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The relationship between breast surgeons and radiation oncologists has always been a close one since we are truly “kindred spirits.” Our mutual goals are local and regional control while optimizing cosmesis without compromising overall cancer treatment. This relationship has grown since 2002 when the FDA cleared the MammoSite radiation therapy system (Hologic) which greatly simplified brachytherapy applicator placement. While previous interstitial brachytherapy required multiple catheter placements, the MammoSite balloon allowed the surgeon to place this single-lumen catheter into the lumpectomy cavity in their office or hospital (usually under ultrasound guidance). This greatly increased the need for communication between the specialties for optimal patient outcome. Discussion of proper patient selection, type of device utilized, and timing of placement were all necessary before the device could be placed by the surgeon.

Background The 70-gene signature (Mammaprint™) has been developed to predict the risk of distant metastases in breast cancer and select those patients who will have benefit in survival from adjuvant treatment. Aside from distant metastases, the development of locoregional recurrence is a significant predictor of survival. Given the strong association between locoregional recurrence and distant recurrence, we hypothesize that the 70-gene signature will be predictive of locoregional recurrence as well. Methods We updated follow-up and radiotherapy details for all 1053 unique breast cancer patients treated at the NKI-AVL who previously participated in various 70-gene signature validation studies. Diagnosis was between 1984 and 2006. All patients were primarily treated surgically with either breast-conservation therapy or mastectomy. Adjuvant treatment consisted of radiotherapy, chemotherapy and/or endocrine therapy as indicated. Known risk factors for locoregional recurrence including age, tumor free resection margins, tumor size, grade, ER status, Her2 status, nodal irradiation and tumor bed boost were included in our analysis in addition to the 70-gene signature result. Results Through 10 years of follow-up, 80 locoregional recurrences occurred. Patients with a 70-gene signature high risk result (n = 492) had a locoregional recurrence risk of 8.8% (95%CI: 6.3–11.3) at 5 years and 13.5 % (95%CI: 10.2–16.8) at 10 years, which was 2.6% (95%CI: 1.2–4.0) at 5 years and 5.7% (95%CI:3.5–7.9) at 10 years for patients with a low risk 70-gene signature (n = 561)(Logrank: p < 0.0001). Accordingly, patients with a high risk 70-gene signature had an approximately 3 times higher risk of locoregional recurrence than patients with a low risk 70-gene signature (univariable hazard ratio (HR) 2.89; 95%CI: 1.80–4.63). Adding the 70-gene signature to a Cox proportional hazard model containing age, size, grade, ER status, involvement of axillary lymph nodes, surgical treatment and adjuvant treatment (radiotherapy, chemotherapy and/or endocrine therapy), significantly improved the model (likelihood ratio: p = 0.007). In that model, the multivariable HR for high versus low 70-gene signature risk was 2.27 (95%CI: 1.24–4.15). Conclusion The 70-gene signature is able to predict the risk of locoregional recurrence, independent of known risk factors. Using the 70-gene signature may help in selecting those patients who will benefit from extensive adjuvant treatment. Additionally, the 70-gene signature may also select a group of patients at a low risk of locoregional recurrence who may be cured with limited local treatment alone. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-42.

Background: To determine six-year outcomes and patterns of failure following accelerated partial breast irradiation (APBI) within a pooled patient population from William Beaumont Hospital (WBH) and the American Society of Breast Surgeons (ASBrS) MammoSite® Registry Trial. Methods: 2,127 cases of early-stage breast cancer were treated using APBI (WBH: n=678; ASBrS: n=1,449). Three forms of APBI were used at WBH (interstitial, n=221; balloon-based, n=255; or 3D-CRT, n=206) while all Registry Trial patients received balloon-based brachytherapy. Patients with complete coding necessary for ASTRO Consensus Panel (CP) group assignment (n = 1,813) were divided into suitable (n = 661, 36.5%), cautionary (n = 850, 46.9%), and unsuitable (n = 302, 16.7%) categories. Tumor characteristics, clinical outcomes, and patterns of failure were analyzed according to CP group. Results: Median age was 65 years (32–94 years), median tumor size was 10.0mm (0–45mm), and median follow up was 59.4 months. The WBH cohort had more node-positive disease (6.9% vs. 2.6%, p < 0.01) and cautionary patients (49.5% vs. 41.8%, p = 0.06). Margin and estrogen receptor (ER) status were not different between WBH and ASBrS cohorts (p = 0.46, 0.82). Six-year rates of ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), and distant metastasis (DM) for the whole cohort were 3.2%, 0.7%, and 1.1%, respectively. Elsewhere failures (EF) were the predominant mode of in-breast recurrence for each CP group (suitable: 2.3%, cautionary: 2.5%, unsuitable: 4.9%, p = 0.16) as compared to true recurrences (TR) near the lumpectomy bed (suitable 0.9%, cautionary: 1.5%, unsuitable: 0.8%). No statistical difference in combined rates of ipsilateral recurrence (TR+EF) were observed between the three consensus panel groups (suitable: 3.2%, cautionary: 4.1%, unsuitable: 5.7%, p = 0.25). The six-year rate of distant metastasis was higher for cautionary and unsuitable groups (3.5–3.6% vs. 1.1% for suitable, p = 0.01), although cause-specific survival was the same for all patient categories (98.0–98.6%, all groups, p = 0.47). On multivariate analysis, no factor was associated with increased risk of true recurrence while ER negative status (OR: 4.13, p < 0.01) and a positive/close margin (OR: 2.70, p = 0.02) were associated with increased rates of elsewhere failure. Conclusions: Excellent overall outcomes following breast conserving surgery and APBI were seen at six years in our pooled analysis. A nonsignificant elevation in the rate of IBTR for cautionary and unsuitable consensus panel groups was due to new primary cancers elsewhere in the breast and not treatment failures. Despite a trend towards increased elsewhere failures in the unsuitable group, the current ASTRO CP guidelines were not able to adequately differentiate patients at an increased risk of IBTR or tumor bed failure within a large patient cohort treated with APBI. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-16-03.

