Lorraine Tafra

Multicenter Trial of Sentinel Node Biopsy for Breast Cancer Using Both Technetium Sulfur Colloid and Isosulfan Blue Dye

ObjectiveTo determine the factors associated with false-negative results on sentinel node biopsy and sentinel node localization (identification rate) in patients with breast cancer enrolled in a multicenter trial using a combination technique of isosulfan blue with technetium sulfur colloid (Tc99). Summary Background DataSentinel node biopsy is a diagnostic test used to detect breast cancer metastases. To test the reliability of this method, a complete lymph node dissection must be performed to determine the false-negative rate. Single-institution series have reported excellent results, although one multicenter trial reported a false-negative rate as high as 29% using radioisotope alone. A multicenter trial was initiated to test combined use of Tc99 and isosulfan blue. MethodsInvestigators (both private-practice and academic surgeons) were recruited after attending a course on the technique of sentinel node biopsy. No investigator participated in a learning trial before entering patients. Tc99 and isosulfan blue were injected into the peritumoral region. ResultsFive hundred twenty-nine patients underwent 535 sentinel node biopsy procedures for an overall identification rate in finding a sentinel node of 87% and a false-negative rate of 13%. The identification rate increased and the false-negative rate decreased to 90% and 4.3%, respectively, after investigators had performed more than 30 cases. Univariate analysis of tumor showed the poorest success rate with older patients and inexperienced surgeons. Multivariate analysis identified both age and experience as independent predictors of failure. However, with older patients, inexperienced surgeons, and patients with five or more metastatic axillary nodes, the false-negative rate was consistently greater. ConclusionsThis multicenter trial, from both private practice and academic institutions, is an excellent indicator of the general utility of sentinel node biopsy. It establishes the factors that play an important role (patient age, surgical experience, tumor location) and those that are irrelevant (prior surgery, tumor size, Tc99 timing). This widens the applicability of the technique and identifies factors that require further investigation.

High-Resolution Fluorodeoxyglucose Positron Emission Tomography with Compression (“Positron Emission Mammography”) is Highly Accurate in Depicting Primary Breast Cancer

Abstract:  We sought to prospectively assess the diagnostic performance of a high‐resolution positron emission tomography (PET) scanner using mild breast compression (positron emission mammography [PEM]). Data were collected on concomitant medical conditions to assess potential confounding factors. At four centers, 94 consecutive women with known breast cancer or suspicious breast lesions received 18F‐fluorodeoxyglucose (FDG) intravenously, followed by PEM scans. Readers were provided clinical histories and x‐ray mammograms (when available). After excluding inevaluable cases and two cases of lymphoma, PEM readings were correlated with histopathology for 92 lesions in 77 women: 77 index lesions (42 malignant), 3 ipsilateral lesions (3 malignant), and 12 contralateral lesions (3 malignant). Of 48 cancers, 16 (33%) were clinically evident; 11 (23%) were ductal carcinoma in situ (DCIS), and 37 (77%) were invasive (30 ductal, 4 lobular, and 3 mixed; median size 21 mm). PEM depicted 10 of 11 (91%) DCIS and 33 of 37 (89%) invasive cancers. PEM was positive in 1 of 2 T1a tumors, 4 of 6 T1b tumors, 7 of 7 T1c tumors, and 4 of 4 cases where tumor size was not available (e.g., no surgical follow‐up). PEM sensitivity for detecting cancer was 90%, specificity 86%, positive predictive value (PPV) 88%, negative predictive value (NPV) 88%, accuracy 88%, and area under the receiver‐operating characteristic curve (Az) 0.918. In three patients, cancer foci were identified only on PEM, significantly changing patient management. Excluding eight diabetic subjects and eight subjects whose lesions were characterized as clearly benign with conventional imaging, PEM sensitivity was 91%, specificity 93%, PPV 95%, NPV 88%, accuracy 92%, and Az 0.949 when interpreted with mammographic and clinical findings. FDG PEM has high diagnostic accuracy for breast lesions, including DCIS. 

