Influence of isolated tumor cells in sentinel nodes on outcome in small, node-negative (pT1N0M0) breast cancer.

PURPOSE: To evaluate the prognostic significance of isolated tumor cells found on sentinel node biopsy. METHODS: The study is based on a prospectively followed up cohort of 1,865 consecutive patients diagnosed with pT1 (tumor size

Outcome of selected breast cancer patients with micrometastasis or isolated tumor cells in sentinel node biopsy and no completion axillary lymph node dissection.

BACKGROUND AND OBJECTIVES: Axillary lymph node dissection (ALND) is the standard of care in patients with tumor-positive sentinel nodes (SN). However, approximately half of these patients do not have additional metastases in their axilla and therefore do not benefit from completion ALND. Our aim was to examine the outcome of highly selected breast cancer patients with tumor-positive SN without completion ALND. METHODS: Altogether 48 patients with tumor-positive SN without ALND were included in this study. Twenty-two patients had micrometastasis and 26 had isolated tumor cells (ITC) in their sentinel node biopsy. The median follow-up time was 37 months (range 9-78). RESULTS: No axillary recurrences occurred during the follow-up. One patient had a local recurrence. Distant metastases as the first event were observed in two patients. One of them died in breast cancer. Nine patients died from intercurrent causes. CONCLUSIONS: Omitting ALND seems safe in selected breast cancer patients with SN micrometastasis or ITC.

Safety of sentinel node biopsy in breast cancer patients who receive a second radioisotope injection after visualization failure in lymphoscintigraphy.

BACKGROUND AND OBJECTIVES: A failure to visualize axillary sentinel nodes in lymphoscintigraphy may lead to an unsuccessful sentinel node biopsy (SNB) and subsequent axillary lymph node dissection (ALND). To avoid unnecessary ALND, a second radioisotope injection may be given but has been considered hazardous. We investigated the axillary recurrence rate after tumor-negative SNB in breast cancer patients who received a second tracer injection after axillary visualization failure in lymphoscintigraphy. METHODS: Altogether 1,309 breast cancer patients who underwent a tumor-negative SNB without an ALND were included. Two hundred seven (15.8%) patients received a second tracer injection due to visualization failure in lymphoscintigraphy and 1,102 (84.2%) did not. All patients received a blue dye injection prior to the SNB. The median follow-up time was 43 months. RESULTS: No isolated cancer recurrences were diagnosed in the ipsilateral axilla among patients who received two radioisotope injections. Disease-free survival and overall survival were similar among patients with one or two radioisotope injections (P = 0.122 and P = 0.200, respectively). CONCLUSIONS: Additional radiocolloid tracer injection after axillary non-visualization in lymphoscintigraphy is safe and does not increase axillary recurrence risk after tumor-negative SNB. The results suggest that such patients can be safely managed with SNB without a need to perform an ALND.

Sentinel node biopsy in breast cancer patients with large or multifocal tumors.

BACKGROUND: The axillary recurrence (AR) rate after negative sentinel node biopsy (SNB) in patients with high risk of axillary metastases is largely unknown. The aim of this study was to analyze the risk factors for isolated AR after negative SNB with special interest in large or multifocal tumors. METHODS: A prospective SNB registry was analyzed for 2,408 invasive breast cancer patients operated between 2001 and 2007. No axillary clearance was performed in 1,309 cases with a negative SNB, including 1,138 small unifocal tumors, 121 small multifocal tumors, 48 large unifocal tumors, and 2 large multifocal tumors. RESULTS: Six (0.5%) isolated AR were observed during a median follow-up of 43 months. Four (0.4%) patients with small unifocal tumors and two (1.6%) with small multifocal tumors had isolated AR (p = 0.179). None of the patients with large unifocal or multifocal tumors had isolated AR. Instead of tumor size and multifocality, estrogen receptor negativity (p < 0.001), nuclear grade III (p < 0.001), Her-2 status (p = 0.002), no radiotherapy (p = 0.005), and mastectomy (p = 0.005) were found to be associated with AR. CONCLUSIONS: A remarkable proportion of patients with large unifocal tumors and small multifocal tumors may avoid unnecessary AC due to tumor negative SNB, without an excessive risk of AR.

Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer.