Objectives: The American Society of Breast Surgeons (ASBS) Nipple Sparing Mastectomy Registry (NSMR) is a prospective, non- randomized, IRB approved multi-center registry. The ASBS NSMR has been designed to facilitate compilation of information on metrics utilized, techniques utilized, aesthetic outcomes, as well as oncologic outcomes for the nipple sparing mastectomy. The NSMR will be ongoing for 10 years with an initial N of 1000. Patient selection entails all patients undergoing a NSM at the participating institutions who have agreed to participate. We evaluated the incidence rate of nipple or nipple areolar complex ischemia after a nipple sparing mastectomy. Method: The first 173 patients entered into the ASBS NSMR (2011–2012) were analyzed for incidence rate of ischemia of the nipple or nipple areolar complex (NAC). Ischemia is defined as epidermolysis (partial thickness necrosis) or full thickness necrosis. Metrics analyzed included: postoperative NAC status, indication for surgery, patient characteristics, incision utilized, sub areolar and flap dissection technique, as well as cosmetic outcomes. Results: (Thirty-five) surgeons entered 265 NSMs on 173 patients into the ASBS NSM Registry. Indications included invasive carcinoma, DCIS, and prophylaxis. Incisions utilized included radial +/− peri -areolar extension, infra mammary fold, peri- areolar ellipse/ hemi batwing, previous lumpectomy site, and previous mastopexy incisions. Sub areolar and flap dissection technique included sharp +/− tumescent injection, electrocautery, or plasma blade. Reconstruction type included tissue expander, immediate implant, or autologous flap. Median follow-up was 5 months (range 1–16 months). The nipple or NAC in 33 (12%) of 265 mastectomies experienced some degree of ischemia. Out of a total of 265 mastectomies 3 (1%) required surgical debridement, 1 (0.3%) required surgical excision, and 29 (11%) experienced epidermolysis with full recovery (17 topical treatment and 12 no treatment). No correlation in incision type, method of dissection, utilization of separate axillary incision for SLNBx/AXLND, size or location of tumor, type of reconstruction, initial fill volume if tissue expanders utilized, previous breast surgery, previous radiation therapy, previous chemotherapy, smoking history, cup size, degree of ptosis, or indication for surgery was found in NACs undergoing ischemia versus those that did not. Cosmetic outcome assessed by the surgeon as well as patient satisfaction did not vary from the population that did not experience nipple/NAC ischemia. Cosmetic results were rated consistently as good or excellent. Conclusion: We report a 12% incidence rate of nipple or nipple areolar complex ischemia ranging from epidermolysis to full thickness necrosis: 3 (1%) requiring surgical debridement, 1 (0.3%) requiring excision, and 29 (11%) exhibiting epidermolysis with full recovery. Surgical debridement or excision was rarely necessary. Epidermolysis was found to resolve with no bearing on perceived cosmetic outcome. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-14-01.

To analyze outcomes in patients with ductal carcinoma-in-situ (DCIS) treated with accelerated partial breast irradiation (APBI) within a pooled set of patients.A total of 300 women with DCIS underwent APBI between April 1993 and November 2010 as part of American Society of Breast Surgeons MammoSite Registry Trial (n = 192) or at William Beaumont Hospital (n = 108). Patients with pure DCIS3 cm (n = 125) were assigned to the cautionary risk group per American Society of Radiation Oncology consensus panel guidelines for off-protocol use of APBI and analyzed compared to a pooled invasive suitable (n = 653) risk group and pooled invasive suitable/cautionary (n = 1,298) risk group.The rate of ipsilateral breast tumor recurrence (IBTR) for all 300 DCIS patients was 2.6 % at 5 years with no regional recurrences, while cause-specific survival was 99.5 % and overall survival (OS) was 96.4 %. When comparing the cautionary DCIS group to the invasive suitable/cautionary group, no difference in IBTR was noted (2.6 vs. 3.1 %, P = 0.90) with significant improvements in distant metastases (0 vs. 2.5 %, P = 0.05), disease-free survival (98.5 vs. 94.4 %, P = 0.05), and OS (95.7 vs. 90.8 %, P = 0.03) noted for DCIS patients. When comparing cautionary DCIS patients to invasive suitable patients, no difference in IBTR were noted (2.6 vs. 2.4 %, P = 0.76), while improved OS for DCIS patients was noted (95.7 vs. 90.9 %, P = 0.02).This analysis of the largest cohort of patients with DCIS treated with APBI supports previously reported excellent outcomes; as a result of small numbers of events, further data are necessary to confirm these findings.

