Objective Assess the performance characteristics of axillary ultrasound (AUS) for accurate exclusion of clinically significant axillary lymph node (ALN) disease. Background Sentinel lymph node biopsy (SLNB) is currently the standard of care for staging the axilla in patients with clinical T1–T2, N0 breast cancer. AUS is a noninvasive alternative to SLNB for staging the axilla. Methods Patients were identified using a prospectively maintained database. Sensitivity, specificity, and negative predictive value (NPV) were calculated by comparing AUS findings to pathology results. Multivariate analyses were performed to identify patient and/or tumor characteristics associated with false negative (FN) AUS. A blinded review of FN and matched true negative cases was performed by two independent medical oncologists to compare treatment recommendations and actual treatment received. Recurrence-free survival was described using Kaplan-Meier product limit methods. Results 647 patients with clinical T1–T2, N0 breast cancer underwent AUS between January, 2008 and March, 2013. AUS had a sensitivity of 70%, NPV of 84% and PPV of 56% for the detection of ALN disease. For detection of clinically significant disease (> 2.0 mm), AUS had a sensitivity of 76% and NPV of 89%. FN AUS did not significantly impact adjuvant medical decision making. Patients with FN AUS had recurrence-free survival equivalent to patients with pathologic N0 disease. Conclusions AUS accurately excludes clinically significant ALN disease in patients with clinical T1–T2, N0 breast cancer. AUS may be an alternative to SLNB in these patients where axillary surgery is no longer considered therapeutic, and predictors of tumor biology are increasingly used to make adjuvant therapy decisions.
Purpose Mammaglobin-A (MAM-A) is overexpressed in 40–80% of primary breast cancers. We initiated a phase 1 clinical trial of a MAM-A DNA vaccine to evaluate its safety and biological efficacy. Experimental Design Breast cancer patients with stable metastatic disease were eligible for enrollment. Safety was monitored with clinical and laboratory assessments. The CD8 T cell response was measured by ELISPOT, flow cytometry, and cytotoxicity assays. Progression-free survival was described using the Kaplan-Meier product limit estimator. Results Fourteen subjects have been treated with the MAM-A DNA vaccine and no significant adverse events have been observed. Eight of fourteen subjects were HLA-A2+, and the CD8 T cell response to vaccination was studied in detail. Flow cytometry demonstrated a significant increase in the frequency of MAM-A-specific CD8 T cells following vaccination (0.9 ± 0.5% vs. 3.8 ± 1.2%, p < 0.001), and ELISPOT analysis demonstrated an increase in the number of MAM-A-specific IFN-γ-secreting T cells (41 ± 32 vs. 215 ± 67 spm, p < 0.001). Although this study was not powered to evaluate progression-free survival, preliminary evidence suggests that subjects treated with the MAM-A DNA vaccine had improved progression-free survival compared to subjects who met all eligibility criteria, were enrolled in the trial, but were not vaccinated because of HLA phenotype. Conclusion The MAM-A DNA vaccine is safe, capable of eliciting MAM-A-specific CD8 T cell responses, and preliminary evidence suggests improved progression-free survival. Additional studies are required to define the potential of the MAM-A DNA vaccine for breast cancer prevention and/or therapy.
Background Axillary surgery is not considered therapeutic in patients with clinical T1-T2 N0 breast cancer. The importance of axillary staging is eroding in an era where tumor biology, as defined by biomarker and gene expression profile, is increasingly important in medical decision making. We hypothesize that axillary ultrasound (AUS) is a noninvasive alternative to sentinel lymph node biopsy (SLNB), and AUS could replace SLNB without compromising patient care. Study Design Patients with clinical T1-T2 N0 breast cancer and normal AUS were eligible for enrollment. Subjects were randomized to no further axillary staging (Arm 1) versus SLNB (Arm 2). Descriptive statistics were used to describe the results of the pilot phase of the randomized controlled trial. Results 68 subjects were enrolled in the pilot phase of the trial (34 subjects in Arm 1, no further staging; 32 subjects in Arm 2, SLNB, and 2 subjects voluntarily withdrew from the trial). The median age was 61 years (range 40-80) in Arm 1 and 59 years (range 31-81) in Arm 2, and there were no significant clinical or pathologic differences between the arms. Median follow-up was 17 months (range 1-32). The negative predictive value (NPV) of AUS for identification of clinically significant axillary disease (> 2.0 mm) was 96.9%. No axillary recurrences have been observed in either arm. Conclusions Successful completion of the pilot phase of the randomized controlled trial confirms the feasibility of the study design, and provides prospective evidence supporting the ability of AUS to exclude clinically significant disease in the axilla. The results provide strong support for a phase 2 randomized controlled trial.