BACKGROUND: There is evidence that the immune systems of patients with breast cancer are dysfunctional. Regulatory T cells (Tregs), and IDO, an immunosuppressive enzyme, are associated with more advanced disease in some cancers and may promote immunologic tolerance to tumors. Our aim was to assess whether expression of Foxp3, a marker of Tregs, and IDO were linked with nodal metastasis in breast cancer patients. Inhibitors of IDO are available and could potentially demonstrate utility in breast cancer if IDO drives progression of disease. METHODS: Sentinel lymph nodes (SLN) of 47 breast cancer patients with varying degrees of nodal disease and 10 controls were evaluated for expression of Foxp3 and IDO using immunohistochemistry. Positively stained cells were quantified and their distribution within the SLN noted. RESULTS: The proportion of Foxp3+ cells was higher in SLN of cancer patients than controls (19% v. 10%, p < 0.001). Specifically, there were more Foxp3+ cells in SLN with metastasis than tumor-free SLN (20% v. 14%, p = 0.02). The proportion IDO+ cell in SLN of cancer patients was not statistically different than controls (4.0% v. 1.6%, p = 0.08). In order to demonstrate the combined immunosuppressive effect of Foxp3 and IDO, we categorized each SLN as positive or negative for Foxp3 and IDO. The Foxp3+/IDO+ group almost exclusively consisted of cancer patients with node positive disease. CONCLUSION: In conclusion, our study shows that Foxp3+ cells are associated with more advanced disease in breast cancer, a finding that is proving to be true in many other cancers. As IDO has been found to promote differentiation of Tregs, IDO may become a suitable target to abrogate the development of T-cell tolerance and to promote an effective immune response to breast cancer. Our results about the combined expression of IDO and Foxp3 in metastastic SLN support this assumption.

The outcome of sentinel node biopsy in breast cancer patients with preoperative surgical biopsy.

BACKGROUND: The aim of the study was to evaluate the outcome of sentinel node biopsy (SNB), especially the medium term axillary recurrence rate after negative SNB in patients with preoperative surgical biopsy (SB). PATIENTS AND METHODS: The study included 1,641 patients with a histological stage T1 tumours and SNB. In 77 patients, the diagnosis was obtained with SB, while 1,564 patients had underwent needle biopsy (NB) only. Axillary clearance was omitted in 56 SB patients and 921 NB patients after negative SNB. The median duration of follow-up in these patients was 54 months. RESULTS: None of the SB patients had axillary recurrences during the follow-up. Six NB patients had isolated axillary recurrences while three patients had concomitant local and axillary recurrences. There were no differences in local or distant recurrences or breast cancer deaths between the SB and the NB patients. CONCLUSIONS: SNB seems a feasible axillary staging method in patients with histological stage T1 tumour also after preoperative SB. The risk of axillary recurrence after negative SNB is negligible in these patients.

Unsuccessful preoperative biopsies, fine needle aspiration cytology or core needle biopsy, lead to increased costs in the diagnostic workup in breast cancer.

Correct preoperative diagnosis of a breast lesion is essential for optimal treatment planning. Our aim was to compare feasibility of fine needle aspiration cytology (FNAC) and core needle biopsy (CNB) in diagnosis of breast lesions. The special aim was to evaluate the extra costs and delay in surgical treatment due to unsuccessful preoperative biopsies. Diagnostic work-ups in 572 patients with 580 breast lesions were retrospectively evaluated. FNAC was the first biopsy method for 339 lesions, CNB for 241 lesions. The postoperative diagnosis was malignant for 503 lesions. The preoperative rate of definitely malignant diagnosis was 67% (194/289) for FNAC and 96% (206/214) for CNB (p < 0.0001), and 95% and 99%, respectively (p = 0.0173), when also suspicious findings were included. In patients with FNAC, an additional needle biopsy was performed for 93 and a surgical biopsy for 62 lesions. In the CNB group, a subsequent CNB was performed for 2 and a surgical biopsy for 33. The frequent need for additional biopsies raised the total expenses of FNAC over those of CNB. Multiple biopsies may also delay cancer surgery. It is therefore recommended to use CNB as the initial needle biopsy method.

Multi-institutional comparison of non-sentinel lymph node predictive tools in breast cancer patients with high predicted risk of further axillary metastasis.