Randomized trials demonstrate that lumpectomy plus whole-breast irradiation (WBI) yields survival equivalent to mastectomy. Studies that use WBI, however, typically report higher tumor bed recurrence rates than elsewhere failures (EF) (historically considered new primary lesions). The rate of true recurrence (TR) versus EF was queried for a large patient cohort treated with accelerated partial breast irradiation (APBI).A total of 1,449 cases of early-stage breast cancer were treated on the American Society of Breast Surgeons MammoSite(®) Registry Trial with lumpectomy plus balloon-based APBI (34 Gy, 10 BID fractions). A total of 1,255 cases (87 %) had invasive breast cancer, and 194 patients (13 %) had ductal carcinoma in situ. Rates of TR versus EF were calculated and compared to historical WBI controls.Median follow-up was 60 (range 0-109) months. Fifty patients (3.5 %) developed an ipsilateral breast tumor recurrence (IBTR). The 5-year actuarial rate of IBTR was 3.6 % (invasive breast cancer 3.6 %, ductal carcinoma in situ 3.4 %). Fourteen IBTR (1.1 %) were TR, while 36 (2.6 %) were EF. Estrogen receptor-negative status was associated with IBTR for invasive malignancies as well as for EF only (p0.001). Trends for increased rates of EF were noted for increased tumor size (p = 0.067) and extensive intraductal component (p = 0.087). No pathologic factors were explicitly associated with TR.IBTR after balloon-based APBI is low and similar to rates reported for WBI. In this data set, APBI had fewer tumor bed recurrences (presumably initial cancer recurrences) than EF (presumably new primary lesions). This suggests that balloon-based APBI has a tumor bed control rate that is at least equal to (and potentially higher than) WBI.

Purpose To compare rates of regional recurrence (RR) and overall survival (OS) between a pooled set of 1400 patients treated on the American Society of Breast Surgeons MammoSite (Hologic, Inc., Bedford, MA) Registry Trial to a cohort of 3600 patients treated with whole breast irradiation (WBI). Methods and Materials A total of 1440 women underwent accelerated partial breast irradiation (APBI) between 2002 and 2004 as part of the American Society of Breast Surgeons Registry Trial and a total of 3593 patients who received WBI were evaluated from the Surveillance Epidemiology and End Results database with treatment received between 1980 and 2009. A matched-pair analysis was performed based on age, receipt of hormonal therapy, chemotherapy, nodal status, and tumor size (1051 patients per arm). Rates of RR and OS were then analyzed for each group. Results After the match, no differences in patient characteristics were noted when tumor size was evaluated as a continuous variable. Rates of RR and OS were similar between the WBI and APBI groups. A Cox regression model found no difference between WBI and APBI with regard to RR; however, OS was improved in the APBI cohort (hazard ratio 0.008, p Conclusions With one of the largest patient populations to date comparing WBI and APBI, no difference in RR or OS was noted between WBI and APBI treatment. Until the publication of prospective Phase III trials, these data support the continued use of APBI on protocol and off protocol in appropriately selected patients.

Purpose To analyze a pooled set of nearly 2,000 patients treated on the American Society of Breast Surgeons (ASBS) Mammosite Registry Trial and at William Beaumont Hospital (WBH) to identify factors associated with local recurrence following accelerated partial breast irradiation (APBI). Methods and Materials A total of 1,961 women underwent partial breast irradiation between April 1993 and November 2010 as part of the ASBS Registry Trial or at WBH. Rates of ipsilateral breast tumor recurrence (IBTR), regional recurrence (RR), distant metastases (DM), disease-free survival (DFS), cause-specific survival (CSS), and overall survival (OS) were analyzed for each group and for the pooled cohort. Clinical, pathologic, and treatment-related variables were analyzed including age, tumor stage/size, estrogen receptor status, surgical margins, and lymph node status to determine their association with IBTR. Results The two groups weres similar, but WBH patients were more frequently node positive, had positive margins, and were less likely to be within the American Society for Radiation Oncology-unsuitable group. At 5 years, the rates of IBTR, RR, DM, DFS, CSS, and OS for the pooled group of patients were 2.9%, 0.5%, 2.4%, 89.1%, 98.5%, and 91.8%, respectively. The 5-year rate of true recurrence/marginal miss was 0.8%. Univariate analysis of IBTR found that negative estrogen receptor status (odds ratio [OR], 2.83, 95% confidence interval 1.55–5.13, p = 0.0007) was the only factor significantly associated with IBTR, while a trend was seen for age less than 50 (OR 1.80, 95% confidence interval 0.90–3.58, p = 0.10). Conclusions Excellent 5-year outcomes were seen following APBI in over 1,900 patients. Estrogen receptor negativity was the only factor associated with IBTR, while a trend for age less than 50 was noted. Significant differences in factors associated with IBTR were noted between cohorts, suggesting that factors driving IBTR may be predicated based on the risk stratification of the patients being treated.

BACKGROUND: The objective of this study was to examine clinical outcomes and patterns of failure in patients with early stage breast cancer who developed an ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) using accelerated partial breast irradiation (APBI). METHODS: In total, 1440 patients (1449 tumors) with early stage breast cancer who underwent BCT were treated with the MammoSite device to deliver APBI (34 Gray [Gy] in 3.4-Gy fractions). One thousand two hundred fifty-five patients (87%) had invasive breast cancer (IBC) (median tumor size, 10 mm), and 194 patients (13%) had ductal carcinoma in situ (DCIS) (median tumor size, 8 mm). The median follow-up was 60 months. RESULTS: Fifty patients (3.5%) developed an IBTR for a 5-year actuarial rate of 3.61% (3.65% for IBC and 3.36% for DCIS). It was determined that 36 recurrences (72%) represented new primary cancers, and 14 recurrences (28%) represented recurrences of the index lesion. Of the 32 recurrences with known histology, 78% were IBC, and 22% were DCIS. After IBTR, 28 of 38 patients (74%) underwent salvage mastectomy, and 9 of 38 patients (26%) had a second attempt at BCT. Adjuvant therapies included tamoxifen in 8 patients (16%) and systemic chemotherapy in 6 patients (12%). The 3-year rates of disease-free survival, cause-specific survival, and overall survival after IBTR were 58.7%, 92.1%, and 80.5%, respectively. CONCLUSIONS: With 5 years of follow-up, APBI produced clinical outcomes and patterns of failure comparable to those achieved with whole breast irradiation. Patients who developed an IBTR after APBI had excellent 3-year survival outcomes after salvage treatments. Cancer 2012. © 2012 American Cancer Society.

