Intraoperative Injection of Technetium-99m Sulfur Colloid for Sentinel Lymph Node Biopsy in Breast Cancer Patients: A Single Institution Experience.

Background. Most institutions require a patient undergoing sentinel lymph node biopsy to go through nuclear medicine prior to surgery to be injected with radioisotope. This study describes the long-term results using intraoperative injection of radioisotope. Methods. Since late 2002, all patients undergoing a sentinel lymph node biopsy at the Yale-New Haven Breast Center underwent intraoperative injection of technetium-99m sulfur colloid. Endpoints included number of sentinel and nonsentinel lymph nodes obtained and number of positive sentinel and nonsentinel lymph nodes. Results. At least one sentinel lymph node was obtained in 2,333 out of 2,338 cases of sentinel node biopsy for an identification rate of 99.8%. The median number of sentinel nodes found was 2 and the mean was 2.33 (range: 1-15). There were 512 cases (21.9%) in which a sentinel node was positive for metastatic carcinoma. Of the patients with a positive sentinel lymph node who underwent axillary dissection, there were 242 cases (54.2%) with no additional positive nonsentinel lymph nodes. Advantages of intraoperative injection included increased comfort for the patient and simplification of scheduling. There were no radiation related complications. Conclusion. Intraoperative injection of technetium-99m sulfur colloid is convenient, effective, safe, and comfortable for the patient.

A PHASE II TRIAL OF BALLOON-CATHETER PARTIAL BREAST BRACHYTHERAPY OPTIMIZATION IN THE TREATMENT OF STAGE 0, I AND IIA BREAST CARCINOMA.

OBJECTIVES: (a) To prospectively determine if multidwell position dose delivery can decrease skin dose and resultant toxicity over single dwell balloon-catheter partial breast irradiation, and (b) to evaluate whether specific skin parameters could be safely used instead of skin-balloon distance alone for predicting toxicity and treatment eligibility. METHODS: A single-arm phase II study using a Simon two-stage design was performed on 28 women with stage 0-II breast cancer. All patients were treated with multiple dwell position balloon-catheter brachytherapy. The primary endpoint was ≥ grade 2 skin toxicity. Initial entry required a balloon-skin distance ≥ 7 mm. Based on the toxicity in the first 16 patients, additional patients were treated irrespective of skin-balloon distance as long as the Dmax to 1 mm skin thickness was < 130%. RESULTS: Compared to the phantom single dwell plans, multidwell planning yielded superior PTV coverage as per median V90, V95 and V100, but had slightly worse V150, V200 and DHI. Dmax to skin was decreased by multidwell planning at multiple skin thicknesses. The most common acute toxicity was grade 1 erythema (57%), and only two patients (7%) developed acute grade 2 toxicity (erythema). Late grade 1 fibrosis was seen in 32%. No patients experienced grade 3, 4, or 5 toxicity. CONCLUSIONS: Multidwell position planning for balloon-catheter brachytherapy results in lower skin doses with equal to superior PTV coverage and an overall low rate of initial skin toxicity. Our data suggest that limiting the Dmax to < 130% to 1 mm thick skin is achievable and results in minimal toxicity.

Is the use of preoperative breast MRI predictive of mastectomy?

BACKGROUND: Several recent studies have described increasing rates of unilateral and bilateral mastectomy among women with newly diagnosed breast cancer. The use of breast magnetic resonance imaging (MRI) has also risen rapidly, leading to speculation that the high false-positive rate and need for multiple biopsies associated with MRI may contribute to more mastectomies. The objective of this study was to determine whether newly diagnosed patients who underwent preoperative MRI were more likely to undergo mastectomy compared with those who did not have a preoperative MRI. METHODS: A retrospective review was performed of all newly diagnosed patients with breast cancer at our academic breast center from 2004 to 2009. RESULTS: The proportion of newly diagnosed patients with breast cancer having MRI prior to surgery increased from 6% in 2004 to 73% in 2009. Of 628 patients who underwent diagnostic MRI, 369 (59%) had abnormal results, 257 (41%) had one or more biopsies, and 73 had additional sites of cancer diagnosed. Patients with a malignant biopsy, or those with an abnormal MRI who did not undergo biopsy, had an increased mastectomy rate (P<0.01). However, patients with a normal MRI or a benign biopsy actually had a decreased mastectomy rate (P<0.05). Although there was a trend toward more bilateral mastectomies, the overall mastectomy rate did not change over this time period. CONCLUSIONS: Although there is a strong relationship between the result of an MRI and the choice of surgery, the overall effect is not always to increase the mastectomy rate. Some patients who were initially considering mastectomy chose lumpectomy after an MRI.

What do breast surgeons do?

