Germline Genetic Testing: What the Breast Surgeon Needs to Know.

PURPOSE: The American Society of Breast Surgeons (ASBrS) sought to provide educational guidelines for breast surgeons on how to incorporate genetic information and genomics into their practice. METHODS: A comprehensive nonsystematic review was performed of selected peer-reviewed literature. The Genetics Working Group of the ASBrS convened to develop guideline recommendations. RESULTS: Clinical and educational guidelines were prepared to outline the essential knowledge for breast surgeons to perform germline genetic testing and to incorporate the findings into their practice, which have been approved by the ASBrS Board of Directors. RECOMMENDATIONS: Thousands of women in the USA would potentially benefit from genetic testing for BRCA1, BRCA2, and other breast cancer genes that markedly increase their risk of developing breast cancer. As genetic testing is now becoming more widely available, women should be made aware of these tests and consider testing. Breast surgeons are well positioned to help facilitate this process. The areas where surgeons need to be knowledgeable include: (1) identification of patients for initial breast cancer-related genetic testing, (2) identification of patients who tested negative in the past but now need updated testing, (3) initial cancer genetic testing, (4) retesting of patients who need their genetic testing updated, (5) cancer genetic test interpretation, posttest counseling and management, (6) management of variants of uncertain significance, (7) cascade genetic testing, (8) interpretation of genetic tests other than clinical cancer panels and the counseling and management required, and (9) interpretation of somatic genetic tests and the counseling and management required.

CXCR6-CXCL16 Axis Promotes Breast Cancer by Inducing Oncogenic Signaling.

Precise mechanisms underlying breast cancer (BrCa) metastasis are undefined, which becomes a challenge for effective treatments. Chemokine signaling instigates the trafficking of cancer cells in addition to leukocytes. This study aimed to ascertain the clinical and biological significance of the CXCR6/CXCL16 signaling axis in the pathobiology of BrCa. Our data show a higher expression of CXCR6 in BrCa cell lines and tissues. Stage-III BrCa tissues express significantly higher CXCR6 compared to stage-II tissues. The ligand, CXCL16, could remain tethered to the cell surface, and, after proteolytic shedding of the ectodomain, the N-terminal fragment is released, converting it to its oncogenic, soluble form. Like CXCR6, N-terminal CXCL16 and ADAM-10 were significantly higher in stage-III than stage-II, but no significant difference was observed in the C-terminal fragment of CXCL16. Further, stimulation of the CXCR6/CXCL16 axis activated Src, FAK, ERK1/2, and PI3K signaling pathways, as per antibody microarray analysis, which also underlie CXCL16-induced F-actin polymerization. The CXCR6/CXCL16 axis induces cytoskeleton rearrangement facilitating migration and invasion and supports BrCa cell survival by activating the PI3K/Akt pathway. This study highlights the significance of the CXCR6/CXCL16 axis and ADAM10 as potential therapeutic targets for advanced-stage BrCa.

Percutaneous excisional breast biopsy.

BACKGROUND: The utility of the vacuum-assisted breast biopsy device (VABB) under stereotactic guidance is well established. We hypothesized that the complete removal of small benign lesions under ultrasonography guidance in an outpatient setting could be obtained with minimal morbidity with the multidirectional hand held vacuum-assisted biopsy. METHODS: Patients enrolled in this study underwent an ultrasound-guided minimally invasive excisional breast biopsy through a 3-mm incision. Removal of the abnormality was accomplished with a handheld 8- or 11-gauge Mammotome. RESULTS: Eighty-one patients had 101 lesions excised. The average (+/- SD) age of the participants was 46.8 +/- 15.4 years. The average size of the lesions was 1.15 +/- 0.43 cm (range 0.5 cm to 2.0 cm). Ninety-four lesions (93%) had benign pathology, five lesions (5%) were malignant, and two (2%) lesions had atypical hyperplasia. Six-month baseline mammogram performed in 71% of patients more than 40 years old documented resolution of percutaneously removed lesions. CONCLUSIONS: Vacuum-assisted excisional breast biopsy under ultrasound guidance is an effective technique for the therapeutic management of benign lesions.

Gut glutathione metabolism and changes with 7,12-DMBA and glutamine.