Most surgical oncologists receive exposure to clinical studies in their fellowships; however they receive little if any practical knowledge as to how to become a clinical researcher. This article will provide a broad introduction to setting up a community based surgical oncology research program with emphasis on the practical issues necessary to be successful. Topics to be discussed include choosing appropriate studies, setting up the team, IRB issues, financial concerns, helpful hints for enrolling patients, and much more. Getting a program going can seem daunting but ultimately will be very rewarding for both the surgeon and their patients. J. Surg. Oncol. 2011; 104:447–451. © 2011 Wiley-Liss, Inc.

Accelerated partial breast irradiation has become an important component of the management of early-stage breast cancer. While local control following APBI continues to be excellent with acceptable rates of acute and late toxicities, further refinement of patient selection guidelines and completion of the ongoing Phase III trials remain priorities for this growing segment of radiation oncology.

Lymphatic mapping with the identification and removal of axillary sentinel lymph nodes (SLNs) currently is standard practice in the surgical management of patients with early stage breast cancer.1-3 SLNs are accurate predictors of the status of nonsentinel lymph nodes, with a negative predictive value (NPV) approaching 100%.4 Intraoperative evaluation of SLNs allows for complete axillary dissection at the time of primary breast surgery if the SLNs are identified as positive for metastatic tumor, eliminating the need for a second surgical procedure with its associated costs, morbidity, and patient distress. Although there is general agreement that SLNs should be sliced at 2-mm intervals for pathologic evaluation, to our knowledge, no consensus exists regarding the optimal method for intraoperative and final pathologic examination of SLNs in breast cancer. Intraoperative evaluation may include frozen section, touch imprint cytology (IC), scrape cytology, or a combination of these techniques. Although the specificity of these techniques is excellent, the sensitivity varies widely, ranging from 50% to 75%.5-8 It has been reported that intraoperative frozen section analysis of the entire lymph node sectioned at 50-μm intervals dramatically increases the sensitivity of detecting metastatic disease, although it is not feasible or practical at most centers.4 Intraoperative rapid cytokeratin immunostaining also can improve the sensitivity of the evaluation9; however, this test is not widely available. There also is much variability in the protocols adopted by different laboratories for the final pathologic evaluation of SLNs in breast cancer. In addition, pathologic assessments examine a very small amount of the lymphoid tissue and are subject to interobserver variability in interpretation,10 prompting the development of standardized techniques. Molecular testing of SLNs can enable standardized, objective, and rapid evaluation. In this report, we describe a novel, fully automated molecular device, the “One Step Nucleic Acid Amplification (OSNA) Breast Cancer System” (Sysmex Corporation, Kobe, Japan), which combines reverse transcription (RT) with isothermal loop-mediated DNA amplification (RT-LAMP) for the detection of cytokeratin 19 (CK19) messenger RNA (mRNA) as a marker of metastatic carcinoma in SLNs. In a large, prospective, multicenter study, we compared the performance of the OSNA system with that of a detailed histopathologic examination of the lymph node and with IC for the detection of metastatic carcinoma in axillary SLNs in patients who had early stage breast cancer.

Peter D Beitsch1, Rakesh R Patel2, John D Lorenzetti3, James C Wurzer4, James C Tucker5, Susan J Laduzinsky6, Morris A Kugler71Dallas Surgical Group, Dallas, TX, USA; 2Valley Medical Oncology Consultants, Pleasanton, CA, USA; 3Breast Specialists, Egg Harbor Township, NJ, USA; 4AtlantiCare Regional Medical Center, Egg Harbor Township, NJ, USA; 5DCH Regional Medical Center – Tuscaloosa, AL, USA; 6Memorial and St Elizabeth’s Cancer Treatment Center, Swansea, IL, USA; 7Southern Illinois Surgical Consultants, Maryville, IL, USAIntroduction: Electronic brachytherapy (EBT) was developed to allow accelerated partial breast irradiation to be performed in a patient procedure room with minimal shielding. This observational, nonrandomized, multicenter study evaluated EBT as a post-surgical adjuvant radiation therapy for early stage breast cancer.Methods: This study included women aged 50 years or more with invasive carcinoma or ductal carcinoma in situ, tumor size ≤3 cm, negative lymph node status, and negative surgical margins. The endpoints were skin and subcutaneous toxicities, efficacy outcomes, cosmetic outcomes, and device performance. In this interim report, 1-month, 6-month, and 1-year follow-up data are available on 68, 59, and 37 patients, respectively.Results: The EBT device performed consistently, delivering the prescribed 34 Gy to all 69 patients (10 fractions/patient). Most adverse events were Grade 1 and included firmness, erythema, breast tenderness, hyperpigmentation, pruritis, field contracture, seroma, rash/desquamation, palpable mass, breast edema, hypopigmentation, telangiectasia, and blistering, which were anticipated. Breast infection occurred in 2 (2.9%) patients. No tumor recurrences were reported. Cosmetic outcomes were excellent or good in 83.9%–100% of evaluable patients at 1 month, 6 months, and 1 year.Conclusion: This observational, nonrandomized, multicenter study demonstrates that this EBT device was reliable and well tolerated as an adjuvant radiation therapy for early stage breast cancer.Keywords: radiation therapy, electronic brachytherapy, breast cancer