BACKGROUND: There are an increasing number of fellowship-trained breast surgeons and surgical oncologists who dedicate their clinical practice exclusively to breast disease. However, there are little published data regarding characteristics of a breast surgical practice. METHODS: All patient visits at a university-based breast surgery practice were reviewed for calendar years 2006 and 2007. RESULTS: There were 10,381 patient visits, of which 2,334 (22%) represented new patients. Of these, 11% were referred with a diagnosis of cancer. Out of the remainder, 29% had a needle biopsy (8% by the surgeon and 21% by radiology), 29% underwent surgery, and 13% were ultimately diagnosed with cancer. After completion of initial therapy, 6 months or 1 year follow-up was recommended for 59% of the patients. CONCLUSIONS: The specialty of breast surgery is unique in its nonoperative volume and extensive duration of follow-up. Strategies need to be designed to make this process more time-efficient for the surgeon.

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.

Preoperative chemotherapy decreases the need for re-excision of breast cancers between 2 and 4 cm diameter.

INTRODUCTION: It is accepted that preoperative chemotherapy can result in increased breast preservation for breast cancers greater than 4 cm. The benefits of preoperative chemotherapy are less clear, however, for patients who present with smaller tumors and are already candidates for breast-preserving surgery. The goal of this study is to assess the effect of preoperative chemotherapy on breast cancers between 2 and 4 cm diameter. METHODS: A retrospective chart review was conducted of patients diagnosed with new breast cancer at the Yale-New Haven Breast Center for the years 2002-2007. Patients were included in the study if their breast cancer was between 2 and 4 cm and their initial surgical treatment had been completed. Patients with distant metastases were excluded. RESULTS: There were 156 new cancers that met study requirements. Forty-seven patients underwent preoperative chemotherapy, and 109 patients had their surgery first, usually followed by chemotherapy. Initial surgery was lumpectomy for 31 out of 47 patients (66%) in the preoperative chemotherapy group compared with 62 out of 109 patients (57%) in the surgery group. For patients with lumpectomies, 2 out of 31 patients (6%) in the preoperative group had positive margins and required re-excision compared with 20 out of 62 patients (37%) in the surgery-first group (P<0.01). CONCLUSIONS: We conclude that, for tumors between 2 and 4 cm, preoperative chemotherapy is associated with a significantly decreased rate of re-excision following lumpectomy. This not only results in fewer mastectomies, but also avoids the morbidity and inferior cosmetic results associated with a re-excision lumpectomy.

Breast sentinel lymph node dissection before preoperative chemotherapy.

HYPOTHESIS: Timing of sentinel lymph node dissection (SLND), before or after preoperative chemotherapy (PC), for breast cancer is controversial. DESIGN: Single-institution experience with SLND before PC. SETTING: Data from prospectively collected Yale-New Haven Breast Center Database. PATIENTS: Fifty-five SLNDs were performed before PC for invasive breast cancer in clinically node-negative patients between October 1, 2003, and September 30, 2007. The results are compared with patients who underwent SLND and definitive breast and axillary surgery before chemotherapy (control group; n = 463 SLNDs). INTERVENTIONS: If sentinel nodes (SNs) were negative before PC, no axillary lymph node dissection (ALND) was performed. If SNs were positive, ALND was performed after PC at the time of definitive breast surgery. MAIN OUTCOME MEASURES: Sentinel node identification rate, false-negative rate, rate of positivity, and rate of residual disease in axilla. RESULTS: Of the 55 SLNDs performed before PC, 30 (55%) had a positive SN. The SN identification rate was 100% and the clinical false-negative rate was 0%. In the control group of those with a positive SN, 55% (56 of 101 patients) had no additional positive nodes, 25% (25 of 101) had 1 to 3 positive nodes, and 20% (20 of 101) had 4 or more positive nodes. In the group with a positive SN before PC, 69% (18 of 26 patients) had no additional positive nodes after PC, 27% (7 of 26) had 1 to 3 nodes, and 4% (1 of 26) had 4 or more nodes. Among the SN-positive patients, a pathologic complete response in the breast was found in 4 of 18 patients who had a tumor-free axilla after PC. CONCLUSIONS: Sentinel lymph node dissection before PC allows accurate staging of the axilla for prognosis and treatment decisions. Despite downstaging by PC, a significant percentage of patients had residual nodal disease in the axillary dissection.

Breast tattoos for planning surgery following neoadjuvant chemotherapy.

