Nora M. Hansen

Prospective Observational Study of Sentinel Lymphadenectomy Without Further Axillary Dissection in Patients With Sentinel Node–Negative Breast Cancer

PURPOSE Immediate complete axillary lymphadenectomy (ALND) after sentinel lymphadenectomy (SLND) has confirmed that tumor-negative sentinel nodes accurately predict tumor-free axillary nodes in breast cancer. Therefore, we hypothesized that SLND alone in patients with tumor-negative sentinel nodes would achieve axillary control, with minimal complications. PATIENTS AND METHODS Between October 1995 and July 1997, 133 consecutive women who had primary invasive breast tumors clinically </= 4 cm in diameter and no axillary lymphadenopathy were prospectively entered onto a trial of SLND using vital blue dye. Sentinel nodes were examined by standard microscopy or immunohistochemistry. SLND was the only axillary surgery if sentinel nodes were tumor-free. Completion ALND was performed only if sentinel nodes contained metastases or if they were not identified. Excluded from subsequent analysis were patients with unsuspected multifocal carcinoma and those who refused completion ALND. The complication and axillary recurrence rates after SLND without ALND were determined. RESULTS Sentinel nodes were identified in 132 (99%) of 133 patients. Eight patients were excluded from further analysis. Of the 125 assessable patients, 57 had tumor-positive sentinel nodes and one had an unsuccessful mapping procedure; these patients underwent completion ALND. In the remaining 67 patients (54%), SLND was the only axillary procedure. Complications occurred in 20 patients (35%) undergoing ALND after SLND but in only two patients (3%) undergoing SLND alone (P =.001). There were no local or axillary recurrences at a median follow-up of 39 months. CONCLUSION Complication rates are negligible after SLND alone. An absence of axillary recurrences supports SLND as an accurate staging alternative for breast cancer and suggests that routine ALND can be eliminated for patients with histopathologically negative sentinel nodes.

Do all patients with sentinel node metastasis from breast carcinoma need complete axillary node dissection

OBJECTIVE To determine the likelihood of nonsentinel axillary metastasis in the presence of sentinel node metastasis from a primary breast carcinoma. SUMMARY BACKGROUND DATA Sentinel lymphadenectomy is a highly accurate technique for identifying axillary metastasis from a primary breast carcinoma. Our group has shown that nonsentinel axillary lymph nodes are unlikely to contain tumor cells if the axillary sentinel node is tumor-free, but as yet no study has examined the risk of nonsentinel nodal involvement when the sentinel node contains tumor cells. METHODS Between 1991 and 1997, axillary lymphadenectomy was performed in 157 women with a tumor-involved sentinel node. Fifty-three axillae (33.5%) had at least one tumor-involved nonsentinel node. The authors analyzed the incidence of nonsentinel node involvement according to clinical and tumor characteristics. RESULTS Only two variables had a significant impact on the likelihood of nonsentinel node metastasis: the size of the sentinel node metastasis and the size of the primary tumor. The rate of nonsentinel node involvement was 7% when the sentinel node had a micrometastasis (< or =2 mm), compared with 55% when the sentinel node had a macrometastasis (>2 mm). In addition, the rate of nonsentinel node tumor involvement increased with the size of the primary tumor. CONCLUSIONS If a primary breast tumor is small and if sentinel node involvement is micrometastatic, then tumor cells are unlikely to be found in other axillary lymph nodes. This suggests that axillary lymph node dissection may not be necessary in patients with sentinel node micrometastases from T1/T2 lesions, or in patients with sentinel node metastases from T1a lesions.

Comparison of Sentinel Lymph Node Biopsy Alone and Completion Axillary Lymph Node Dissection for Node-Positive Breast Cancer