Preoperative chemotherapy and sentinel lymphadenectomy for breast cancer

BACKGROUND Sentinel lymphadenectomy (SL) for breast cancer is becoming the standard of care for selected patients treated by experienced surgeons. One of the few contraindications for performing SL alone is prior chemotherapy (PC). There are, however, no data to support that PC interferes with the ability of the sentinel node to predict the presence of disease in the remaining axillary lymph nodes. The goal of this study was to determine the effect of PC on patients undergoing SL for breast cancer. METHODS A multicenter trial was organized in 1997 to evaluate the diagnostic accuracy of SL in patients with breast cancer. Investigators were recruited after attending a course on the technique of SL. Technetium-99 and isosulfan blue were injected into the peritumor region and a gamma probe was used to aid identification of the sentinel nodes. The only exclusion criteria for entrance into the trial were palpable or suspicious axillary lymph nodes. A total of 968 patients were enrolled in the trial. Twenty-nine patients were treated with PC and compared with 939 patients not receiving PC. RESULTS The overall, sentinel node identification rate for the PC patients was 93% (27 of 29) compared with 88% (822 of 939) for patients not treated with PC. There were no false negatives in those patients receiving PC compared with a 13% (25 of 193) false negative rate in those patients not receiving PC. The mean tumor size was 1.4 cm for the PC group and 0.6 cm for the remaining patients (P <0.005). The mean number of sentinel nodes found was 2.0 for the non-PC group and 2.5 for the PC group (not significant). As expected, a higher proportion of patients had positive axillary nodes in the PC group (52%, 15 of 29) compared with the remaining patients (21%, 200 of 939). CONCLUSION In this small group of patients, PC did not adversely impact the false negative or identification rate. Most patients receiving chemotherapy have larger tumors and a higher chance of harboring metastatic disease but a significant group of these patients (48%) without metastases can potentially be spared an axillary node dissection.

Prognostic Implications of Isolated Tumor Cells and Micrometastases in Sentinel Nodes of Patients with Invasive Breast Cancer: 10-Year Analysis of Patients Enrolled in the Prospective East Carolina University/Anne Arundel Medical Center Sentinel Node Multicenter Study

BACKGROUND Sentinel lymph node biopsy (SLNB) is a more sensitive and accurate nodal staging procedure than axillary lymph node dissection (ALND). Because of increased pathologic evaluation in the sentinel node era, more nodal micrometastases (MIC) (> 0.2 mm to 2 mm) and isolated tumor cells (ITC; < or = 0.2 mm) have been identified. We present the 10-year analysis of our prospective SLN study, focusing on regional axillary node status and distant metastases in patients with nodal ITC and MIC. STUDY DESIGN From 1996 to 2005, breast cancer patients were enrolled in an Institutional Review Board-approved, multicenter study. SLNs were examined at multiple levels by hematoxylin and eosin; most (85%) hematoxylin and eosin-negative SLNs were also examined by cytokeratin immunohistochemistry. Data from 1,259 patients with invasive breast cancer and in whom an SLN was found were reviewed for this analysis. RESULTS Of the 1,259 patients, 893 (71%) had negative SLNs, 25 (2%) had ITCs, 57 (5%) had MIC, and 284 (23%) had positive SLNs. None of the 13 patients with ITCs who underwent an ALND had additional positive nodes, compared with 27% (11 of 41) of patients with MIC. At a mean followup of 4.9 years, the distant recurrence rates for SLN-negative, ITC, MIC, and SLN-positive groups were 6%, 8%, 14%, and 21%, respectively. The presence of MIC in the SLN was associated with a significantly shorter disease-free interval than was SLN negativity (p < 0.02 by Cox regression model). CONCLUSIONS This prospective breast cancer study found that sentinel node MIC, but not ITCs, were associated with additional positive nodes and with distant recurrence. These data suggest that ALND may be unnecessary in patients with ITCs. But ALND and more aggressive adjuvant therapy should be considered in patients with SLN micrometastases.

