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Summary: Accurate assessment of human epidermal growth factor receptor 2 is critical for the management of patients with breast cancer. We set out to study the impact of the 2007 American Society of Clinical Oncology/College of American Pathologists guidelines on the interpretation of human epidermal growth factor receptor 2 IHC results and its correlation with fluorescence in situ hybridization results. Invasive breast carcinomas with IHC HercepTest 3+ were retrieved from the archive of Mayo Clinic Rochester. The human epidermal growth factor receptor 2 slides were rereviewed, and results were recorded as percentage of invasive tumor cells with 3+, 2+, 1+, and 0 staining intensity. Human epidermal growth factor receptor 2 gene amplification by fluorescence in situ hybridization was performed on all tumors with 3+ staining in 70% or less of tumor cells. Of the 141 cases studied, 12 cases showed intense membrane staining in 11% to 30% of the invasive tumor cells and would have been scored as 2+ according to the new American Society of Clinical Oncology/College of American Pathologists guidelines. Of these 12 cases, 6 were positive for human epidermal growth factor receptor 2 gene amplification by fluorescence in situ hybridization (ratio >2.2), 4 cases were negative (HER2/CEP17 ratio of < 1.8), and 2 cases were equivocal (ratio of 1.8-2.2). One human epidermal growth factor receptor 2–positive case showed dramatic intratumoral heterogeneity with high-level amplification (ratio of 12.2) in the IHC 3+ area and no amplification (ratio of 1.0) in the IHC 1+/2+ areas. The 2007 American Society of Clinical Oncology/College of American Pathologists guidelines down-scored 2.8% of tumors from human epidermal growth factor receptor 2–positive (IHC 3+) to human epidermal growth factor receptor 2–negative (IHC 2+ equivocal and fluorescence in situ hybridization negative) in this study. Clinical studies are needed to determine whether the updated guidelines are better at predicting response to anti–human epidermal growth factor receptor 2 therapy. [Copyright &y& Elsevier]

Background: We sought to determine how often axillary node metastases were present in patients with intramammary lymph node (IMLN) metastasis and if the method of IMLN discovery impacts likelihood of axillary node metastasis. Methods: A retrospective review of our breast cancer database was conducted to identify patients in whom an IMLN was found. IMLNs were classified into 2 groups: those found “preoperatively” (evident on mammography, ultrasonography, magnetic resonance imaging or lymphogram), and those found “incidentally” (found by the surgeon intraoperatively or on pathologic review). Patterns of discovery and their correlation with axillary disease were evaluated using Fisher''s exact test. Results: Between March 1994 and October 2007, IMLNs were identified in 93 breast specimens. Twenty-three IMLNs were found preoperatively, while 70 were identified incidentally. Thirty-two patients (34%) harbored cancer in IMLNs with additional axillary node involvement present in 22 (69%). Metastasis was more frequent in the IMLNs detected by imaging (10/23, 43%) than in IMLNs detected incidentally (22/70, 31%, P = NS). Patients with positive IMLNs were more likely to have axillary disease than patients with negative IMLNs (69% versus 18%, P < .0001). Conclusion: The majority of identified IMLNs are histologically negative. If breast cancer is identified in an IMLN, additional axillary lymph node disease is common, regardless of the method of detection of the IMLN. [Copyright &y& Elsevier]

We have studied the use of polymethyl methacrylate (PMMA) as an alternative biopsy marker that is readily detectable with ultrasound Doppler twinkling in cases of in vitro, ex vivo , or limited duration in vivo settings. This study investigates the long-term safety and ultrasound Doppler twinkling detectability of a PMMA breast biopsy marker following local perturbations and different dwell times in a 6-mo animal experiment. This study, which was approved by our Institutional Animal Care and Use Committee, involved three pigs and utilized various markers, including PMMA (Zimmer Biomet), 3D-printed, and Tumark Q markers. Markers were implanted at different times for each pig. Mesh material or ethanol was used to induce a local inflammatory reaction near certain markers. A semiquantitative twinkling score assessed twinkling for actionable localization during monthly ultrasounds. At the primary endpoint, ultrasound-guided localization of lymph nodes with detectable markers was performed. Following surgical resection of the localized nodes, histomorphometric analysis was conducted to evaluate for tissue ingrowth and the formation of a tissue rind around the markers. No adverse events occurred. Twinkling scores of all markers for all three pigs decreased gradually over time. The Q marker exhibited the highest mean twinkling score followed by the PMMA marker, PMMA with mesh, and Q with ethanol. The 3D-printed marker with mesh and PMMA with ethanol had the lowest scores. All wire-localized lymph nodes were successfully resected. Despite varying percentages of tissue rind around the markers and a significant reduction in overall twinkling (p < 0.001) over time, mean PMMA twinkling scores remained clinically actionable at 6 and 5 mo using a General Electric C1-6 probe and 9L-probe, respectively. In this porcine model, the PMMA marker demonstrates an acceptable safety profile. Clinically actionable twinkling aids PMMA marker detection even after 6 mo of dwell time in porcine lymph nodes. The Q marker maintained the greatest twinkling over time compared to all the other markers studied. [ABSTRACT FROM AUTHOR]

