Isabelle Bedrosian

Circulating tumour cells in non-metastatic breast cancer: a prospective study

BACKGROUND The identification of circulating tumour cells correlate with poor prognosis in metastatic breast cancer, but there are few data describing the importance of circulating tumour cells in patients with non-metastatic disease. Our aim was to establish if circulating tumour cells predicted worse outcome in patients with non-metastatic breast cancer. METHODS We prospectively collected data on circulating tumour cells at the time of definitive surgery from chemonaive patients with stage 1-3 breast cancer from February, 2005, to December, 2010. We deemed eligible all patients with operable breast cancer presenting at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients were ineligible if they had bilateral breast cancer or any other malignancy within 5 years of the diagnosis of the present cancer. We measured circulating tumour cells with the CellSearch System (Veridex, Raritan, NJ). We correlated findings of circulating tumour cells with standard tumour characteristics, including tumour size and grade; oestrogen and progesterone receptor and human epidural growth factor receptor 2 (HER2) status; and axillary lymph node status with χ(2) or Fisher exact tests. We assessed outcomes at a median follow-up of 35 months. Log-rank test and Cox regression analysis was applied to establish the association of circulating tumour cells with progression-free and overall survival. FINDINGS No patients reported adverse events or complications from blood collections. We identified one or more circulating tumour cells in 73 (24%) of 302 patients. Detection of one or more circulating tumour cells predicted both decreased progression-free survival (log-rank p=0·005; hazard ratio [HR] 4·62, 95% CI 1·79-11·9) and overall survival (log-rank p=0·01; HR 4·04, 1·28-12·8). INTERPRETATION The presence of one or more circulating tumour cells predicted early recurrence and decreased overall survival in chemonaive patients with non-metastatic breast cancer. These results suggest that assessment of circulating tumour cells might provide important prognostic information in these patients. FUNDING Society of Surgical Oncology, Morgan Welch Inflammatory Breast Cancer Program, The University of Texas MD Anderson Cancer Center, and the State of Texas Rare and Aggressive Breast Cancer Research Program.

Immunohistochemistry with pancytokeratins improves the sensitivity of sentinel lymph node biopsy in patients with breast carcinoma

Sentinel lymph node (SLN) biopsy is being investigated as a staging procedure for breast carcinoma. The authors evaluated whether immunohistochemical (IHC) analysis improves the sensitivity of this procedure.

Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients

Objective:Sentinel lymph node (SLN) surgery is widely used for nodal staging in early-stage breast cancer. This study was performed to evaluate the accuracy of SLN surgery for patients undergoing neoadjuvant chemotherapy versus patients undergoing surgery first. Summary Background Data:Controversy exists regarding the timing of SLN surgery in patients planned for neoadjuvant chemotherapy. Proponents of SLN surgery after chemotherapy prefer a single surgical procedure with potential for fewer axillary dissections. Opponents cite early studies with low identification rates and high false-negative rates after chemotherapy. Methods:A total of 3746 patients with clinically node negative T1-T3 breast cancer underwent SLN surgery from 1994 to 2007. Clinicopathologic data were reviewed and comparisons made between patients receiving neoadjuvant chemotherapy and those undergoing surgery first. Results:Of the patients, 575 (15.3%) underwent SLN surgery after chemotherapy and 3171 (84.7%) underwent surgery first. Neoadjuvant patients were younger (51 vs. 57 years, P < 0.0001) and had more clinical T2-T3 tumors (87.3% vs. 18.8%, P < 0.0001) at diagnosis. SLN identification rates were 97.4% in the neoadjuvant group and 98.7% in the surgery first group (P = 0.017). False-negative rates were similar between groups (5/84 [5.9%] in neoadjuvant vs. 22/542 [4.1%] in the surgery first group, P = 0.39). Analyzed by presenting T stage, there were fewer positive SLNs in the neoadjuvant group (T1: 12.7% vs. 19.0%, P = 0.2; T2: 20.5% vs. 36.5%, P < 0.0001; T3: 30.4% vs. 51.4%, P = 0.04). Adjusting for clinical stage revealed no differences in local-regional recurrences, disease-free or overall survival between groups. Conclusions:SLN surgery after chemotherapy is as accurate for axillary staging as SLN surgery prior to chemotherapy. SLN surgery after chemotherapy results in fewer positive SLNs and decreases unnecessary axillary dissections.