BACKGROUND: Although neoadjuvant chemotherapy is increasingly used for breast cancer, if a patient has a complete clinical response, it is often difficult for the surgeon to know exactly where and how much breast tissue to remove. METHODS: A method is described where the edges of the tumor are tattooed prior to chemotherapy, allowing all tissue initially involved with tumor to be resected following the chemotherapy. RESULTS: Thirty-four cases have been tattooed prior to neoadjuvant chemotherapy, and the clinical and pathological complete response rates were 56% and 22%, respectively. The tattoos allowed very accurate localization of the residual tumor location and extent. Of the 22 patients who have so far undergone lumpectomy, 77% had residual pathologic evidence of tumor, but the margins were negative in 91% at the first operation. Only 2 patients had to undergo a mastectomy because of persistently positive margins. CONCLUSIONS: The technique of breast tattooing is a simple and practical method to guide the extent of breast surgery following neoadjuvant chemotherapy. In contrast to placement of clips, the technique does not require needle localization, and it allows accurate determination of the initial tumor size and margins.

Manipulation of the primary breast tumor and the incidence of sentinel node metastases from invasive breast cancer.

HYPOTHESIS: The incidence of sentinel node (SN) metastases from invasive breast cancer might be affected by the technique used to obtain biopsy specimens from the primary tumor before sentinel lymph node dissection. DESIGN: Prospective database study. SETTING: The John Wayne Cancer Institute. PATIENTS AND METHODS: We identified 663 patients with biopsy-proven invasive breast cancer who underwent sentinel lymph node dissection between January 1, 1995, and April 30, 1999. Patients were divided into 3 groups based on type of biopsy: fine-needle aspiration (FNA), large-gauge needle core, and excisional. A logistic regression model was used to correlate tumor size, tumor grade, and type of biopsy with the incidence of SN metastases. RESULTS: Of the 676 cancers, 126 were biopsied by FNA, 227 by large-gauge needle core biopsy, and 323 by excisional biopsy before sentinel lymph node dissection. Mean patient age was 58 years (range, 28-96 years), and mean tumor size was 1.85 cm (range, 0.1-9.0 cm). In multivariate analysis based on known prognostic factors, the incidence of SN metastases was higher in patients whose cancer was diagnosed by FNA (odds ratio, 1.531; 95% confidence interval, 0.973-2.406; P =.07, Wald test) or large-gauge needle core biopsy (odds ratio, 1.484; 95% confidence interval, 1.018-2.164; P =.04, Wald test) than by excision. Tumor size (P<.001) and grade (P =.06) also were significant prognostic factors. CONCLUSIONS: Manipulation of an intact tumor by FNA or large-gauge needle core biopsy is associated with an increase in the incidence of SN metastases, perhaps due in part to the mechanical disruption of the tumor by the needle. The clinical significance of this phenomenon is unclear.

Axillary dissection is not required for all patients with breast cancer and positive sentinel nodes.

HYPOTHESIS: Sentinel node (SN) biopsy for breast cancer enhances staging sensitivity, often demonstrating only micrometastases (<2 mm) or isolated, keratin-positive cells. When SN metastasis is present, the value of additional axillary dissection is unclear and not all patients benefit from axillary lymph node dissection (ALND). DESIGN: Prospective cohort study, median 32-month follow-up. SETTING: Multidisciplinary breast cancer centers. PATIENTS: Forty-six women having SN metastases diagnosed between May 1, 1996, and September 1, 2001, who refused ALND or were recommended to omit ALND owing to serious comorbid conditions. INTERVENTIONS: Isosulfan blue dye-directed SN biopsy. Axillary lymph node dissection was not performed. Standard breast irradiation was given. Adjuvant systemic therapy was provided as determined by an oncologist. Interval clinical evaluation was performed. MAIN OUTCOME MEASURE: Axillary and systemic failure rates. RESULTS: Mean patient age was 61.6 years (age range, 36-92 years). Mean tumor size was 1.65 cm (range, 0.4-5.5 cm). Thirty-five (76%) of 46 tumors were ductal carcinomas and 39 (87%) of 45 were estrogen receptor-positive. A mean of 2.6 SNs were identified (median, 2; range, 1-7). Thirty-nine patients (85%) had a single positive SN; the remaining 7 patients (15%) had 2 positive SNs. Seven patients (15%) had macrometastases (>2 mm); 16 (35%) had micrometastases (<2 mm); and 23 (50%) had cellular metastases. Only 16 positive SNs (35%) were seen on hematoxylin-eosin staining, while 30 SNs (65%) had positive immunohistochemical staining. There have been no axillary recurrences. One patient (2%) developed distant metastases during follow-up (range, 4-61 months). CONCLUSIONS: Patients with SN metastases who did not have ALND had a low incidence of regional failure. To confirm this observation, we suggest that patients with SN metastases are ideal candidates for trials evaluating the necessity of ALND.

The time has come to change the algorithm for the surgical management of early breast cancer.

