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BackgroundThe MF07-01 trial is a multicenter, phase III, randomized, controlled study comparing locoregional treatment (LRT) followed by systemic therapy (ST) with ST alone for treatment-naïve stage IV breast cancer (BC) patients.MethodsAt initial diagnosis, patients were randomized 1:1 to either the LRT or ST group. All the patients were given ST either immediately after randomization or after surgical resection of the intact primary tumor.ResultsThe trial enrolled 274 patients: 138 in the LRT group and 136 in the ST group. Hazard of death was 34% lower in the LRT group than in the ST group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.49–0.88; p = 0.005). Unplanned subgroup analyses showed that the risk of death was statistically lower in the LRT group than in the ST group with respect to estrogen receptor (ER)/progesterone receptor (PR)(+) (HR 0.64; 95% CI 0.46–0.91; p = 0.01), human epidermal growth factor 2 (HER2)/neu(–) (HR 0.64; 95% CI 0.45–0.91; p = 0.01), patients younger than 55 years (HR 0.57; 95% CI 0.38–0.86; p = 0.007), and patients with solitary bone-only metastases (HR 0.47; 95% CI 0.23–0.98; p = 0.04).ConclusionIn the current trial, improvement in 36-month survival was not observed with upfront surgery for stage IV breast cancer patients. However, a longer follow-up study (median, 40 months) showed statistically significant improvement in median survival. When locoregional treatment in de novo stage IV BC is discussed with the patient as an option, practitioners must consider age, performance status, comorbidities, tumor type, and metastatic disease burden.

Breast tomosynthesis (pseudo-3D mammography) improves breast cancer detection when added to 2D mammography. In this study, we examined whether integrating 3D mammography with either standard 2D mammography acquisitions or with synthetic 2D images (reconstructed from 3D mammography) would detect more cases of breast cancer than 2D mammography alone, to potentially reduce the radiation burden from the combination of 2D plus 3D acquisitions. The Screening with Tomosynthesis Or standard Mammography-2 (STORM-2) study was a prospective population-based screening study comparing integrated 3D mammography (dual-acquisition 2D–3D mammography or 2D synthetic–3D mammography) with 2D mammography alone. Asymptomatic women aged 49 years or older who attended population-based screening in Trento, Italy were recruited for the study. All participants underwent digital mammography with 2D and 3D mammography acquisitions, with the use of software that allowed synthetic 2D mammographic images to be reconstructed from 3D acquisitions. Mammography screen-reading was done in two parallel double-readings conducted sequentially for 2D acquisitions followed by integrated acquisitions. Recall based on a positive mammography result was defined as recall at any screen read. Primary outcome measures were a comparison between integrated (2D–3D or 2D synthetic–3D) mammography and 2D mammography alone of the number of cases of screen-detected breast cancer, the cancer detection rate per 1000 screens, the incremental cancer detection rate, and the number and percentage of false-positive recalls. Between May 31, 2013, and May 29, 2015, 10 255 women were invited to participate, of whom 9672 agreed to participate and were screened. In these 9672 participants (median age 58 years [IQR 53–63]), screening detected 90 cases of breast cancer, including 74 invasive breast cancers, in 85 women (five women had bilateral breast cancer). To account for these bilateral cancers in cancer detection rate estimates, the number of screens used for analysis was 9677. Both 2D–3D mammography (cancer detection rate 8·5 per 1000 screens [82 cancers detected in 9677 screens]; 95% CI 6·7–10·5) and 2D synthetic–3D mammography (8·8 per 1000 [85 in 9677]; 7·0–10·8) had significantly higher rates of breast cancer detection than 2D mammography alone (6·3 per 1000 [61 in 9677], 4·8–8·1; p<0·0001 for both comparisons). The cancer detection rate did not differ significantly between 2D–3D mammography and 2D synthetic–3D mammography (p=0·58). Compared with 2D mammography alone, the incremental cancer detection rate from 2D–3D mammography was 2·2 per 1000 screens (95% CI 1·2–3·3) and that from 2D synthetic–3D mammography was 2·5 per 1000 (1·4–3·8). Compared with the proportion of false-positive recalls from 2D mammography alone (328 of 9587 participants not found to have cancer at assessment) [3·42%; 95% CI 3·07–3·80]), false-positive recall was significantly higher for 2D–3D mammography (381 of 9587 [3·97%; 3·59–4·38], p=0·00063) and for 2D synthetic–3D mammography (427 of 9587 [4·45%; 4·05–4·89], p<0·0001). Integration of 3D mammography (2D–3D or 2D synthetic–3D) detected more cases of breast cancer than 2D mammography alone, but increased the percentage of false-positive recalls in sequential screen-reading. These results should be considered in the context of the trade-off between benefits and harms inherent in population breast cancer screening, including that significantly increased breast cancer detection from integrating 3D mammography into screening has the potential to augment screening benefit and also possibly contribute to overdiagnosis. None.