Population-Based Study of Contralateral Prophylactic Mastectomy and Survival Outcomes of Breast Cancer Patients

BACKGROUND Despite increased demand for contralateral prophylactic mastectomy (CPM), the survival benefit of this procedure remains uncertain. METHODS We used the Surveillance, Epidemiology, and End Results database to identify 107 106 women with breast cancer who had undergone mastectomy for treatment between 1998 and 2003 and a subset of 8902 women who also underwent CPM during the same period. Associations between predictor variables and the likelihood of undergoing CPM were evaluated by use of chi(2) analyses. Risk-stratified (estrogen receptor [ER] status, stage, and age) adjusted survival analyses were performed by using Cox regression. Statistical tests were two-sided. RESULTS In a univariate analysis, CPM was associated with improved disease-specific survival (hazard ratio [HR] of death = 0.63, 95% confidence interval [CI] = 0.57 to 0.69; P < .001). Risk-stratified analysis showed that this association was because of a reduction in breast cancer-specific mortality in women aged 18-49 years with stages I-II ER-negative cancer (HR of death = 0.68, 95% CI = 0.53 to 0.88; P = .004). Five year-adjusted breast cancer survival for this group was improved with CPM vs without (88.5% vs 83.7%, difference = 4.8%). Although rates of contralateral breast cancer among young women with stages I-II disease undergoing CPM were independent of ER status, women with ER-positive tumors in the absence of prophylactic mastectomy also had a lower overall risk for contralateral breast cancer than women with ER-negative tumors (0.46% vs 0.90%, difference = 0.44%; P < .001). CONCLUSIONS CPM is associated with a small improvement in 5-year breast cancer-specific survival mainly in young women with early-stage ER-negative breast cancer. This effect is related to a higher baseline risk of contralateral breast cancer.

Intranodal Administration of Peptide-Pulsed Mature Dendritic Cell Vaccines Results in Superior CD8+ T-Cell Function in Melanoma Patients

PURPOSE We evaluated the feasibility, safety, and immunogenicity of mature, peptide-pulsed dendritic cell (DC) vaccines administered by different routes. PATIENTS AND METHODS We performed a randomized, phase I, dose-escalation study in 27 patients with metastatic melanoma receiving four autologous peptide-pulsed DC vaccinations. Patients were randomly assigned to an intravenous (IV), intranodal (IN), or intradermal (ID) route of administration (ROA). For each route, primary end points were dose-limiting toxicity, maximum-tolerated dose, and T-cell sensitization. Sensitization was evaluated through tetramer staining, in vitro peptide recognition assays, and delayed-type hypersensitivity (DTH) responses. RESULTS Twenty-two (81.5%) of 27 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited grade 1 to 2 toxicities including rash, fever, and injection site reaction. All routes of administration induced comparable increases in tetramer-staining CD8+ T cells (five of seven IV, four of seven IN, and four of six ID patients). However, the IN route induced significantly higher rates for de novo development of CD8+ T cells that respond by cytokine secretion to peptide-pulsed targets (six [85.7%] of seven IN patients v two [33%] of six ID patients v none [0%] of six IV patients; P =.005) and de novo DTH (seven [87.5%] of eight IN patients v two [33.3%] of six ID patients v one [14.3%] of seven IV patients; P =.01) compared with other routes. CONCLUSION Administration of this peptide-pulsed mature DC vaccine by IN, IV, or ID routes is feasible and safe. IN administration seems to result in superior T-cell sensitization as measured by de novo target-cell recognition and DTH priming, indicating that IN may be the preferred ROA for mature DC vaccines.

Incidence of sentinel node metastasis in patients with thin primary melanoma (≤1 mm) with vertical growth phase

Background: Patients with thin primary melanomas (#1 mm) generally have an excellent prognosis. However, the presence of a vertical growth phase (VGP) adversely impacts the survival rate. We report on the rate of occurrence of nodal metastasis in patients with thin primary melanomas with a VGP who are offered sentinel lymph node (SLN) biopsy.Methods: Among 235 patients with clinically localized cutaneous melanomas who underwent successful SLN biopsy, 71 had lesions 1 mm or smaller with a VGP. The SLN was localized by using blue dye and a radiotracer. If negative for tumor by using hematoxylin and eosin staining, the SLN was further examined by immunohistochemistry.Results: The rate of occurrence of SLN metastasis was 15.2% in patients with melanomas deeper than 1 mm and 5.6% in patients with thin melanomas. Three patients with thin melanomas and a positive SLN had low-risk lesions, based on a highly accurate six-variable multivariate logistic regression model for predicting 8-year survival in stage I/II melanomas. The fourth patient had a low- to intermediate-risk lesion based on this model. At the time of the lymphadenectomy, one patient had two additional nodes with metastasis.Conclusions: VGP in a melanoma 1 mm or smaller seems to be a risk factor for nodal metastasis. The risk of nodal disease may not be accurately predicted by the use of a multivariate logistic regression model that incorporates thickness, mitotic rate, regression, tumor-infiltrating lymphocytes, sex, and anatomical site. Patients with thin lesions having VGP should be evaluated for SLN biopsy and trials of adjuvant therapy when stage III disease is found.