Background: Standard surgical techniques result in positive lumpectomy margins 20-40% of the time. These positive margins require surgical re-excision which places significant burden on the healthcare system and patients. The LUM Imaging System consists of a fluorescence-based imaging agent, a hand-held wide-field detector (LUM Imaging Device) used to image the surgical cavity walls intraoperatively in real-time after the resection of the main lumpectomy specimen, and a proprietary tumor detection algorithm that highlights regions in the tumor bed suspected to contain residual cancer. This imaging system was previously tested in a single-site clinical study. The current study is evaluating the imaging system in a multi-study, large patient cohort. Trial Design / Methods This trial (NCT03321929) is a non-randomized, open-label, multi-site trial designed to further refine the tumor detection algorithm utilized by the LUM Imaging System. This is a prospective, interventional feasibility study and is a pilot arm to a pivotal study which will evaluate the safety and efficacy of the LUM Imaging System. Up to 250 adult female breast cancer patients undergoing lumpectomies are being enrolled at sixteen medical centers across the US. LUM015, a fluorescence-based imaging agent, is injected prior to the subject’s lumpectomy procedure. Surgeons perform their standard of care lumpectomy followed by intraoperative imaging of the lumpectomy cavity with the LUM Imaging System. Specific Aims The primary objective is to assess performance characteristics of the LUM Imaging System and to refine the tumor detection algorithm. A secondary objective is to develop and refine the process of implementing the LUM Imaging System into institution-specific workflows during lumpectomies. Eligibility Criteria This study seeks to enroll women, over the age of 18 and with histologically or cytologically confirmed primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. In addition to be willing to follow study procedures, participating in an informed consent discussion, signing an informed consent form, and having baseline lab and screening values within protocol limits, enrolled subjects must meet the following key exclusion criteria: have no history of allergic reaction to polyethylene glycol, no history of allergic reaction to intravenous contrast agents, have not undergone any systemic therapies to treat their cancer, and will not be administered methylene blue or other dye for sentinel lymph node detection during their lumpectomy. Additional detailed eligibility criteria are listed in the protocol. Statistical Methods For categorical variables, summary tabulations of the number and percentage of patients within each category (with a category for missing data) of the parameter will be presented. For continuous variables, the number of patients, mean, median, standard deviation, minimum, and maximum values will be presented. The secondary objective will be met by evaluating a robust training and proficiency protocol for all enrolling institutions. Accrual To date, 208 subjects have participated in this LUM Imaging System trial. Contact Information Jorge Ferrer: jmferrer@lumicell.com Kate Smith: kate@lumicell.com Citation Format: Kate Smith, Jorge Ferrer, David Carr, Peter Blumencranz, Daleela Dodge, Nayana Dekhne, Irene Wapnir, Kelly Hunt, Linsey Gold, Stephanie Valente, Peter Beitsch, Donna Dyess, Shelly Hwang, Lynne Clark, Beth-Ann Lesnikoski, Anees Chagpar, Stephen Karp, Brian Schlossberg, Livia Gjylameti, Barbara Smith. Expansion into multiple institutions for training in the use of the LUM Imaging System for intraoperative detection of residual cancer in the tumor bed of female subjects with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-06-02.

BACKGROUND: The American Society for Radiation Oncology (ASTRO) consensus statement (CS) for the application of accelerated partial breast irradiation (APBI) was applied to patients who were treated with this technique on the American Society of Breast Surgeons MammoSite Registry Trial to determine potential differences in clinical outcome based on classification group. METHODS: Patients were classified based on the CS groups of “suitable,” “cautionary,” and “unsuitable.” Rates of ipsilateral breast tumor recurrence (IBTR), regional lymph node failure, distant metastases, disease-free survival, cause-specific survival, and overall survival were assessed. RESULTS: Of the 1449 cases who were treated, 1025 patients (71%) could be classified according to the CS groupings, including 419 patients (41%) who fit the “suitable” criteria, 430 patients (42%) who fit the “cautionary” criteria, and 176 patients (17%) who fit the “unsuitable” criteria. At a median follow-up of 53.5 months, the 5-year actuarial rates of IBTR for the “suitable,” “cautionary,” and “unsuitable” groups were 2.59%, 5.43%, and 5.28%, respectively (P = .1884). Univariate analysis of factors potentially associated with IBTR indicated that negative estrogen receptor status was the only variable associated with IBTR among patients with invasive breast cancer (odds ratio [OR], 4.01; P = .0003). Larger tumor size was associated with a greater risk of distant metastasis (OR, 3.05; P = .0001). Among patients with ductal carcinoma in situ, only age

Since the initial reports on use of MammoSite accelerated partial breast irradiation (APBI) for treatment of ductal carcinoma in situ (DCIS), additional follow-up data were collected. We hypothesized that APBI delivered via MammoSite would continue to be well tolerated, associated with a good cosmetic outcome, and carry a low risk for recurrence in patients with DCIS.From 2002-2004, 194 patients with DCIS were enrolled in a registry trial to assess the MammoSite. Follow-up data were available for all 194 patients. Median follow-up was 54.4 months; 63 patients had at least 5 years of follow-up. Data obtained included patient-, tumor-, and treatment-related factors, and recurrence incidence.Of the 194 patients, 87 (45%) had the MammoSite placed at lumpectomy; 107 patients (55%) had the device placed postlumpectomy. In the first year of follow-up, 16 patients developed a breast infection, though the method of device placement was not associated with infection risk. Also, 46 patients developed a seroma that was associated with applicator placement at the time of lumpectomy (P = 0.001). For patients with at least 5 years of follow-up, 92% had favorable cosmetic results. There were 6 patients (3.1%) who had an ipsilateral breast recurrence, with 1 (0.5%) experiencing recurrence in the breast and axilla, for a 5-year actuarial local recurrence rate of 3.39%.During an extended follow-up period, APBI delivered via MammoSite continued to be well tolerated for patients with DCIS. Use of this device may make lumpectomy possible for patients who would otherwise choose mastectomy because of barriers associated with standard radiation therapy.

