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Purpose: Breast density (BD), an important risk factor for breast cancer, can change over time in some women, but the underlying mechanism is unclear. Very little is known about the impact of surgical weight loss on BD. Our hypothesis is that weight loss after bariatric surgery is associated with a significant and favorable change in mammographic BD., Methods: We identified 1097 women 40 years of age or older who underwent gastric bypass or sleeve gastrectomy at our institution from 2010 to 2014. Women who did not have either pre- and post-bariatric surgery mammograms performed at our institution were excluded; 110 had both mammograms and comprised the cohort. Breast density was determined both qualitatively, using reported BI-RADS density, and quantitatively, using the Laboratory for Individualized Breast Radiodensity Assessment., Results: Qualitative BI-RADS density, quantitative breast area, and percent BD significantly decreased in post-bariatric surgery mammograms (p = 0.009, <0.001, and <0.001, respectively)., Conclusions: Our retrospective study demonstrated that surgical weight loss was associated with a significant decrease in breast density. Additional studies are warranted to validate our findings and elucidate the molecular mechanisms underlying breast density change after weight loss surgery.

Purpose: Prognostic factors are useful in order to identify early-stage breast cancer patients who might benefit from adjuvant treatment. The metastasis-promoting protein S100A4 has previously been associated with poor prognosis in breast cancer patients. The protein is expressed in diverse subcellular compartments, including the cytoplasm, extracellular space, and nucleus. Nuclear expression is an independent predictor of poor outcome in several cancer types, but the significance of subcellular expression has not yet been assessed in breast cancer., Methods: Nuclear and cytoplasmic expression of S100A4 was assessed by immunohistochemistry in prospectively collected tumor samples from early-stage breast cancer patients using tissue microarrays., Results: In patients not receiving adjuvant systemic therapy, nuclear or cytoplasmic expression was found in 44/291 tumors (15%). Expression of either nuclear or cytoplasmic S100A4 was associated with histological grade III, triple-negative subtype, and Ki-67-expression. Patients with S100A4-positive tumors had inferior metastasis-free and overall survival compared to S100A4-negative. When expression was analyzed separately, nuclear S100A4 was a significant predictor of outcome, while cytoplasmic was not. In patients who received adjuvant treatment 23/300 tumors (8%) were S100A4-positive, but no tumors displayed nuclear staining alone. S100A4-expression was strongly associated with histological grade III and triple-negative subtype. Although not significant, metastasis-free and overall survival was numerically reduced in patients with S100A4-positive tumors., Conclusion: S100A4-expression was associated with poor outcome in early-stage breast cancer, but the low percentage of positive tumors and the modest survival differences imply that the clinical utility in selection of patients for adjuvant treatment is limited.

Detection of disseminated tumour cells (DTCs) in bone marrow by immunocytochemistry (ICC) includes morphological evaluation of cytokeratin immunopositive cells. The aim of this study was to disclose the prognostic significance of different morphological categories of ICC-positive cells according to treatment status and tumour subtype. Bone marrow samples (at surgery) were analysed for the presence of cytokeratin-positive DTCs by a standard immunocytochemical method. The immunopositive cells were classified into the following categories, prior to any analysis of the association between DTCs and clinical outcome: tumour cells (TC), uninterpretable cells (UIC), hematopoietic cells (HC), and questionable HC (QHC). The analysis included 747 early breast cancer patients. Median follow-up was 84 months for relapse, and 99 months for death. The categorisation of the ICC positive cells revealed TC in 13.3 % of the patients, whereas 13.1, 17.8, and 21.4 % of the cases were positive for UIC, QHC, and HC, respectively. Analysing all patients, only TC and UIC predicted systemic relapse. Separate analysis of all patients not receiving adjuvant systemic treatment (No-Adj; n = 389) showed that only QHC were associated with reduced survival (DDFS: p = 0.008; BCSS: p = 0.004, log rank) and the presence of QHC also remained significant in multivariate analysis. Primary tumour subgroup analysis (of all patients) by hormone receptors (HR) and HER2, demonstrated that only TC/UIC had prognostic impact in the HR+/HER2- patients, whereas presence of QHC was associated with unfavourable outcome only in triple negative patients (DDFS: p = 0.004; BCSS: p = 0.024). Patients with ≥3HC had improved outcome compared to those with fewer/no HC (DDFS: p = 0.005; BCSS: p = 0.009). Hence, morphological DTC subgroups may differ in clinical significance according to primary tumour subtype and treatment status. This emphasises the importance of DTC characterisation, and separate analyses of DTC categories according to tumour subtype. Hematopoietic ("false positive") cells might predict an immune-related favorable clinical outcome.

The factors determining the clinical relevance of disseminated tumor cells (DTC) in breast cancer patients are largely unknown. Here we compared the specificity and clinical performance of two antibodies frequently used for DTC detection. Reactivities of antibodies A45-B/B3 (A45) and AE1/AE3 (AE) for selected cytokeratins (CK) were assessed by 2-DE Western Blot analysis. Using these antibodies bone marrow aspirates from 391 breast cancer patients (M(0), pT1-3, pN0-3) were screened for the presence of DTC. To obtain prognostic information, patients were followed up over a median of 83 months for time to relapse and 99 months for time to death. Among the analyzed CK, AE detected CK5, CK7, CK8, and CK19, whereas A45 recognized CK7 and CK18. In total, 24 of 391 patients (6.1%) were DTC-positive for A45, and 41 (10.5%) for AE. Although concordance between the two antibodies was 84.4%, overlap among positive cases was only 3.2%. DTC-positivity with AE and A45 was more frequent in patients of higher nodal status (P=0.019 and P=0.036, respectively). Nearly all patients with A45-positive DTC had hormone receptor-positive tumors (23/24), while detection of AE-positive DTC was more frequent among hormone receptor negative patients (P=0.006). Survival analyses of all patients revealed shorter distant disease-free survival (P=0.039) for patients with A45-positive DTC, whereas the prognostic relevance of AE-positive DTC was restricted to node-positive patients. The clinical utility of immunocytochemical (ICC) DTC detection depends on the anti-CK antibody used, which may reflect the complex CK composition of DTC.

The clinical relevance of isolated tumor cell (ITC: 0.2-2.0 mm) in axillary lymph nodes (ALNs) remains unknown. The aim of this study was to determine their prognostic significance. A total of 295 patients considered as pN0 after routine histological assessment, were reevaluated with ten-level cytokeratin immunohistochemistry (IHC) and two-level hematoxylin-eosin sections. Survival rates, i.e. disease-free survival (DFS), distant disease-free survival (DDFS) and breast cancer specific survival (BCSS) were compared with those of reevaluated node-negative patients. A total of 84 patients (28%) had ITC/MM identified on IHC sections. ITC had no impact on survival at a median 8.2 years of follow-up, whereas MM showed a trend toward poorer DFS (P = 0.091, log rank) and DDFS (P = 0.066) and significantly reduced BCSS (P = 0.016). In multivariate analyses, detection of MM was an independent prognostic factor for DDFS (P = 0.025) and BCSS (P = 0.01) in adjuvant un-treated patients. Micrometastases (MMs) in axillary lymph nodes have prognostic impact. This was not found for ITC. This finding supports the use of systemic adjuvant therapy in patients with MM.