Background: The American College of Surgeons Oncology Group Z0011 prospective randomized trial demonstrated no local control or survival advantage with more extensive axillary surgery, even in the setting of known axillary disease. These results convincingly showed that axillary surgery provides little, if any, therapeutic benefit. Given that axillary surgery is not associated with local control or survival benefit, the current role of sentinel lymph node (SLNB) is limited to staging the axilla (in other words, SLNB provides staging information but is not therapeutic). Objectives: In this randomized, controlled non-inferiority trial we aim to determine the utility of axillary ultrasound (AUS) as a pre-operative staging modality for patients with clinically node-negative invasive breast cancer with the hope that it will be a minimally invasive replacement for SLNB. 1. Primary Objective: To assess whether axillary recurrence rates for patients randomized to Arm 1 (no SLNB) is equivalent to axillary recurrence rates for patients randomized to Arm 2 (SLNB). 2. Secondary Objective: To assess disease-free survival in Arm 1 vs. Arm 2. 3. Tertiary Objective: To assess overall survival in Arm 1 vs. Arm 2. Study Design: A randomized non-inferiority trial comparing no further axillary staging versus SLNB in women with clinical T1-T2, N0 M0 breast cancer and negative AUS. Following a negative AUS, four hundred sixty women will be randomized in a 1:1 fashion to no further axillary staging or SLNB. Subjects will be monitored for local-regional and distant recurrence per NCCN guidelines. We have recruited 28 study participants. Eligibility Criteria: To be eligible the patient must be 18-y.o. or older; female; have tissue-diagnosis of invasive breast cancer; cT1-2N0M0 cancer; negative AUS; ECOG </=2; available for follow-up; candidate for SLNB. A patient is ineligible if pregnant or lactating; has concurrent invasive bilateral breast malignancies or multicentric disease or is considered a poor surgical candidate. Statistical Methods: Power analysis: A power analysis was performed to determine the accrual goal. The power analysis is based on axillary recurrence, our primary endpoint. We expect an axillary recurrence rate of 1% in patients undergoing SLNB. By assuming a noninferiority limit of 2% difference, our sample size will allow us 80% power at 1-sided 0.1 significance level to assure such a noninferiority. Data analysis: Longer-term formal data analysis for the study will be performed following the intent-to-treat (ITT) principle. Demographic and clinical characteristics of the sample, as well as efficacy, complication rates and loss to follow-up will be summarized using descriptive statistics. The balance of demographic and baseline clinical characteristics between two arms will be compared using t-test, Mann-Whitney rank-sum test, or Chi-square test as appropriate. The differences in OS and DFS between treatment arms will be compared using log-rank test. Citation Format: Natalia S Tucker, William E Gillanders, Timothy Eberlein, Rebecca Aft, Julie Margenthaler, Feng Gao, Catherine Appleton, Imran Zoberi, Ademuyiwa Foluso, Amy Cyr. A prospective, randomized trial of sentinel lymph node biopsy versus no additional staging in patients with T1-T2 invasive breast cancer and negative axillary ultrasound [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-5-01.