590Background: In the multi-institutional NBRST study (NCT01479101), conducted from June 2011 to December 2014, 20% of ER+/HER2- patients were classified as Basal subtype by the 80-gene functional ...

e24289Background: Gene expression analysis using the 80-gene signature (80-GS) classifies breast cancers as luminal-, basal- or HER2-type based on intact signaling within the corresponding molecula...

Introduction Some melanoma patients who undergo sentinel lymph node (SLN) biopsy will have false-negative (FN) results. We sought to determine the factors and outcomes associated with FN SLN biopsy.

The American Society of Breast Surgeons enrolled women onto a registry trial to prospectively study patients treated with the MammoSite Radiation Therapy System (RTS) breast brachytherapy device. This report examines local recurrence (LR), toxicity, and cosmesis as a function of age in women enrolled onto the trial. A total of 1449 primary early-stage breast cancers were treated in 1440 women. Of these, 130 occurred in women younger than 50 years of age. Fisher’s exact test was performed to correlate age (

Purpose To evaluate cosmetic outcome and radiation recall in the American Society of Breast Surgeons registry trial, as a function of the interval between accelerated partial breast irradiation (APBI) and initiation of chemotherapy (CTX). Methods and Materials A total of 1440 patients at 97 institutions participated in this trial. After lumpectomy for early-stage breast cancer, patients received APBI (34 Gy in 10 fractions) with MammoSite RTS brachytherapy. A total of 148 patients received CTX within 90 days of APBI. Cosmetic outcome was evaluated at each follow-up visit and dichotomized as excellent/good or fair/poor. Results Chemotherapy was initiated at a mean of 3.9 weeks after the final MammoSite procedure and was administered ≤3 weeks after APBI in 54 patients (36%) and >3 weeks after APBI in 94 patients (64%). The early and delayed groups were well balanced with respect to multiple factors that may impact on cosmetic outcome. There was a superior cosmetic outcome in those receiving chemotherapy >3 weeks after APBI (excellent/good in 72.2% at ≤3 weeks vs. excellent/good in 93.8% at >3 weeks; p = 0.01). Radiation recall in those receiving CTX at ≤3 weeks was 9 of 50 (18%), compared with 6 of 81(7.4%) in those receiving chemotherapy at >3 weeks ( p = 0.09). Conclusion The majority of patients receiving CTX after APBI have excellent/good cosmetic outcomes, with a low rate of radiation recall. Chemotherapy initiated >3 weeks after the final MammoSite procedure seems to be associated with a better cosmetic outcome and lower rate of radiation recall. An excellent/good cosmetic outcome in patients receiving CTX after 3 weeks was similar to the cosmetic outcome of the overall patient population who did not receive CTX.

Purpose Patients with breast cancer metastasis to the sentinel lymph nodes (SLNs) generally undergo completion axillary lymph node dissection (cALND), either concurrently with SLN biopsy or at a second procedure. The impact of the timing of cALND on pathologic results and complications in these patients has not been examined. Patients and Methods We examined outcomes from SLN-positive patients in American College of Surgeons Oncology Group (ACOSOG) trials Z0010 and Z0011. Pathologic data examined included primary tumor characteristics, total number of SLNs recovered, positive SLN(s) and non-SLN(s) identified. Complications assessed included axillary seroma, paresthesia, arm morbidity and range of motion, and lymphedema. Results A total of 1,003 assessable patients with SLN metastasis had immediate (n = 425) or delayed (n = 578) cALND. The median number of SLNs and axillary LNs removed were the same between groups. Patients who had immediate cALND more often had larger tumors, SLN metastasis identified intraoperatively, two or more positive SLNs, and higher pathologic N stage. Axillary paresthesia, seroma, and impaired extremity range of motion were more common in the immediate group during the early postoperative period, but not at later time points. There was no difference in lymphedema at any time point. Conclusion In ACOSOG trials Z0010 and Z0011, LN recovery and long-term complications were similar after either delayed or immediate cALND for patients with metastasis to SLNs. Patients who undergo immediate cALND experience more short-term morbidity. With respect to staging and complications, there is no clear detriment for patients with a positive SLN who undergo a second procedure for cALND.

PurposeAn accurate, intraoperative sentinel lymph node (SLN) test could decrease delayed axillary dissections. Molecular tests may be more sensitive than current intraoperative tests but historically have not been rapid enough and have not been properly validated. We present the results from a large, prospective evaluation of the first rapid molecular SLN test, the Breast Lymph Node (BLN) Assay.MethodsA beta trial (n = 304) to determine the threshold levels of mammaglobin and cytokeratin 19 correlating with metastasis greater than 0.2 mm and a validation trial (n = 416) to validate the threshold cutoffs were conducted. Alternating portions from each SLN were processed for histology and the BLN Assay.ResultsBLN Assay performance against extensive permanent-section histology verified by central pathology review was similar to that expected of standard permanent-section histology: sensitivity, 87.6%; specificity, 94.2%; positive predictive value, 86.2%; and negative predictive value (NPV), 94.9%. In 319 patients with both frozen-section hematoxylin and eosin results and BLN Assay results, the BLN Assay had higher sensitivity (95.6%) and NPV (98.2%) than frozen section (sensitivity, 85.6%; NPV, 94.5%). The assay can be performed in approximately 36 to 46 minutes for one to three nodes.ConclusionThe BLN Assay allows a rapid evaluation of 50% of each SLN. Comparison with permanent-section histology on adjacent node pieces evaluated by expert pathologists indicated that the BLN Assay was more sensitive than current intraoperative techniques while maintaining high specificity. These data indicate that the assay may be clinically useful for intraoperative or postoperative axillary lymph node dissection decisions.

