Is there a role of sentinel lymph node biopsy in ductal carcinoma in situ?: analysis of 587 cases

BACKGROUND: The role of sentinel lymph node biopsy (SLNB) in patients with a core needle-biopsy diagnosis of ductal carcinoma in situ (DCIS) has been intensely debated. Core needle-biopsy has an inherent sampling error leading to histologic underestimation of invasive disease. If SLNB is not performed at the time of the definitive operative procedure, patients found to have an invasive cancer, will require a second operative procedure. The study was designed to determine when the risk of finding invasive disease on final pathology in patients with an initial diagnosis of DCIS was sufficiently high to justify the use of SLNB. METHODS: We identified 587 women with an initial core needle-biopsy diagnosis of DCIS in the prospective Breast Test Wales (BTW) database from 1995 through 2005. A variety of clinical, mammographic and histologic features were identified and correlated with the presence of invasion at excision using univariate and multivariate analyses. RESULTS: Median age of patients at the time of diagnosis was 58 years (range 41 to 83 years). 201 patients (36%) were treated by mastectomy and 354 (64%) by breast conservation surgery. 220 of 587 patients (38%) were found to have invasive disease on final pathology. On univariate analysis, the rate of upstaging was related to the presence of a clinically palpable mass and size of the mass (both p<0.0001, Mann-Whitney test); mammographic presence of a mass and size of the mass (both p<0.0001, Mann-Whitney test). Multivariate logistic regression analysis revealed 2 independent predictors of invasive cancer on final pathology: mass on clinical examination (odds ratio [OR], 5.09; p<0.0001) and mammographic mass (OR, 7.37; p<0.0001). Age, grade of DCIS, microinvasion and presence of comedonecrosis did not help in distinguishing between patients with DCIS and those upstaged to invasive carcinoma at definitive surgery. Axillary nodal staging (four node sampling or clearance) was done at the time of surgery in 269 patients. Axillary nodal metastases were found in 35 of 269 patients (13%). All 35 patients had invasive carcinoma on final pathology. CONCLUSION: The indiscriminate use of SLNB in patients with DCIS seems excessive. Our study suggests that patients with a mass on clinical examination or mammogram have an increased risk of invasive disease at the time of definitive operative procedure and should undergo SLNB at the initial procedure. In addition, SLNB should be performed in patients undergoing mastectomy because mastectomy precludes SLNB if invasive disease is subsequently discovered

Detection of breast cancer metastasis in sentinel lymph nodes using intra-operative real time GeneSearch™ BLN Assay in the operating room: results of the Cardiff study

Background. Intra-operative assessment is not routinely performed in the UK due to poor sensitivity of available methods and overburdened pathology resources. We conducted a prospective clinical feasibility study of the GeneSearch™ Breast Lymph Node (BLN) Assay (Veridex, LLC, Warren, NJ) to confirm its potential usefulness within the UK healthcare system. Methods In the assay 50% of the lymph node was processed to detect the presence of cytokeratin-19 and mammaglobin mRNA. The assay was calibrated to detect metastases >0.2 mm. Assay results were compared to H&E performed on each face of ~2 mm alternating node slabs and 3 additional sections cut at ~150 μm interval from each face of the node slab. Results 124 sentinel lymph nodes were removed from 82 breast cancer patients. The assay correctly identified all 6 patients with sentinel node macrometastases (>2.0 mm), and 2 of 3 patients with sentinel node micrometastases (0.2–2.0 mm). Sentinel lymph nodes in 4 patients were assay positive but histology negative. Two of these four patients had isolated tumor cells seen by histology. The overall concordance with histology was 93.9% (77/82), with sensitivity of 88.9% (8/9, 95% CI 56.5–98%), specificity of 94.6% (69/73, 95% CI 86.7–97.8%), positive predictive value of 66.7% (8/12, 95% CI 39.1–86.2%) and negative predictive value of 98.6% (69/70, 95% CI 92.3–99.7%). The assay was performed in a median time of 32 min (range 26–69 min). Conclusion Intra-operative assessment of sentinel lymph node can be performed rapidly and accurately using the GeneSearch™ BLN Assay

Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial

BACKGROUND: Sentinel lymph node biopsy in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized trials on morbidity and mortality outcomes. We conducted a multicenter randomized trial to compare quality-of-life outcomes between patients with clinically node-negative invasive breast cancer who received sentinel lymph node biopsy and patients who received standard axillary treatment. METHODS: The primary outcome measures were arm and shoulder morbidity and quality of life. From November 1999 to October 2003, 1031 patients were randomly assigned to undergo sentinel lymph node biopsy (n = 515) or standard axillary surgery (n = 516). Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy (depending on the protocol at the treating institution). Intention-to-treat analyses of data at 1, 3, 6, and 12 months after surgery are presented. All statistical tests were two-sided. RESULTS: The relative risks of any lymphedema and sensory loss for the sentinel lymph node biopsy group compared with the standard axillary treatment group at 12 months were 0.37 (95% confidence interval [CI] = 0.23 to 0.60; absolute rates: 5% versus 13%) and 0.37 (95% CI = 0.27 to 0.50; absolute rates: 11% versus 31%), respectively. Drain usage, length of hospital stay, and time to resumption of normal day-to-day activities after surgery were statistically significantly lower in the sentinel lymph node biopsy group (all P .05). CONCLUSION: Sentinel lymph node biopsy is associated with reduced arm morbidity and better quality of life than standard axillary treatment and should be the treatment of choice for patients who have early-stage breast cancer with clinically negative nodes

LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues

Somatic inactivation of the serine/threonine kinase gene STK11/LKB1/PAR-4 occurs in a variety of cancers, including ∼10% of melanoma. However, how the loss of LKB1 activity facilitates melanoma invasion and metastasis remains poorly understood. In LKB1-null cells derived from an autochthonous murine model of melanoma with activated Kras and Lkb1 loss and matched reconstituted controls, we have investigated the mechanism by which LKB1 loss increases melanoma invasive motility. Using a microfluidic gradient chamber system and time-lapse microscopy, in this paper, we uncover a new function for LKB1 as a directional migration sensor of gradients of extracellular matrix (haptotaxis) but not soluble growth factor cues (chemotaxis). Systematic perturbation of known LKB1 effectors demonstrated that this response does not require canonical adenosine monophosphate–activated protein kinase (AMPK) activity but instead requires the activity of the AMPK-related microtubule affinity-regulating kinase (MARK)/PAR-1 family kinases. Inhibition of the LKB1–MARK pathway facilitated invasive motility, suggesting that loss of the ability to sense inhibitory matrix cues may promote melanoma invasion