PURPOSE For women with breast cancer, the role of completion axillary lymph node dissection (ALND) after identification of nodal metastases by sentinel lymph node biopsy (SLNB) has been questioned. Our objectives were to assess national nodal evaluation practice patterns and to examine differences in recurrence and survival for SLNB alone versus SLNB with completion ALND. PATIENTS AND METHODS From the National Cancer Data Base (1998 to 2005), women with clinically node-negative breast cancer who underwent SLNB and who had nodal metastases were identified. Practice patterns and outcomes were examined for patients who underwent SLNB alone versus SLNB with completion ALND (median follow-up, 63 months). RESULTS Of 97,314 patients, 20.8% underwent SLNB alone, and 79.2% underwent SLNB with completion ALND. In 2004 to 2005, patients were significantly more likely to undergo SLNB alone if they were older, had smaller tumors, or were treated at non-National Cancer Institute-designated cancer centers. In patients with macroscopic nodal metastases (n = 20,075 during 1998 to 2000), there was a nonsignificant trend toward better outcomes for completion ALND (v SLNB alone) after analysis was adjusted for differences between the two groups: axillary recurrence (hazard ratio [HR], 0.58; 95% CI, 0.32 to 1.06) and overall survival (HR, 0.89; 95% CI, 0.76 to 1.04). In patients with microscopic nodal metastases (n = 2,203 during 1998 to 2000), there were no significant differences in axillary recurrence or survival for patients who underwent SLNB alone versus completion ALND. CONCLUSION Compared with SLNB alone, completion ALND does not appear to improve outcomes for breast cancer patients with microscopic nodal metastases; however, there was a nonsignificant trend toward better outcomes with completion ALND for those with macroscopic disease.

New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients

BackgroundCurrent practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model.MethodsWe constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University.Results285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size.ConclusionWe present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets.

Learning sentinel node biopsy: Results of a prospective randomized trial of two techniques

BACKGROUND Evidence indicates that sentinel node (SN) biopsy can accurately predict axillary nodal status. Debate exists as to the optimal method of SN identification. METHODS Patients with clinical T1 or T2 tumors and negative axillae were randomized to SN localization with blue dye (B) alone (n = 50) or blue dye plus radioactivity (B+R) (n = 42). Patients undergoing needle localization (n = 47) were assigned to blue dye. RESULTS The SN was identified in 110 patients (79%) and contained metastases in 28. The SN predicted the axillary nodal status in 96% of cases. The SN identification rate did not differ between B (88%) or B+R (86%) but was significantly lower in patients requiring localization (64%). The time to SN identification also did not differ between B and B+R. The number of cases done by an individual surgeon was a significant predictor of SN identification. A stepwise logistic regression analysis of factors influencing the success of SN identification identified tumor location, needle localization, number of operations, and body mass index as significant predictors. CONCLUSIONS Our study does not identify any advantage for the use of the more expensive and complex method of SN identification using B+R compared with B alone, even for surgeons learning the techniques.

Distinct Hypermethylation Profile of Primary Breast Cancer Is Associated with Sentinel Lymph Node Metastasis

Purpose: Gene promoter region hypermethylation is a significant event in primary breast cancer. However, its impact on tumor progression and potential predictive implications remain relatively unknown. Experimental Design: We conducted hypermethylation profiling of 151 primary breast tumors with association to known prognostic factors in breast cancer using methylation-specific PCR for six known tumor suppressor and related genes: RASSF1A, APC, TWIST, CDH1, GSTP1, and RAR-β2. Furthermore, correlation with sentinel lymph node (SLN) tumor status was assessed as it represents the earliest stage of metastasis that is readily detected. Hypermethylation for any one gene was identified in 147 (97%) of 151 primary breast tumors. The most frequently hypermethylated gene was RASSF1A (81%). Results: Hypermethylation of the CDH1 was significantly associated with primary breast tumors demonstrating lymphovascular invasion (P = 0.008), infiltrating ductal histology (P = 0.03), and negative for the estrogen receptor (P = 0.005), whereas RASSF1A and RAR-β2 gene hypermethylation were significantly more common in estrogen receptor–positive (P < 0.001) and human epidermal growth factor receptor 2–positive (P < 0.001) tumors, respectively. In multivariate analysis, hypermethylation of GSTP1 and/or RAR-β2 was significantly associated with patients having macroscopic SLN metastasis compared with those with microscopic or no sentinel node metastasis (odds ratio, 4.59; 95% confidence interval, 2.02-10.4; P < 0.001). In paired SLN metastasis, CDH1 was the most frequently methylated gene (90%) and provides evidence in patients corroborating its role in the clinical development of metastasis. Conclusion: Hypermethylation profiling of primary breast tumors is significantly associated with known pathologic prognostic factors and may have additional clinical and pathologic utility for assessing patient prognosis and predicting early regional metastasis.