The Society of Surgical Oncology (SSO) created a task force to address the issue of surgical outcomes as it pertains to clinical practice. A survey of its members was conducted to determine which domains of “outcomes” are important and relevant to surgical oncologists. Participation of 1,929 SSO members was solicited via e-mail; 1,881 messages were successfully delivered. The survey instrument was administered via a web-based portal. The questionnaire was comprised of three parts: demographic information; rating scales to assess interest, involvement, and knowledge in the various domains of surgical outcomes; and questions to elicit preferences and opinions on current topics in the field of surgical outcomes. There was an overall response rate of 30% (570 of 1,881). Respondents were representative of the general membership with respect to demographics acquired in self-reported profiles. Most members valued the clinical application of evidence-based medicine, adoption of new technologies, and quality monitoring of cancer care as particularly important areas in outcomes research. SSO members also rated quality improvement measures as important. However, there is uncertainty whether current efforts to enforce quality indicators by third party payers or with public accountability would be helpful. Overall, this survey successfully delineated beliefs and views of the SSO members with regard to areas of particular interest in surgical outcomes, including improving the quality of cancer care. These findings have implications for planning future agendas for outcomes and health service research and in guiding national policy efforts on behalf of all SSO members.

BACKGROUND. This report presents 3 years of data on treatment efficacy, cosmetic results, and toxicities for patients enrolled on the American Society of Breast Surgeons MammoSite (Cytyc, Bedford, Mass) Breast Brachytherapy Registry Trial. METHODS. A total of 1440 patients (1449 cases) with early stage breast cancer who were undergoing breast-conserving therapy were treated with the MammoSite device to deliver accelerated partial breast irradiation (APBI) (34 Gy in 3.4 Gy fractions). Of these, 1255 (87%) cases had invasive breast cancer (IBC; median size = 10 mm), and 194 (13%) cases had ductal carcinoma in situ (DCIS; median size = 8 mm). Median follow-up was 30.1 months. RESULTS. Twenty-three (1.6%) cases developed an ipsilateral breast tumor recurrence (IBTR) for a 2-year actuarial rate of 1.04% (1.11% for IBC and 0.59% for DCIS). No variables were associated with IBTR. Six (0.4%) patients developed an axillary failure. The percentages of breasts with good to excellent cosmetic results at 12 (n = 980), 24 (n = 752), 36 (n = 403), and 48 months (n = 67 cases) were 95%, 94%, 93%, and 93%, respectively. Breast seromas were reported in 23.9% of cases (30% in open-cavity implants and 19% in closed-cavity implants). Symptomatic seromas occurred in 10.6% of cases, and 1.5% of cases developed fat necrosis. A subset analysis of the first 400 consecutive cases enrolled was performed (352 with IBC, 48 DCIS). With a median follow-up of 37.5 months, the 3-year actuarial rate of IBTR was 1.79%. CONCLUSIONS. Treatment efficacy, cosmesis, and toxicity 3 years after treatment with APBI using the MammoSite device are good and similar to those reported with other forms of APBI with similar follow-up. Cancer 2008. © 2008 American Cancer Society.

Introduction. We sought to evaluate the factors that affect sentinel lymph node (SLN) metastasis and survival among young melanoma patients (≤30 y). Methods. The Sunbelt Melanoma Trial is a multi-institutional prospective randomized trial of patients aged 18 to 70 y. Statistical analyses were performed to determine if patients ≤30 y of age had a significantly different outcome in terms of SLN metastasis, disease-free survival (DFS), and overall survival (OS) compared to older patients. Results. The median age of the 3031 patients in this study was 50 y (range 18 to 77 y); the 315 patients (10.4%) ≤30 y old were compared with those >30 y old. Of the 1944 patients with follow-up, the median follow-up was 48 mo. On univariate analysis, younger patients were more often female (54.7% versus 40.9%, P < 0.0005), with tumors

Purpose The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors. Experimental Design Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor. Results In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers. Conclusion Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors. Trial Registration Clinical Trial Registration: NCT00359190

Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively.

Background This study compared the surgical results of 2 localization methods—cryo-assisted localization (CAL) and needle-wire localization (NWL)—in patients undergoing breast lumpectomy for breast cancer. Methods A total of 310 patients were treated in an institutional review board–approved study with 18 surgeons at 17 sites. Patients were randomized 2:1 to undergo either intraoperative CAL or NWL. A cryoprobe was inserted under ultrasound guidance in the operating room and an ice ball created an 8- to 10-mm margin around the lesion. The palpable ice ball then was dissected. NWL was placed according to institutional practice and resection was performed in a standard fashion. Surgical margins, complications, re-excisions, tissue volume, procedure times, ease of localization, specimen quality, and patient satisfaction were evaluated. Positive margins were defined as any type of disease present 1 mm or less from any specimen edge. Results Positive margin status did not differ between the 2 groups (28% vs. 31%). The volume of tissue removed was significantly less in the CAL group (49 vs. 66 mL, P = .002). Re-excisions were similar in both groups. CAL was superior in ease of lumpectomy, quality of specimen, acute surgical cosmesis, short-term cosmesis, patient satisfaction, and overall procedure time for the patient. CAL had a lower invasive positive margin rate (11% vs. 20%, P = .039) but a higher observed ductal carcinoma in situ–positive margin rate (30% vs. 18%, approaching statistical significance, P = .052). Conclusions CAL is a preferred alternative to standard wire localization because it provides a palpable template, removes less tissue and improves cosmesis, decreases overall procedure time, and is more convenient for the patient and surgeon.