Metaplastic breast carcinoma (MBC) is a highly aggressive form of triple-negative cancer (TNBC), defined by the presence of metaplastic components of spindle, squamous, or sarcomatoid histology. The protein profiles underpinning the pathological subtypes and metastatic behavior of MBC are unknown. Using multiplex quantitative tandem mass tag-based proteomics we quantify 5798 proteins in MBC, TNBC, and normal breast from 27 patients. Comparing MBC and TNBC protein profiles we show MBC-specific increases related to epithelial-to-mesenchymal transition and extracellular matrix, and reduced metabolic pathways. MBC subtypes exhibit distinct upregulated profiles, including translation and ribosomal events in spindle, inflammation- and apical junction-related proteins in squamous, and extracellular matrix proteins in sarcomatoid subtypes. Comparison of the proteomes of human spindle MBC with mouse spindle ( CCN6 knockout) MBC tumors reveals a shared spindle-specific signature of 17 upregulated proteins involved in translation and 19 downregulated proteins with roles in cell metabolism. These data identify potential subtype specific MBC biomarkers and therapeutic targets. Metaplastic breast carcinoma (MBC) is among the most aggressive subtypes of triple-negative breast cancer (TNBC) but the underlying proteome profiles are unknown. Here, the authors characterize the protein signatures of human MBC tissue samples and their relationship to TNBC and normal breast tissue.

BackgroundWhile breast cancer has historically been treated with surgery followed by adjuvant chemotherapy (AC) and radiation when indicated, neoadjuvant chemotherapy (NAC) use is thought to be increasing; however, the trends of its use in various biological subtypes have not been evaluated. We sought to evaluate the trend of NAC use over time by biological subtype.MethodsWe identified all patients with invasive breast cancer who underwent curative intent surgery and were treated with chemotherapy from 2010 to 2015 from the National Cancer Database. An unadjusted analysis of trends in proportions over time was performed using Cochran–Armitage trend tests stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status.ResultsOf 315,264 patients who received chemotherapy, 251,726 (79.8%) received AC and 63,538 (20.2%) received NAC. From 2010 to 2015, significant increases in NAC use were seen in all biologic subtypes (all p < 0.001). The highest proportions and greatest increases in proportions of NAC were seen among triple-negative breast cancers (TNBC; 19.5–33.7%) and HER2+ (HR−/HER2+, 21.5–39.8%; HR+/HER2+, 17.0–33.7%) tumors. HR+/HER2− tumors also had a statistically significant increase in use but this increase was less dramatic (13.0–16.8%) and NAC use in recent years was significantly lower than in other subtypes (p < 0.001).ConclusionWithin patients receiving chemotherapy for breast cancer, its receipt in the neoadjuvant setting has been increasing among all biologic subtypes. The highest use of NAC is in TNBC and HER2+ disease, with use in these subgroups being twice as frequent as in HR+/HER2− disease.

Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. Here we show that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. p38-mediated EZH2 phosphorylation at T367 promotes EZH2 cytoplasmic localization and potentiates EZH2 binding to vinculin and other cytoskeletal regulators of cell migration and invasion. Ectopic expression of a phospho-deficient T367A-EZH2 mutant is sufficient to inhibit EZH2 cytoplasmic expression, disrupt binding to cytoskeletal regulators, and reduce EZH2-mediated adhesion, migration, invasion, and development of spontaneous metastasis. These results point to a PRC2-independent non-canonical mechanism of EZH2 pro-metastatic function. Polycomb group protein EZH2 is overexpressed in ER- breast cancer, promoting metastasis. Here, the authors show that independent of the polycomb group, phosphorylation of EZH2 at T367 by p38 promotes cytoplasmic localization of EZH2, binding to vinculin and other regulators of cell migration and invasion.

BackgroundRecent trials have suggested the feasibility of performing a sentinel lymph node biopsy (SNB) following neoadjuvant chemotherapy (NAC). The selection of suitable patients for this approach remains controversial. We developed a predictive model to identify patients most likely to benefit from SNB following NAC.MethodsThe National Cancer Data Base was used to identify patients with clinically node positive (cN+) breast cancer undergoing NAC followed by breast surgery and axillary lymph node dissection (ALND). Patients were randomly assigned to a 70% testing or 30% validation cohort for model development. A predictive model was built based on significant factors associated with pathologic nodal response (pN0) and breast response.ResultsUsing the testing cohort (n = 13,396), multivariate regression was used to identify predictors of pN0 based on preoperative factors. Younger age, hormone receptor (HR)-negative/Her2-negative, HR-positive/Her2-positive, HR-negative/Her2-positive, high-grade, ductal histology, cN1 versus cN2, and extent of breast response were all significant independent predictors of pN0 on adjusted analysis. The odds ratios translated into a 10-point scale correlating to a stepwise increase in pN0 response. The area under the curve for the ROC curves for the testing and validation cohorts was 0.781 and 0.788, respectively (p < 0.01).ConclusionsOur model incorporates known preoperative factors to predict the likelihood of pN0 response in patients with cN+ disease who undergo NAC. For patients with high scores, SNB should be considered over ALND, because these patients have a greater likelihood of having negative nodes at final pathology.