Identification and Characterization of Optimal Gene Expression Markers for Detection of Breast Cancer Metastasis

Sentinel lymph node (SLN) status is highly predictive of overall axillary lymph node involvement in breast cancer. Historically, SLN-positive patients have undergone axillary lymph node dissection in a second surgery. Intraoperative SLN analysis could reduce the cost and complications of a second surgery; however, existing histopathological methods lack standardization and exhibit poor sensitivity. Rapid molecular methods may lead to improved intraoperative diagnosis of SLN metastasis. In this study, we used a genome-wide gene expression analysis of breast and other tissues to identify seven putative markers for detecting breast cancer metastasis. We assessed the utility of these markers for identifying clinically actionable metastases in lymph nodes through reverse transcriptase-polymerase chain reaction analysis of SLNs from 254 breast cancer patients. Polymerase chain reaction signals were compared to pathology on a per-patient basis. The optimal two-gene combination, mammaglobin and cytokeratin 19, detected clinically actionable metastasis in breast SLNs with 90% sensitivity and 94% specificity. Application of stringent criteria for identifying presumptive hematoxylin- and eosin-positive samples increased sensitivity and specificity to 91 and 97%, respectively. This study represents the first comprehensive demonstration of the utility of gene expression markers for detecting clinically actionable breast metastases. An intraoperative molecular assay using these markers has the potential to significantly reduce second surgeries for patients undergoing SLN dissection.

Credentialing issues with sentinel lymph node staging for breast cancer

Sentinel lymphadenectomy (SL) is a minimally invasive approach for staging patients with breast cancer. SL, when performed in lieu of axillary dissection, is associated with less morbidity and is potentially more cost effective and more accurate than the historical axillary dissection in the detection of regional nodal metastases. The credentialing and privileging of SL, as with any surgical procedure, is by the policies of the local hospital or institution. The suggested credentialing criteria for local hospitals has been an area of controversy. Herein the authors outline the credentialing controversy and suggest criteria for the implementation of sentinel lymph node staging for breast cancer.

Pilot trial of cryoprobe-assisted breast-conserving surgery for small ultrasound-visible cancers

Background: Stereotactic and ultrasonography-guided large core needle biopsy has replaced wire localization biopsy as the diagnostic method of choice. Lumpectomy alternatives are being sought to eliminate the need for preoperative wire localization, to facilitate easier and more accurate resection, and to decrease positive margin rates. Cryoprobe-assisted lumpectomy (CAL) was investigated as an alternative.Methods: Patients with ultrasonographically visible breast cancers that otherwise would have required wire localization participated. Before lumpectomy, a cryoprobe (Visica; Sanarus, Pleasanton, CA) was inserted through a 3-mm skin incision and directed by ultrasonography through the center of the tumor. An ice ball was created that enveloped the tumor plus an adjacent 5–10 mm of sonographically normal breast tissue.Results: Twenty-four CAL procedures were performed and all lesions were successfully localized. Mean (±SD) tumor size was 1.2 ± .4 cm (range, .7–2.0 cm). Mean dimensions of the ice ball before excision were 3.9 ± .3 cm by 2.5 ± .5 cm, and the ice margin around the tumor was 8 ± 2 mm. The size of the ice ball was controlled to the millimeter, and the ice ball itself provided a precise template around which to dissect. The margin re-excision rate was 5.6% among patients with an ice margin greater than 6 mm.Conclusions: CAL is a superior alternative to wire localization. Ultrasonographic visualization of the ice ball allows the size of the margin and tissue resected to be individually tailored and accurate within millimeters. The created template allows a precise lumpectomy, adding a dimension of control not previously realized with any other technology.

Does Breast Tumor Heterogeneity Necessitate Further Immunohistochemical Staining on Surgical Specimens

