Faculty Bibliography

Objective Sentinel lymph node biopsy (SLNB) is a widely accepted and safe technique that increases the accuracy of axillary staging in breast cancer for patients with clinically node-negative disease. Results from the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial found no benefit for completion axillary lymph node dissection (ALND) in patients with breast cancer involving 1 to 2 positive sentinel nodes. The purpose of our study was to characterize the population of patients who had ALND since the publication of the Z0011 results. Methods This was an IRB-approved retrospective review of women with newly diagnosed breast cancer between 1/2010 and 6/2013 who were clinically node-negative and had >1 positive sentinel lymph node (SLN). Variables of interest included age, method of presentation, body mass index (BMI), tumor characteristics, surgery type, and preop imaging. Patients who received neoadjuvant therapy were excluded. Descriptive statistics and Pearson's chisquare analyses were utilized. Results Out of a total of 1,513 patients, 191 (12%) patients had >1 positive SLN in their initial surgery. The mean age was 56 years. Of the patients with a positive SLN, 139 (73%) went on to have a completion ALND. The distribution of age and tumor type was similar in patients who had SLNB alone and who underwent completion ALND. However, a higher proportion of patients who underwent completion ALND had later stage disease (p < 0.0001), larger tumors (p = 0.012), and greater number of positive SLN (p = 0.004), and had a higher BMI (p = 0.05). Among the 139 patients who went on to have a complete ALND, 127 (91%) patients had frozen section analysis with > 1 positive lymph node. Of these patients, 72 (57%) had 1 lymph node positive for metastasis and 41 (32%) had 2 lymph nodes positive for metastasis on final pathology. Conclusion Our study showed that women who had a completion ALND presented with later stage disease, larger tumors, and greater number of positive SLN. Frozen section analysis at the time of SLNB led to ALND in 113 patients with 1 or 2 positive SLN on final pathology. These patients would not meet the criteria for axillary dissection based on the results of Z0011. This suggests that patients should either undergo completion axillary dissection if 3 or more lymph nodes are found to have metastatic disease on frozen section or that completion dissection should be deferred until final pathology confirms the presence of 3 or more positive lymph nodes

Background: Current methods for intraoperative assessment of lumpectomy margins are limited, and a meaningful proportion of patients require re-excision to achieve acceptable margins. There is little available information regarding the relationship of mammographic breast density (BD) and positive margin rate. Methods: The MarginProbe device uses radiofrequency spectroscopy to evaluate the margins of lumpectomy specimens. The current study utilized data from the MarginProbe Pivotal Trial (Dune Medical Devices, Israel, NCT00749931 ). This randomized clinical trial compared adjunctive intraoperative use of the MarginProbe device with surgeons' standard approach to lumpectomy surgery. For the current analysis, data was compiled from the period prior to patient randomization and device use. Variables of interest included BD, patient and tumor characteristics, and the margin status of the main lumpectomy specimen (prior to device use in the device arm). For the purpose of this analysis, a positive margin was considered tumor on ink. Statistical analysis was performed with univariate and multivariate analysis, and linear/logistic regression. Results: A total of 664 patients were enrolled in the trial. 450 patients had preoperative breast density information available, and formed the basis for this analysis. As expected, higher BD was associated with younger age, lower BMI and smaller breast and specimen volume. Increased BD was also associated with increased use of preoperative MRI imaging (odds ratio 2.2, p<0.0001). Higher BD was also associated with a significant increase in main lumpectomy specimen positive margin rate (Table). The odds ratio was 1.46 per change in density category (p=0.011). BD remained significantly associated with positive margins after controlling for age, BMI and breast volume. Conclusions: Higher BD is an independent risk factor for positive margins in main lumpectomy specimens, suggesting that adjunctive methods for intraoperative margin assessment may be particularly helpful in these patients. (table present)

With the completion of the Human Genome Project and the development of high throughput technologies, such as next-generation sequencing, the use of multiplex genetic testing, in which multiple genes are sequenced simultaneously to test for one or more conditions, is growing rapidly. Reflecting underlying heterogeneity where a broad range of genes confer risks for one or more cancers, the development of genetic cancer panels to assess these risks represents just one example of how multiplex testing is being applied clinically. There are a number of issues and challenges to consider when conducting genetic testing for cancer risk assessment, and these issues become exceedingly more complex when moving from the traditional single-gene approach to panel testing. Here, we address the practical considerations for clinical use of panel testing for breast, ovarian, and colon cancers, including the benefits, limitations and challenges, genetic counseling issues, and management guidelines.

