represent a major obstacle in genetic counseling of high-risk breast cancer families. We analyzed a missense VUS located in BRCA2 (p.Asn3124Ile; HGVS: BRCA2 c.9371A > T) present in seven independent high-risk breast cancer families that were counseled and genetically tested in South-West Germany. The VUS was identified by DNA sequencing. We analyzed co-occurrence with deleterious BRCA1/2 mutations, segregation, evolutionary conservation, in silico impact prediction, and prevalence in the general population. All carriers of the VUS suffered from breast or ovarian cancer. In two families, an additional high burden of other cancers such as pancreatic, prostate, and gastric cancers was reported, one further family included two cases of male breast cancer. The VUS did not co-occur with deleterious BRCA1/2 mutations and segregated in two affected individuals of one family. In contrast to the 7/1,347 (0,5 %) tested high-risk BC families without clearly pathogenic mutations in BRCA1/2, none of 3,126 healthy population controls sharing the same ethnic and geographical background were found to carry this VUS (p = 0.0002). In-silico prediction revealed strong evolutionary conservation of the asparagine residue, residing in the C-terminal oligonucleotide-binding-fold-3 region, and a most likely damaging impact of this exchange on the protein structure. The BRCA2 p.Asn3124Ile (BRCA2 c.9371A > T) variant is a rare mutation with a damaging effect on the BRCA2 protein that is strongly associated with familial breast and ovarian cancer risk, indicating its most likely pathogenic nature and clinical relevance.

The detection of circulating tumor cells (CTCs) in the peripheral blood of metastatic breast cancer (MBC) patients is an independent marker of prognosis. This large prospective multicenter study aimed to assess the impact of CTCs on overall survival (OS) and progression free survival (PFS) in patients with predefined molecular subgroups of MBC. To this end, 468 MBC patients were divided into three subgroups based on immunohistochemical staining of the primary tumor: (1) hormone receptor-positive/HER2-negative (HorR+/HER2-), (2) HER2-positive (HER2+), and (3) HorR-negative/HER2-negative (HorR-/HER2-) patients. CTC status (<5 CTCs/7.5 ml blood (CTC-negative) vs. ≥5 CTCs/7.5 ml blood (CTC-positive)) was determined using the CellCearch(®) system before patients started a new line of therapy. At baseline, 205 (42 %) patients were CTC-positive. On multivariate analysis, CTC-positivity was an independent prognostic factor for shorter PFS and OS. In HorR+/HER2- patients, median PFS [95 % CI] of CTC-negative versus CTC-positive patients was 8.60 [5.93-11.27] versus 4.33 [3.29-5.38] months (p < 0.001), in HER2+ patients 7.60 [5.40-9.79] versus 6.60 [4.20-9.00] months (p = 0.477) and in HorR-/HER2- patients 5.83 [5.09-6.78] versus 3.05 [1.81-4.29] months (p < 0.001), respectively. Median OS [95 % CI] of CTC-negative versus CTC-positive patients was as follows: not reached by either in the HorR+/HER2- subgroup (p < 0.001), not reached versus 18.07 [11.10-25.05] months (p = 0.001) in the HER2+ subgroup, and not reached versus 8.57 [4.07-13.07] months in the HorR-/HER2- subgroup (p = 0.001). In conclusion, our results strongly confirm the independent prognostic value of CTC enumeration in MBC patients. In contrast to recent reports, there was no association between primary tumor-based molecular subgroups and the impact of CTC status on OS. Hence, CTC status may help to identify patients who require aggressive therapy, especially among those with triple-negative MBC.

In this study, we analyzed a "variant of uncertain significance" (VUS) located in exon 23 of the BRCA2 gene exhibited by six members of five distinct families with hereditary breast cancer (BC). The variant was identified by DNA sequencing, and cDNA analysis revealed its co-expression with wild-type mRNA. We analyzed co-occurrence with other pathological mutations in BRCA1/2, performed a case-control study, looked for evolutionary data and used in-silico analyses to predict its potential clinical significance. Sequencing revealed an in frame deletion of 126 nucleotides in exon 23, leading to a deletion of 42 amino acids (c.9203&#95;9328del126, p.Pro2992&#95;Thr3033del). All of the VUS-carriers suffered from either BC or ovarian/pancreatic cancer. No other definite pathologic mutation of BRCA genes was found in the five families. The identified deletion could not be observed in a control cohort of 2,652 healthy individuals, but in 5 out of 916 (0.5%) tested BC families without a bona fide pathogenic BRCA1/2 mutation (P = 0.0011). According to these results, the in frame deletion c.9203&#95;9328del126 is a rare mutation strongly associated with familial BC. In summary, our investigations indicate that this BRCA2 deletion is pathogenic.

MicroRNAs (miRNAs) are 20-22 nt non-coding RNAs which promote the degradation of target mRNAs or repression of the translation of mRNAs by sequence specific targeting. Many miRNAs are considered as oncogenes or tumor suppressors. MiR-126 and miR-335 play roles in the suppression of breast cancer metastasis by inhibiting tumor growth, proliferation, and cell invasion. The effects of SNPs within the two miRNAs are still unknown. In our study, we analyzed two SNPs, rs4636297 within miR-126 and rs41272366 within miR-335, in three study populations for a putative association with breast cancer risk. We compared the genotype and allele frequencies of rs4636297 and rs41272366 in 2854 cases versus 3188 controls of the three study populations independently and combined. None of the performed analyses showed statistically significant results. In conclusion, our data suggest that the two genetic variants within miR-126 and miR-335 are not associated with breast cancer risk.