BACKGROUND Prognostic and predictive tumor markers in breast cancer are most commonly performed on core needle biopsies (CNB) of the primary tumor. Because treatment recommendations are influenced by these markers, it is imperative to verify strong concordance between tumor markers on CNB specimens and the corresponding surgical specimens (SS). STUDY DESIGN A prospective study was performed on 165 women (205 samples) with breast cancer diagnosed from January 2009 to July 2011. Tumor type, grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2), and Ki67 expression by immunohistochemical (IHC) testing were retrospectively analyzed in the CNB and SS. Contingency tables and agreement modeling were performed. RESULTS There was substantial agreement between the CNB and SS for PR% and HER2; moderate agreement for tumor type, grade, and ER%; and fair agreement for Ki67%. In 8% of patients (n = 13), tumor heterogeneity was seen. In heterogeneous tumors the overall concordance between the CNB and SS was worse, especially for HER2. Six of these patients had areas of tumor that were positive for HER2, which were not detected in their CNBs. Nine patients had multiple distinct molecular subtypes within their tumor(s). CONCLUSIONS The heterogeneous distribution of antigens in breast cancer tumors raises concern that the CNB may not adequately represent the true biologic profile in all patients. There is strong concordance for tumor type, ER, and PR between CNB and SS (although a quantitative decline was noted from CNB to SS); however, HER2 activity does not appear to be adequately detected on CNB in patients with heterogeneous tumors. These data suggest that IHC testing on the CNB alone may not be adequate to tailor targeted therapy in all patients.

The details of successful sentinel lymph node staging for breast cancer.

Sentinel lymphadenectomy is an effective and accurate tool for staging breast cancer. In recent years the details of a successful program have become better defined. The authors outline practical considerations for the performance of successful sentinel lymph node staging from a multidisciplinary perspective.

Positron Emission Tomography (PET) and Mammography (PEM) for breast cancer: importance to surgeons.

The unique aspect of positron emission tomography (PET) is the ability of the image to represent the physiology or metabolism of the area of interest as opposed to just its anatomic appearance. Malignancies frequently function at a higher metabolic rate than normal tissue and therefore concentrate [F-18]fluorodeoxyglucose (FDG, the most commonly used intravenous agent) to a higher degree than normal tissue. Use of PET for the evaluation of breast cancer was initiated with a study published in 1989 evaluating 17 breast cancer patients with advanced disease. The patients primary tumors (all greater than 5 cm), axillary, liver, and bone metastases were well-visualized, and this spawned a series of studies to determine the usefulness of this technology in patients at various stages of disease. The initial trials were limited, secondary to selection bias (patients chosen with large tumors and advanced disease), and only in more recent studies has the actual accuracy of PET for the evaluation of breast disease been determined. Fifteen years of evaluation has shown that most of its usefulness rests in the evaluation of patients with either an advanced breast cancer and/or those presenting with a recurrent breast cancer. As of October 1, 2002, the Centers for Medicare and Medicaid Services approved FDG PET for the staging of patients with distant disease, restaging for patients with locoregional recurrence or metastases, and for monitoring therapy. Although it has not been specifically approved for the initial diagnosis of breast cancer or for staging the axilla, it can be useful in patients with an advanced primary. Although the sensitivity of whole-body PET is not very high, it is quite specific for the detection of metastatic disease. This has made the technology useful in patients with poor prognostic findings, such as numerous involved lymph nodes or local regional recurrence. The few number of false positives are secondary to inflammation, and infrequently, fibrocystic change and lactation. Despite the limited sensitivity, PET is important, as it better enables surgeons to tailor surgical management of these advanced disease patients who frequently have to balance aggressive treatment with limited survival and quality of life. The development of newer technology that allows imaging specifically isolated to the breast, now referred to as positron emission mammography (PEM), has also been introduced. This technology has the potential for resolution down to 1.8 mm and had its origins in a device known as a microPET (a small animal PET scanner used for oncology research). PEM is now being investigated in clinical trials at a number of sites to determine its sensitivity and specificity, and initial results are discussed below. A summary of the various aspects of PET imaging important for the surgeon caring for patients with breast disease is presented in this review. The specific topics will focus on 1) the technique of PET and use of SUVs (peak standard uptake values); 2) patients with newly diagnosed primary breast cancer; 3) newly diagnosed patients with advanced tumors or those receiving neoadjuvant chemotherapy; and 4) breast cancer patients presenting with a local or distant recurrence. Table 1 is an overview of recommendations for each clinical setting. The final discussions will include PEM imaging, and a review of the very Received August 1, 2005; accepted May 1, 2006; published online October 25, 2006. Address correspondence and reprint requests to: Lorraine Tafra, MD; E-mail: ltafra@aahs.org