Impact of Micrometastases in the Sentinel Node of Patients With Invasive Breast Cancer

PURPOSE Lymph node metastases are the most significant prognostic indicator for patients with breast cancer. Sentinel node biopsy (SNB) has led to an increase in the detection of micrometastases in the sentinel node (SN). This prospective study was designed to determine the survival impact of micrometastases in SNs of patients with invasive breast cancer. This study is based on the new sixth edition of the American Joint Committee on Cancer (AJCC) staging criteria. PATIENTS AND METHODS Between January 1, 1992 and April 30, 1999, 790 patients entered this prospective study at the John Wayne Cancer Institute. The SN was examined first by hematoxylin and eosin (HE), and if the SN was negative with HE, then immunohistochemical staining was performed. The patients were then divided into four groups based on AJCC nodal staging: pN0(i-), no evidence of tumor (n = 486); pN0(i+), tumor deposit < or = 0.2 mm (n = 84); pN1mi, tumor deposit more than 0.2 mm but < or = 2 mm (n = 54), and pN1, tumor deposit more than 2 mm (n = 166). Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to determine differences in DFS and OS of patients from different groups. RESULTS At a median follow-up of 72.5 months, the size of SN metastases was a significant predictor of DFS and OS. CONCLUSION Patients with micrometastatic tumor deposits, pN0(i+) or pN1mi, do not seem to have a worse 8-year DFS or OS compared with SN-negative patients. As expected, there was a significant decrease in 8-year DFS and OS in patients with pN1 disease in the SN.

Biopsy method and excision volume do not affect success rate of subsequent sentinel lymph node dissection in breast cancer

Introduction: Sentinel lymph node dissection (SLND) is becoming a recognized technique for accurately staging patients with breast cancer. Its success in patients with large tumors or prior excisions has been questioned. The purpose of this study was to evaluate the effect of biopsy method, excision volume, interval from biopsy to SLND, tumor size, and tumor location on SLND success rate.Methods: Consecutive patients who underwent SLND followed by completion axillary lymph node dissection from October 1991 to December 1995 were analyzed. Included were cases performed early in the series before the technique was adequately developed. Excision volume was derived from the product of three dimensions as measured by the pathologist. Two end points were analyzed: sentinel node identification rate and accuracy of SLND in predicting axillary status. Univariate analyses using x2 or Fisher’s exact test for categorical variables and Wilcoxon rank sums for continuous variables were performed. Multivariate analysis was performed using logistic regression.Results: There were 284 SLND procedures performed on 283 patients. Median age was 55 years. The most recent biopsy method used before SLND was stereotactic core biopsy in 41 (14%), fine-needle aspiration in 62 (22%), and excision in 181 (64%) procedures. The mean excision volume was 32 ml with a range of 0.3–169 ml. The mean time from biopsy to SLND was 17 days with a range of 0–140 days. The mean tumor size was 2.0 cm (15 Tis [5%], 184 T1 [65%], 72 T2 [25%], and 13 T3 [5%]). Tumors were located in the outer quadrants in 74%, the inner quadrants in 18%, and subareolar region in 8%. The sentinel node was identified in 81%, and 39% had metastases. There were three false-negative cases early in the series. Sensitivity was 97%, and accuracy was 99%. Negative predictive value was 98% in cases in which the sentinel node was identified. On the basis of biopsy method, excisional volume, time from biopsy to SLND, tumor size, and tumor location, there was no statistically significant difference (P..05) in sentinel node identification rate or accuracy of SLND.Conclusions: SLND has a high success rate in breast cancer patients regardless of the biopsy method or the excision volume removed before SLND. In addition, the interval from biopsy to SLND, tumor size, and tumor location have no effect on the success rate of SLND, even in this series which included patients operated on before the technique was adequately defined. Patients with breast cancers located in any quadrant and diagnosed either with a needle or excisional biopsy could be evaluated for trials of SLND.