Although axillary lymph node dissection (ALND) has been the standard intervention in breast cancer patients with sentinel lymph node (SLN) metastasis, only a small proportion of patients benefit from this operation, because most do not harbor additional metastases in the axilla. Several predictive tools have been constructed to identify patients with low risk of non-SLN metastasis who could be candidates for the omission of ALND. In the present work, predictive nomograms were used to predict a high (>50 %) risk of non-SLN metastasis in order to identify patients who would most probably benefit from further axillary treatment. Data of 1000 breast cancer patients with SLN metastasis and completion ALND from 5 institutions were tested in 4 nomograms. A subset of 313 patients with micrometastatic SLNs were also tested in 3 different nomograms devised for the micrometastatic population (the high risk cut-off being 20 %). Patients with a high predicted risk of non-SLN metastasis had higher rates of metastasis in the non-SLNs than patients with low predicted risk. The positive predictive values of the nomograms ranged from 44 % to 64 % with relevant inter-institutional variability. The nomograms for micrometastatic SLNs performed much better in identifying patients with low risk of non-SLN involvement than in high-risk-patients; for the latter, the positive predictive values ranged from 13 % to 20 %. The nomograms show inter-institutional differences in their predictive values and behave differently in different settings. They are worse in identifying high risk patients than low-risk ones, creating a need for new predictive models to identify high-risk patients.

International multicenter tool to predict the risk of nonsentinel node metastases in breast cancer.

BACKGROUND: Axillary treatment of breast cancer patients is undergoing a paradigm shift, as completion axillary lymph node dissections (ALNDs) are being questioned in the treatment of patients with tumor-positive sentinel nodes. This study aims to develop a novel multi-institutional predictive tool to calculate patient-specific risk of residual axillary disease after tumor-positive sentinel node biopsy. METHODS: Breast cancer patients with a tumor-positive sentinel node and a completion ALND from five European centers formed the original patient series (N = 1000). Statistically significant variables predicting nonsentinel node involvement were identified in logistic regression analysis. A multivariable predictive model was developed and validated by area under the receiver operating characteristics curve (AUC), first internally in 500 additional patients and then externally in 1068 patients from other centers. All statistical tests were two-sided. RESULTS: Nine tumor- and sentinel node-specific variables were identified as statistically significant factors predicting nonsentinel node involvement in logistic regression analysis. A resulting predictive model applied to the internal validation series resulted in an AUC of 0.714 (95% confidence interval [CI] = 0.665 to 0.763). For the external validation series, the AUC was 0.719 (95% CI = 0.689 to 0.750). The model was well calibrated in the external validation series. CONCLUSIONS: We present a novel, international, multicenter, predictive tool to assess the risk of additional axillary metastases after tumor-positive sentinel node biopsy in breast cancer. The predictive model performed well in internal and external validation but needs to be further studied in each center before application to clinical use.

High expression of maspin is associated with early tumor relapse in breast cancer.

Maspin is a serine protease inhibitor with tumor suppressor activity. Maspin can suppress tumor growth and metastasis in vivo and tumor cell motility and invasion in vitro. Maspin also modulates apoptosis of tumor cells, possibly by modulating the expression of the B-cell lymphoma-2 family member. p53 regulates the expression of the tumor suppressor gene maspin. Breast cancer is known for its propensity to recur even after decades. The biology behind this phenomenon of tumor dormancy is poorly understood. This study was conducted to clarify the role of maspin and B-cell lymphoma-2 in early and late recurring breast cancer. The expression of maspin, B-cell lymphoma-2, p53, and estrogen receptor was studied by immunohistochemistry in 73 primary breast cancers and in their metastatic relapses detected within 2 years, or 5 or 10 years after primary surgery. The cytoplasmic expression of maspin was significantly higher in the primary tumors of the early metastasizing breast cancers (first tumor relapse within 2 years) and also in their metastases compared to late metastasizing cancers. An opposite activity was observed in the expression of B-cell lymphoma-2. The level of B-cell lymphoma-2 staining was lower in the early relapsing cancers and significantly lower in their metastases, compared to tumors which metastasized 5 or 10 years after primary surgery. High cytoplasmic expression of maspin and low expression of B-cell lymphoma-2 in primary breast cancer predict early tumor relapse.