BACKGROUND: The presence of tumor cells at the margins of breast lumpectomy specimens is associated with an increased risk of ipsilateral tumor recurrence. Twenty to 30 % of patients undergoing breast-conserving surgery require second procedures to achieve negative margins. This study evaluated the adjunctive use of the MarginProbe device (Dune Medical Devices Ltd, Caesarea, Israel) in providing real-time intraoperative assessment of lumpectomy margins. METHODS: This multicenter randomized trial enrolled patients with nonpalpable breast malignancies. The study evaluated MarginProbe use in addition to standard intraoperative methods for margin assessment. After specimen removal and inspection, patients were randomized to device or control arms. In the device arm, MarginProbe was used to examine the main lumpectomy specimens and direct additional excision of positive margins. Intraoperative imaging was used in both arms; no intraoperative pathology assessment was permitted. RESULTS: In total, 596 patients were enrolled. False-negative rates were 24.8 and 66.1 % and false-positive rates were 53.6 and 16.6 % in the device and control arms, respectively. All positive margins on positive main specimens were resected in 62 % (101 of 163) of cases in the device arm, versus 22 % (33 of 147) in the control arm (p < 0.001). A total of 19.8 % (59 of 298) of patients in the device arm underwent a reexcision procedure compared with 25.8 % (77 of 298) in the control arm (6 % absolute, 23 % relative reduction). The difference in tissue volume removed was not significant. CONCLUSIONS: Adjunctive use of the MarginProbe device during breast-conserving surgery improved surgeons' ability to identify and resect positive lumpectomy margins in the absence of intraoperative pathology assessment, reducing the number of patients requiring reexcision. MarginProbe may aid performance of breast-conserving surgery by reducing the burden of reexcision procedures for patients and the health care system.

Background: Epigenetic regulatory pathways are intensely studied for their involvement in breast tumorigenesis, however little is currently known about the genetic variation in epigenome components contributing to the risk and/or prognosis of breast cancer. In this study we have tested how the novel germline genetic signatures identified in epigenetic regulatory genes (ERGs) may potentially contribute to clinical prediction of breast cancer risk. Methods: We have genotyped 711 SNPs tagging 87 ERGs in 1985 breast cancer cases and 1609 controls, using Sequenom i-Plex. The samples were of white European origin with the fraction of Ashkenazi Jewish (AJ) ancestry (n=1642). The association of SNPs with breast cancer risk was assessed using logistic regression, adjusted by age, AJ status and estrogen-receptor (ER) status. The predictive ability of SNP signatures was tested by ROC curves using logistic regression fitting the SNP/clinical covariate models, and the area under the curve (AUC) was used to assess their utility in the classification of breast cancer risk. Results: We have identified the signature of 20 SNPs tagging 13 ERGs, significantly associated with breast cancer risk. The strongest association has been observed for RUNX1 (rs7280097, OR=0.83, CI 95%: 0.71-0.94, p=0.006) and PRDM16 (rs12135987, OR=1.22, CI 95%: 1.06-1.42, p=0.007). The inclusion of predictor variables (age, AJ status, ER status) and 20 associated SNPs in logistic regression ROC curve analysis yielded in best fitting model involving 10 SNPs tagging 8 ERGs with AUC of 0.723, compared to 0.660 with predictor variables alone (p=0.003). Conclusions: We have identified a signature of 20 SNPs in epigenetic regulatory genes (20-SNP-ERG) significantly associated with breast cancer risk. In addition, the incorporation of 10 SNPs from 20-SNP-ERG into risk prediction model increases the ability to classify breast cancer risk in addition to other clinical and demographic covariates. The results suggest the promising clinical potential!