INTRODUCTION: The mechanism by which oral glutamine (GLN) prevents 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer is unknown. While GLN triples the negative extraction of gut glutathione (GSH) in rats, DMBA significantly disrupts it. Actual gut GSH flux has not been reported. We hypothesized that the gut is a producer of GSH; DMBA blocks gut GSH production and supplemental oral GLN antagonizes this effect. MATERIALS AND METHODS: Eighty Sprague-Dawley rats were randomized to four groups (n = 20/group): DMBA + GLN, DMBA + FA, OIL + GLN, OIL + FA. Rats (age 50 days) were gavaged with a one-time dose of 100 mg/kg DMBA or oil. Rats were gavaged with AES-14 as GLN (1 gm/kg/day) or an isonitrogenous amount of Freamine (FA) from 1 week before till sacrifice at 1 week after DMBA (greatest effect on gut GSH extraction). Arterial and portal blood was taken for GLN and GSH levels, and blood flow was measured using (14)C-PAH. Gut GLN and GSH fluxes (uptake or production) were calculated. RESULTS: DMBA abrogated the normal GSH production (negative flux) in OIL + FA while not affecting GLN metabolism. GLN maintained GSH production in DMBA + GLN. CONCLUSIONS: Oral GLN restores to normal GSH production in DMBA-treated animals suggesting one of the mechanism(s) by which GLN prevents breast cancer in this model. Unchanged uptake of GLN in the DMBA-treated animals may indicate a block in GSH transport rather than actual intracellular production.

Effect of glutamine on glutathione, IGF-I, and TGF-beta 1.

BACKGROUND: Our previous results have showed that oral glutamine (GLN) supplementation decreased carcinogenesis in 7,12-dimethylbenz[a]antracene (DMBA) breast cancer model. We also have found that GLN raises blood glutathione (GSH) levels in an implantable breast cancer model. The process of tumor growth was accompanied by depressed GSH production and increased levels of insulin-like growth factor-I (IGF-I) and transforming growth factor beta1 (TGF-beta 1). GSH is counter-regulatory to IGF-I. We therefore hypothesized that in DMBA model of breast cancer, the increased GSH levels seen with oral GLN would be associated with lowered levels of IGF-I &TGF-beta(1). METHODS: Time-dated pubertal Sprague-Dawley rats were gavaged at time 0 with 1 g/kg/day glutamine (GLN) (n = 18), isonitrogenous Freamine (FA) (n = 18), or water (H(2)O) (n = 18). Rats were further randomized on day 7 to 100 mg/kg DMBA or oil. After 14 days, the animals were sacrificed and blood GSH, IGF-1, TGF-beta 1, breast tissue, and gut mucosa GSH levels were measured. RESULTS: Oral GLN increased significantly blood, breast tissue, and gut mucosa levels of GSH in both DMBA and control groups in comparison with the control groups not treated with GLN. At the same time, the levels of blood IGF-I and TGF-beta 1 decreased significantly in both DMBA-treated and control groups. DMBA did not significantly affect any of these levels. CONCLUSIONS ;Oral GLN increased GSH levels and lowered IGF-I and TGF-beta 1 in a range that is considered clinically significant. However, the effect of GLN in maintaining normal gut GSH production in the presence of DMBA was much more significant. Inconsistent with our hypothesis, reduction in IGF and TGF-beta 1 levels did not correlate with DMBA's effect on gut GSH production.

Intraoperative touch preparation for sentinel lymph node biopsy: a 4-year experience.

BACKGROUND: The optimal technique for intraoperative pathologic examination of sentinel lymph nodes (SLNs) is still controversial. Recent small series report sensitivity between 60% and 100% for various techniques. The aim of this study was to evaluate our long-term experience with touch preparation cytology (TPC) and frozen section (FS) in the intraoperative examination of SLNs for breast cancer. METHODS: A total of 247 patients with operable breast cancer underwent an SLN biopsy for staging of the axilla. The SLN was identified by (99m)Tc-labeled sulfur colloid unfiltered dye, blue dye, or both and dissected, and then intraoperative TPC or FS and permanent section, or both, were performed. RESULTS: A total of 479 SLNs were submitted for TPC and permanent hematoxylin and eosin. A total of 68 SLNs were positive by hematoxylin and eosin; 65 SLNs were positive by TPC, with a false-negative rate of 5.8%. The sensitivity for TPC was 94.2%, with a false-positive rate of 0.2%. A total of 165 SLNs were submitted for FS, with a sensitivity of 85.7% and a specificity of 98.6%. The false-positive rate was 1.4%, with a false-negative rate of 15.8%. CONCLUSIONS: In a large series, TPC is as accurate as FS but is simpler and faster in the detection of intraoperative metastasis in SLNs for breast cancer.