Poor responses of liver metastases to the anti-angiogenic agent bevacizumab in patients with colorectal and breast cancer correlate with tumor co-option of pre-existing blood vessels, a mechanism of tumor resistance that might be targeted by the inhibition of cancer cell motility. The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.

Background The significance of androgen receptor (AR) expression in triple-negative breast cancer (TNBC) is unclear, and published studies so far have been inconclusive. Methods A tissue microarray was constructed using tissue obtained from 119 patients with primary TNBC and stained for AR expression. Other tissue types obtained included recurrent TNBC, normal breast tissue, adjacent ductal carcinoma-in situ (DCIS), lymph node (LN) and distant metastases. Positive AR expression was defined as ≥10 % nuclear staining. Results Epithelial tissue was present and evaluable in 94 TNBC patients with a total of 177 tissue cores. AR expression in TNBC was 22 of 94 (23 %). AR expression was higher in normal breast tissue (88 %) and adjacent DCIS (73 % overall). All LN metastases from AR-positive TNBC patients were also AR positive; in addition, no AR-negative TNBC patient had AR-positive LNs. AR expression was associated with older patient age (63 vs. 57 years, respectively, p  = 0.051) and LN metastases ( p  = 0.033). Locoregional recurrence and overall/disease-specific survival were similar between AR-positive and AR-negative patients, although AR-positive patients had more advanced disease. On multivariate analysis, the presence of LN metastases was associated with poorer recurrence-free survival in AR-positive patients (hazard ratio, 4.34) ( p  = 0.031). Conclusions The AR is expressed in normal breast tissue, and expression decreases with advancement to DCIS and invasive cancer. AR-positive TNBC was more common in older patients and had a higher propensity for LN metastases. AR-positive TNBC may represent a breast cancer subtype with unique features that may be amenable to treatment with alternative targeted therapies.

Background Breast-conserving therapy (BCT) and mastectomy (MTX) has been considered to have a similar long-time survival. However, better survival in women undergoing BCT compared with MTX is found in two recent register studies from the United States. The purpose of this study was to compare survival after BCT and MTX for women with early-stage breast cancer in Norway. Methods Women with invasive, early-stage breast cancer (1998–2008) where BCT and MTX were considered as equally beneficial treatments were included for a total of 13,015 women. Surgery was divided in two main cohorts (primary BCT, primary MTX) and five subcohorts. Analyses were stratified into T1N0M0, T2N0M0, T1N1M0, T2N1M0, and age groups (<50, 50–69, ≥70). Overall survival and breast cancer-specific survival (BCSS) were calculated in life tables, hazard ratios by Cox regression, and sensitivity analyses. Results Five-year BCSS for women who underwent primary BCT or primary MTX was 97 and 88 %, respectively. Women who underwent primary MTX had a hazard ratio of 1.64 (95 % confidence interval 1.43–1.88) for breast cancer death compared with women who underwent primary BCT after adjusting for the year of diagnosis, age at diagnosis, stage, histology, and grade. Conclusions Survival was better or equal after breast-conserving therapy than mastectomy in all early stages, surgical subcohorts, and age groups. This advantage could not only be attributed to differences in tumor biology.

Background: MicroRNAs (miRs) are involved in the regulation of many processes that contribute to malignancy, including cell proliferation, radiation resistance, invasion and metastasis. The role of miR-330-3p, an miR upregulated in breast cancer, remains unclear. Methods: We examine the association of miR-330-3p with distant relapse-free survival in the Oxford cohort of breast cancer patients. We also study miR-330-3p function using in vitro invasion and ex ovo metastasis assays. Using in vitro luciferase assays, we validate a novel target gene for miR-330-3p, Collagen And Calcium Binding EGF Domains 1 (CCBE1). We assess functional consequences of CCBE1 loss by using siRNA-mediated knockdown followed by in vitro invasion assays. Lastly, we examine the expression profile of CCBE1 in breast carcinomas in the Curtis and TCGA Breast Cancer data sets using Oncomine Platform as well as distant relapse-free and overall survival of patients in the Helsinki University breast cancer data set according to CCBE1 expression status. Results: miR-330-3p is enriched in breast cancer, and higher levels of miR-330-3p expression are associated with lower distant relapse-free survival in a cohort of breast cancer patients. Consistent with these observations, overexpression of miR-330-3p in breast cancer cell lines results in greater invasiveness in vitro , and miR-330-3p-overexpressing cells also metastasise more aggressively ex ovo . We identify CCBE1 as a direct target of miR-330-3p, and show that knockdown of CCBE1 results in a greater invasive capacity. Accordingly, in breast cancer patients CCBE1 is frequently downregulated, and its loss is associated with reduced distant relapse-free and overall survival. Conclusions: We show for the first time that miR-330-3p targets CCBE1 to promote invasion and metastasis. miR-330-3p and CCBE1 may represent promising biomarkers in breast cancer.