Rapid High Efficiency Sensitization of CD8+ T Cells to Tumor Antigens by Dendritic Cells Leads to Enhanced Functional Avidity and Direct Tumor Recognition Through an IL-12-Dependent Mechanism

Myeloid-origin dendritic cells (DCs) can develop into IL-12-secreting DC1 or non-IL-12-secreting DC2 depending on signals received during maturation. Through rapid culture techniques that prepared either mature, CD83+ DC1 or DC2 from CD14+ monocytes in only 2 days followed by a single 6–7 day DC-T cell coculture, we sensitized normal donor CD8+ T cells to tumor Ags (HER-2/neu, MART-1, and gp100) such that peptide Ag-specific lymphocytes constituted up to 16% of the total CD8+ population. Both DC1 and DC2 could sensitize CD8+ T cells that recognized peptide-pulsed target cells. However, with DC2, a general decoupling was observed between recognition of peptide-pulsed T2 target cells and recognition of Ag-expressing tumor cells, with peptide-sensitized T cells responding to tumor only about 15% of the time. In contrast, direct recognition of tumor by T cells was dramatically increased (to 85%) when DC1 were used for sensitization. Enhanced tumor recognition was accompanied by 10- to 100-fold increases in peptide sensitivity and elevated expression of CD8β, characteristic of high functional avidity T cells. Both of these properties were IL-12-dependent. These results demonstrate the utility of rapid DC culture methods for high efficiency in vitro T cell sensitization that achieves robust priming and expansion of Ag-specific populations in 6 days. They also demonstrate a novel function of IL-12, which is enhancement of CD8+ T cell functional avidity. A new approach to DC-based vaccines that emphasizes IL-12 secretion to enhance functional avidity and concomitant tumor recognition by CD8+ T cells is indicated.

Improved Axillary Evaluation Following Neoadjuvant Therapy for Patients With Node-Positive Breast Cancer Using Selective Evaluation of Clipped Nodes: Implementation of Targeted Axillary Dissection

PURPOSE Placing clips in nodes with biopsy-confirmed metastasis before initiating neoadjuvant therapy allows for evaluation of response in breast cancer. Our goal was to determine if pathologic changes in clipped nodes reflect the status of the nodal basin and if targeted axillary dissection (TAD), which includes sentinel lymph node dissection (SLND) and selective localization and removal of clipped nodes, improves the false-negative rate (FNR) compared with SLND alone. METHODS A prospective study of patients with biopsy-confirmed nodal metastases with a clip placed in the sampled node was performed. After neoadjuvant therapy, patients underwent axillary surgery and the pathology of the clipped node was compared with other nodes. Patients undergoing TAD had SLND and selective removal of the clipped node using iodine-125 seed localization. The FNR was determined in patients undergoing complete axillary lymphadenectomy (ALND). RESULTS Of 208 patients enrolled in this study, 191 underwent ALND, with residual disease identified in 120 (63%). The clipped node revealed metastases in 115 patients, resulting in an FNR of 4.2% (95% CI, 1.4 to 9.5) for the clipped node. In patients undergoing SLND and ALND (n = 118), the FNR was 10.1% (95% CI, 4.2 to 19.8), which included seven false-negative events in 69 patients with residual disease. Adding evaluation of the clipped node reduced the FNR to 1.4% (95% CI, 0.03 to 7.3; P = .03). The clipped node was not retrieved as an SLN in 23% (31 of 134) of patients, including six with negative SLNs but metastasis in the clipped node. TAD followed by ALND was performed in 85 patients, with an FNR of 2.0% (1 of 50; 95% CI, 0.05 to 10.7). CONCLUSION Marking nodes with biopsy-confirmed metastatic disease allows for selective removal and improves pathologic evaluation for residual nodal disease after chemotherapy.

Impact of Clinicopathological Factors on Sensitivity of Axillary Ultrasonography in the Detection of Axillary Nodal Metastases in Patients With Breast Cancer