• Breast tissue composition differences were observed between benign and malignant disease states. • Immune cell infiltrates were more marked in the setting of breast cancer. • Microbial communities, by deep sequencing of breast tissue, varied with tissue composition. • Alpha and beta diversity of the tissue microbiome varied with percentage fat and fibrosis in tissue. • Observed effects were independent of patient BMI. Stromal and immune cell composition alterations in benign breast tissue associate with future cancer risk. Pilot data suggest the innate microbiome of normal breast tissue differs between women with and without breast cancer. Microbiome alterations might explain tissue microenvironment variations associated with disease status. Prospectively-collected sterile normal breast tissues from women with benign (n=16) or malignant (n=17) disease underwent 16SrRNA sequencing with Illumina MiSeq and Hybrid-denovo pipeline processing. Breast tissue was scored for fibrosis and fat percentages and immune cell infiltrates (lobulitis) classified as absent/mild/moderate/severe. Alpha and beta diversity were calculated on rarefied OTU data and associations analyzed with multiple linear regression and PERMANOVA. Breast tissue stromal fat% was lower and fibrosis% higher in benign disease versus cancer (median 30% versus 60%, p=0.01, 70% versus 30%, p=0.002, respectively). The microbiome varied with stromal composition. Alpha diversity (Chao1) correlated with fat% (r=0.38, p=0.02) and fibrosis% (r=-0.32, p=0.05) and associated with different microbial populations as indicated by beta diversity metrics (weighted UniFrac, p=0.08, fat%, p=0.07, fibrosis%). Permutation testing with FDR control revealed taxa differences for fat% in Firmicutes, Bacilli, Bacillales, Staphylococcaceae and genus Staphylococcus , and fibrosis% in Firmicutes, Spirochaetes, Bacilli, Bacillales, Spirochaetales, Proteobacteria RF32, Sphingomonadales, Staphylococcaceae, and genera Clostridium, Staphylococcus, Spirochaetes, Actinobacteria Adlercreutzia. Moderate/severe lobulitis was more common in cancer (73%) than benign disease (13%), p=0.003, but no significant microbial associations were seen. These data suggest a link between breast tissue stromal alterations and its microbiome, further supporting a connection between the breast tissue microenvironment and breast cancer. [ABSTRACT FROM AUTHOR]

: BackgroundGene amplification is the primary mechanism of HER-2/neu overexpression in breast cancer and is a strong predictor of prognosis. Currently screening for HER-2/neu gene amplification in breast cancer is done by fluorescent in-situ hybridization (FISH), which is accurate but costly and labor intensive. We have evaluated a new PCR (polymerase chain reaction)-based assay for the detection of HER-2/neu gene amplification in human breast cancer.: Study designA total of 15 breast cancer cell lines and 14 breast cancer specimens were evaluated. HER-2/neu status of the tumors was evaluated by FISH and then assessed using a quantitative polymerase chain reaction/ligase detection reaction (PCR/LRD) technique.: ResultsAmplification of the HER-2/neu gene was detected in seven cell lines previously reported to have amplification and no amplification was found in any of the six that had been reported not to have amplification. In the assessment of breast specimens the PCR/LDR and FISH assays were in complete agreement. All 10 tumors with amplification by FISH were also amplified by PCR/LDR.: ConclusionsThe PCR/LDR technique successfully detects HER-2/neu gene amplification in clinical breast cancer specimens and shows 100% concordance with FISH. This technique is an accurate and rapid alternative to FISH with the potential for automation and high throughput analysis of HER-2/neu status in breast cancer. [Copyright &y& Elsevier]