<p>Supplementary Figure 1: Expression of MAM-A and HLA-A2 in breast cancer cell lines. Supplementary Figure 2: MAM-A DNA vaccination increases breast cancer-induced TNF-α production by MAM-A-specific CD8 T cells. Supplementary Figure 3: MAM-A DNA vaccination increases NKG2D expression in MAM-A-specific CD8 T cells. Supplementary Figure 4: MAM-A DNA vaccination increases DAP10 adapter protein expression in MAM-A-specific CD8 T cells. Supplementary Figure 5: MAM-A DNA vaccination increases perforin expression in MAM-A-specific CD8 T cells. Supplementary Figure 6: Therapy received by the patients (screen failed and vaccinated).</p>
<p>Supplementary Figure 1: Expression of MAM-A and HLA-A2 in breast cancer cell lines. Supplementary Figure 2: MAM-A DNA vaccination increases breast cancer-induced TNF-α production by MAM-A-specific CD8 T cells. Supplementary Figure 3: MAM-A DNA vaccination increases NKG2D expression in MAM-A-specific CD8 T cells. Supplementary Figure 4: MAM-A DNA vaccination increases DAP10 adapter protein expression in MAM-A-specific CD8 T cells. Supplementary Figure 5: MAM-A DNA vaccination increases perforin expression in MAM-A-specific CD8 T cells. Supplementary Figure 6: Therapy received by the patients (screen failed and vaccinated).</p>
<div>Abstract<p><b>Purpose:</b> Mammaglobin-A (MAM-A) is overexpressed in 40% to 80% of primary breast cancers. We initiated a phase I clinical trial of a MAM-A DNA vaccine to evaluate its safety and biologic efficacy.</p><p><b>Experimental Design:</b> Patients with breast cancer with stable metastatic disease were eligible for enrollment. Safety was monitored with clinical and laboratory assessments. The CD8 T-cell response was measured by ELISPOT, flow cytometry, and cytotoxicity assays. Progression-free survival (PFS) was described using the Kaplan–Meier product limit estimator.</p><p><b>Results:</b> Fourteen subjects have been treated with the MAM-A DNA vaccine and no significant adverse events have been observed. Eight of 14 subjects were HLA-A2<sup>+</sup>, and the CD8 T-cell response to vaccination was studied in detail. Flow cytometry demonstrated a significant increase in the frequency of MAM-A–specific CD8 T cells after vaccination (0.9% ± 0.5% vs. 3.8% ± 1.2%; <i>P</i> < 0.001), and ELISPOT analysis demonstrated an increase in the number of MAM-A–specific IFNγ-secreting T cells (41 ± 32 vs. 215 ± 67 spm; <i>P</i> < 0.001). Although this study was not powered to evaluate progression-free survival (PFS), preliminary evidence suggests that subjects treated with the MAM-A DNA vaccine had improved PFS compared with subjects who met all eligibility criteria, were enrolled in the trial, but were not vaccinated because of HLA phenotype.</p><p><b>Conclusion:</b> The MAM-A DNA vaccine is safe, capable of eliciting MAM-A–specific CD8 T-cell responses, and preliminary evidence suggests improved PFS. Additional studies are required to define the potential of the MAM-A DNA vaccine for breast cancer prevention and/or therapy. <i>Clin Cancer Res; 20(23); 5964–75. ©2014 AACR</i>.</p></div>
<div>Abstract<p><b>Purpose:</b> Mammaglobin-A (MAM-A) is overexpressed in 40% to 80% of primary breast cancers. We initiated a phase I clinical trial of a MAM-A DNA vaccine to evaluate its safety and biologic efficacy.</p><p><b>Experimental Design:</b> Patients with breast cancer with stable metastatic disease were eligible for enrollment. Safety was monitored with clinical and laboratory assessments. The CD8 T-cell response was measured by ELISPOT, flow cytometry, and cytotoxicity assays. Progression-free survival (PFS) was described using the Kaplan–Meier product limit estimator.</p><p><b>Results:</b> Fourteen subjects have been treated with the MAM-A DNA vaccine and no significant adverse events have been observed. Eight of 14 subjects were HLA-A2<sup>+</sup>, and the CD8 T-cell response to vaccination was studied in detail. Flow cytometry demonstrated a significant increase in the frequency of MAM-A–specific CD8 T cells after vaccination (0.9% ± 0.5% vs. 3.8% ± 1.2%; <i>P</i> < 0.001), and ELISPOT analysis demonstrated an increase in the number of MAM-A–specific IFNγ-secreting T cells (41 ± 32 vs. 215 ± 67 spm; <i>P</i> < 0.001). Although this study was not powered to evaluate progression-free survival (PFS), preliminary evidence suggests that subjects treated with the MAM-A DNA vaccine had improved PFS compared with subjects who met all eligibility criteria, were enrolled in the trial, but were not vaccinated because of HLA phenotype.</p><p><b>Conclusion:</b> The MAM-A DNA vaccine is safe, capable of eliciting MAM-A–specific CD8 T-cell responses, and preliminary evidence suggests improved PFS. Additional studies are required to define the potential of the MAM-A DNA vaccine for breast cancer prevention and/or therapy. <i>Clin Cancer Res; 20(23); 5964–75. ©2014 AACR</i>.</p></div>
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