Uncoupling Ceramide Glycosylation by Transfection of Glucosylceramide Synthase Antisense Reverses Adriamycin Resistance

Previous work from our laboratory demonstrated that increased competence to glycosylate ceramide conferred adriamycin resistance in MCF-7 breast cancer cells (Liu, Y. Y., Han, T. Y., Giuliano, A. E., and M. C. Cabot. (1999) J. Biol. Chem. 274, 1140–1146). This was achieved by cellular transfection with glucosylceramide synthase (GCS), the enzyme that converts ceramide to glucosylceramide. With this, we hypothesized that a decrease in cellular ceramide glycosylation would result in heightened drug sensitivity and reverse adriamycin resistance. To down-regulate ceramide glycosylation potential, we transfected adriamycin-resistant breast cancer cells (MCF-7-AdrR) with GCS antisense (asGCS), using a pcDNA 3.1/his A vector and developed a new cell line, MCF-7-AdrR/asGCS. Reverse transcription-polymerase chain reaction assay and Western blot analysis revealed marked decreases in both GCS mRNA and protein in MCF-7-AdrR/asGCS cells compared with the MCF-7-AdrR parental cells. MCF-7-AdrR/asGCS cells exhibited 30% less GCS activity by in vitro enzyme assay (19.7 ± 1.1 versus 27.4 ± 2.3 pmol GC/h/μg protein,p < 0.001) and were 28-fold more sensitive to adriamycin (EC50, 0.44 ± 0.01 versus12.4 ± 0.7 μm, p < 0.0001). GCS antisense transfected cells were also 2.4-fold more sensitive to C6-ceramide compared with parental cells (EC50= 4.0 ± 0.03 versus 9.6 ± 0.5 μm,p < 0.0005). Under adriamycin stress, GCS antisense transfected cells compared with parental cells displayed time- and dose-dependent increases in endogenous ceramide and dramatically higher levels of apoptotic effector, caspase-3. Western blotting showed that adriamycin sensitivity, introduced by asGCS gene transfection, was independent of P-glycoprotein and Bcl-2 expression. In summary, this work shows that transfection of GCS antisense tempers the expression of native GCS and restores cell sensitivity to adriamycin. Therefore, limiting the potential to glycosylate ceramide, which is an apoptotic signal in chemotherapy and radiotherapy, provides a promising approach to combat drug resistance.

Sentinel Node Metastasis in Patients with Breast Carcinoma Accurately Predicts Immunohistochemically Detectable Nonsentinel Node Metastasis

Background: Sentinel lymphadenectomy is highly accurate for identifying axillary metastasis from a primary breast carcinoma. Nonsentinel axillary lymph nodes (NSNs) are unlikely to contain tumor cells if the axillary sentinel node (SN) is tumor free. We previously showed that the size of the primary tumor and the size of its SN metastasis predict the risk of NSN tumor involvement detected by hematoxylin and eosin staining. This study used immunohistochemical staining (IHC) to determine the likelihood of NSN axillary metastasis in the presence of SN metastasis.Methods: Between 1991 and 1997, axillary lymphadenectomy was performed in 156 women (157 axillary basins) who had primary breast carcinoma with SN metastasis. By hematoxylin and eosin staining, we identified NSN metastasis in 55 axillae (35%). IHC was then used to re-examine all NSNs (1827 lymph nodes) from the remaining 102 axillae. The incidence of IHC-detected NSN involvement was analyzed with respect to clinical and tumor characteristics.Results: By using IHC, we identified NSN metastasis in 15 (14.7%) of the 102 axillae. By multivariate analysis, the size of the SN metastasis (P = .0001) and the size of the primary tumor (P = .038) were the only independent variables predicting NSN metastasis determined by using either hematoxylin and eosin staining or IHC. Only the number of SN metastases (1 vs. >1) was a significant (P = .04) predictor of IHC-detected NSN metastasis.Conclusions: Use of IHC increases the likelihood of detection of NSN metastasis, and the risk of IHC-detected metastasis increases with the size of the SN metastasis and the size of the primary tumor. If SN involvement is micrometastatic (≤2 mm) or detected by using IHC, tumor cells are unlikely to be found in other axillary lymph nodes in patients with a small primary tumor. The clinical significance of micrometastatic disease in lymph nodes is controversial, and a prospective randomized study is necessary to resolve this important issue.