HYPOTHESIS: If the sentinel lymph nodes (SNs) draining a primary invasive breast cancer are free of tumor, then axillary lymph node dissection is not necessary for management of disease. DESIGN AND INTERVENTION: In July 2000, we reported our initial experience of a small cohort of patients who underwent axillary lymph node dissection only if their SNs were involved with metastases. We now report outcome data for all patients who underwent breast conservation and sentinel lymph node dissection without completion axillary lymph node dissection between October 1, 1995, and April 30, 1999. SETTING: Tertiary breast referral center. PATIENTS: Two hundred thirty-eight patients whose SN staining results were negative for tumor by both hematoxylin-eosin and imunohistochemical stains. Median age was 58.4 years. Most patients (85%) had a T1 tumor; 15% had a T2 tumor. Most (86%) had infiltrating ductal carcinoma with or without extensive ductal carcinoma in situ; 10% had invasive lobular cancer. RESULTS: At a median follow-up of 38.9 months (range, 6-69 months), we found no axillary recurrences, and 98.3% of patients are alive without evidence of disease. Three patients have died of causes not related to breast cancer. Four patients are alive with metastatic disease but have not developed axillary recurrences. CONCLUSIONS: Sentinel lymph node dissection is a safe and efficacious treatment option for patients with early breast cancer. It provides excellent regional control and is associated with excellent survival. A multicenter trial such as the American College of Surgeons Oncology Group Z0010 is needed to corroborate findings of this single-institution study.

Tumor characteristics predictive of sentinel node metastases in 105 consecutive patients with invasive lobular carcinoma.

BACKGROUND: Identification of nodal metastases in invasive lobular carcinoma (ILC) is difficult. Sentinel node (SN) biopsy offers a potential advantage. This study reports the feasibility of SN identification and predictors of SN metastases for ILC. METHODS: All cases of ILC undergoing sentinel lymphadenectomy between October 1991 and May 2001 were evaluated. Patients enrolled in ACOSOG Z0010/Z0011 were excluded. Presentation, surgical treatment, tumor characteristics, and prognostic factors were analyzed for statistical significance. RESULTS: SN mapping was performed in 105 patients with 106 cases of ILC. SN identification was 97%, accuracy 100%, and positivity 50% with 45% macrometastases, 16% micrometastases, and 39% immunometastases. There are no axillary recurrences at 43.73 months. Palpable tumor, increasing tumor size, and angiolymphatic invasion are statistically significant for SN-positive status. CONCLUSIONS: SN staging for ILC is feasible and accurate. Receptor status and proliferative indices are not useful markers for metastases. However, large tumor size and presence of angiolymphatic invasion are positive predictors.

Prevention and treatment of breast cancer by suppressing aromatase activity and expression.

Estrogen promotes the proliferation of breast cancer cells. Aromatase is the enzyme that converts androgen to estrogen. In tumors, expression of aromatase is upregulated compared to that of surrounding noncancerous tissue. Tumor aromatase is thought to stimulate breast cancer growth in both an autocrine and a paracrine manner. A treatment strategy for breast cancer is to abolish in situ estrogen formation with aromatase inhibitors. In addition, aromatase suppression in postmenapausal women is being evaluated as a potential chemopreventive modality against breast cancer. One area of aromatase research in this laboratory is the identification of foods and dietary compounds that can suppress aromatase activity. In vitro and in vivo studies have found that grapes and mushrooms contain chemicals that can inhibit aromatase. Therefore, a diet that includes grapes and mushrooms would be considered preventative against breast cancer. Another area of our aromatase research is the elucidation of the regulatory mechanism of aromatase expression in breast cancer tissue. Increased aromatase expression in breast tumors is attributed to changes in the transcriptional control of aromatase expression. Whereas promoter I.4 is the main promoter that controls aromatase expression in noncancerous breast tissue, promoters II and I.3 are the dominant promoters that drive aromatase expression in breast cancer tissue. Our recent gene regulation studies revealed that in cancerous versus normal tissue, several positive regulatory proteins (e.g., nuclear receptors and CREB1) are present at higher levels and several negative regulatory proteins (e.g., snail and slug proteins) are present at lower levels. This may explain why the activity of promoters II and I.3 is upregulated in cancerous tissue. In addition, our in vitro transcription/translation analysis using plasmids containing T7 promoter and the human snail gene as a reporter capped with different untranslated exon Is revealed that exon PII-containing transcripts were translated more effectively than were exon I.3-containing transcripts. An understanding of the molecular mechanisms of aromatase expression between noncancerous and cancerous breast tissue, at both transcriptional and translational levels, may help in the design of a therapy based on suppressing aromatase expression in breast cancer tissue.