Background: Ultrasonography and fine-needle aspiration (FNA) are used to evaluate the breast and regional nodes in breast cancer patients. We sought to identify factors influencing the sensitivity of ultrasonography for detection of nodal metastasis.Methods: Patients with a clinically negative axilla who underwent axillary ultrasonography and sentinel lymph node biopsy were included.Results: Of 208 patients, axillary ultrasonography was negative in 180 (86%) and suspicious or indeterminate in 28 (14%). FNA was performed in 22 patients whose findings were indeterminate or suspicious, and 3 were positive for malignancy. Final pathological examinations revealed positive nodes in 53 patients: 39 (22%) of 180 with negative ultrasonographic findings and 14 (50%) of 28 with indeterminate or suspicious ultrasonographic findings (P = .001). Excisional biopsy was more common for patients with indeterminate or suspicious findings on preoperative ultrasonography (P = .038). There were no significant differences in tumor size, histological features, size of nodal metastasis, or number of positive nodes between patients whose ultrasonography findings were negative and those whose findings were indeterminate or suspicious.Conclusions: Ultrasonographically suggested nodal metastasis is associated with the finding of nodal disease on final pathological examination. No significant clinicopathologic criteria were found to impact sensitivity of ultrasonography; however, excisional biopsy for diagnosis may be a confounding variable in subsequent axillary ultrasonography.

Multidisciplinary considerations in the implementation of the findings from the American College of Surgeons Oncology Group (ACOSOG) Z0011 study: a practice-changing trial.

Surgical management of breast cancer has evolved from routine use of radical mastectomy to less disfiguring and extensive procedures, including breast-conserving approaches, for appropriately selected patients. Whereas this transition occurred over several decades, until recently axillary lymph node dissection (ALND) remained standard practice for patients with both node-positive and node-negative breast cancer. The introduction of sentinel lymph node dissection (SLND) was a major departure from ALND allowing for an alternative for nodal staging with less morbidity for the increasing population of patients presenting with clinically node-negative disease.1,2 Although some early studies suggested a survival advantage for patients who undergo ALND compared with no axillary surgery, the likelihood that removing negative nodes could improve outcomes has been questioned. SLND has become the standard of care for patients with clinically node-negative disease. With fewer nodes removed, pathologists can perform a more detailed examination. This allows for improved staging and increases the detection of small-volume metastases. As the population of patients with small burden nodal disease has increased, there has been a growing debate regarding the optimal treatment of node-positive disease. The consensus statement from the American Society of Clinical Oncology and the guidelines from the National Comprehensive Cancer Network recommend a completion ALND (cALND) when metastases are identified on SLND.3,4 These recommendations are supported by data from a meta-analysis of 69 trials, which included 8,059 patients who underwent SLND and cALND, where 53% of the patients with a positive SLN were found to have additional disease in non-SLNs.5 The cALND allows for assessment of the total number of nodes involved, which has prognostic and potentially therapeutic implications. The American Joint Committee on Cancer staging system includes designations for metastases in ≥10 lymph nodes (pN3), 4–9 lymph nodes (pN2), and 1–3 lymph nodes (pN1), as well as micrometastasis (pN1mi; >0.2–2.0 mm) and isolated tumor cells (pN0(i +); ≤0.2 mm).6 The extent of nodal disease may have implications in terms of local-regional control as well as use of systemic therapy and regional and nodal irradiation.7,8 Although cALND has been standard practice when SLNs are involved with metastatic disease, many have questioned the need for cALND in patients with small-volume metastases. The meta-analysis previously discussed showed that 53% of patients had additional nodes with metastatic disease on cALND.5 When considering patients with micrometastatic disease in the SLN(s), the rate of non-SLN involvement is as low as 20%; and for patients with isolated tumor cells the rate decreases to 12%.9,10 These findings have prompted a trend toward omitting cALND in selected patients. In an analysis of the surveillance, epidemiology, and end results (SEER) data from 1998 to 2004, up to 16% of SLN-positive patients did not undergo cALND—a trend seen in older women with low-grade, estrogen receptor (ER)-positive tumors. Considering only patients with micrometastasis in the SLN, the proportion treated with SLND alone increased from 21 to 38%.11 Similarly, a review of the National Cancer Data Base (NCDB) data from 1998 to 2005 revealed that 20.8% of patients with a positive SLN did not undergo cALND. To evaluate a more contemporary cohort, these authors analyzed data from patients diagnosed between 2004 and 2005 and found that the proportion of patients who underwent SLND alone increased in patients with micrometastases, whereas the proportion of patients who underwent SLND alone after macrometastases were identified in the SLN declined slightly during the same time period. At a median follow-up of just more than five years, there were no differences in axillary recurrence rates or survival for patients who underwent SLND alone versus SLND with cALND. This was true for patients with both micrometastases and macrometastases in the SLN.12 These data suggest that many clinicians do not believe that cALND plays an important role in the management of patients with small-volume metastases in the SLN. The American College of Surgeons Oncology Group (ACOSOG) recently reported the results of the Z0011 trial—a prospective, randomized trial designed to evaluate the impact of cALND on local-regional recurrence and survival in patients with early-stage breast cancer and a positive SLN. The purpose of this article is to review the results of the Z0011 trial and to discuss how these data can be implemented in multidisciplinary practice.