PurposeTo evaluate the prognostic significance of molecular staging using reverse transcriptase polymerase chain reaction (RT-PCR) in detecting occult melanoma cells in sentinel lymph nodes (SLNs) and circulating bloodstream.Patients and MethodsIn this multicenter study, eligibility criteria included patient age 18 to 71 years, invasive melanoma ≥ 1.0 mm Breslow thickness, and no clinical evidence of metastasis. SLN biopsy and wide excision of the primary tumor were performed. SLNs were examined by serial-section histopathology and S-100 immunohistochemistry. A portion of each SLN was frozen for RT-PCR. In addition, RT-PCR was performed on peripheral-blood mononuclear cells (PBMCs). RT-PCR analysis was performed using four markers: tyrosinase, MART1, MAGE3, and GP-100. Disease-free survival (DFS), distant–DFS (DDFS), and overall survival (OS) were analyzed.ResultsA total of 1,446 patients with histologically negative SLNs underwent RT-PCR analysis. At a median follow-up of 30 months, there was no difference in DFS, DDFS, or OS between the RT-PCR–positive (n = 620) and RT-PCR–negative (n = 826) patients. Analysis of PBMC from 820 patients revealed significant differences in DFS and DDFS, but not OS, for patients with detection of more than one RT-PCR marker in peripheral blood.ConclusionIn this large, prospective, multi-institutional study, RT-PCR analysis on SLNs and PBMCs provides no additional prognostic information beyond standard histopathologic analysis of SLNs. Detection of more than one marker in PBMC is associated with a worse prognosis. RT-PCR remains investigational and should not be used to direct adjuvant therapy at this time.

The MammoSite device was designed as a breast brachytherapy applicator and is currently used to deliver accelerated partial breast irradiation (APBI). We hypothesized that APBI delivered with the MammoSite device would be well tolerated and be associated with a good cosmetic outcome in patients with ductal carcinoma-in-situ (DCIS).From 2002 to 2004, 191 patients with DCIS were enrolled in a registry trial to assess the MammoSite applicator. Fifteen patients were excluded from analysis because of device- or patient-related factors; 7 patients were excluded after receiving a radiotherapy boost, thus leaving 169 patients available for study. Follow-up information was available for 158 patients. The average length of follow-up was 7.35 months. Forty-three patients had at least 1 year of follow-up.Skin spacing for the MammoSite applicator was as follows:5 mm, 3 patients (1.78%); 5 to 7 mm, 18 patients (10.65%); andor = 7 mm, 148 patients (87.57%). Patients with a device-to-skin distance ofor = 7 mm had the best cosmetic result. Patients with a device-to-skin distance ofor = 7 mm also had a lower incidence of radiation dermatitis. Data on 43 patients who were followed up for at least 1 year confirmed these findings. Additional adverse events were primarily related to skin changes, with breast infections occurring in five patients (3.16%). No patient in the study has experienced a recurrence.APBI delivered via MammoSite is well tolerated in patients with DCIS, and the lowest toxicity was obtained in patients with the greatest device-to-skin distance. Long-term follow-up data regarding patient satisfaction, cosmesis, and efficacy are needed and will be determined from a recently opened large randomized study.

Objective: To better understand the factors associated with the well-established gender difference in survival for patients with melanoma. Background Data: Gender is an important factor in patients with cutaneous melanoma. Male patients have a worse outcome when compared with females. The reasons for this difference are poorly understood. Methods: This prospective multi-institutional study included patients aged 18 to 70 years with melanomas ≥1.0 mm Breslow thickness. Wide excision and sentinel lymph node (SLN) biopsy was performed in all patients. Clinicopathologic factors, including gender, were assessed and correlated with disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). Results: A total of 3324 patients were included in the covariate analyses; 1829 patients had follow-up data available and were included in the survival analyses. Median follow-up was 30 months. On univariate analysis, men (n = 1906) were more likely than women to be older than 60 years (P < 0.0001), have thicker melanomas (P < 0.0001), have primary tumor regression (P = 0.0054), ulceration (P < 0.0001), and axial primary tumor location (P < 0.0001). On multivariate analysis, age (P = 0.0002), thickness (P < 0.0001), ulceration (P = 0.015), and location (P < 0.0001) remained significant in the model. There was no difference in the rate of SLN metastasis between men and women (P = 0.37) on multivariate analysis. When factors affecting survival were considered, the prognosis was worse for men as validated by lower DFS (P = 0.0005), DDFS (P < 0.0001), and OS (P < 0.0001). Conclusions: Male gender is associated with a greater incidence of unfavorable primary tumor characteristics without an increased risk for nodal metastasis. Nonetheless, gender is an independent factor affecting survival.

Background Cryoablation is a recent technological advance and has been used for the percutaneous treatment of breast fibroadenomas. Herein, we provide a retrospective summary of the early experience from a nationwide group. Methods We organized a national registry to document the community practice and adoption of an office-based system of cryoablation for breast fibroadenoma. Data were abstracted during the first 6 weeks after the procedure to assess acute outcome and potential complications. At 6-and 12-month follow-up intervals, additional data were collected regarding fibroadenoma resolution, cosmesis, and patient satisfaction. Results Fifty-three sites ablated 310 fibroadenomas. Early follow-up data on 256 lesions showed that the procedure was well tolerated with infrequent minor complications immediately after the procedure. At 6 and 12 months postprocedure, the remaining fibroadenoma volume progressively involuted.At both intervals, cosmesis was excellent, and patient satisfaction was rated high. Conclusions An early community experience with office-based cryoablation of breast fibroadenomas is encouraging and comparable to the initial experience of high-volume tertiary centers. More follow-up is necessary to determine long-term results and residual mammographic changes.

Amplification and overexpression of the HER-2 oncogene in breast cancer is felt to be stable over the course of disease and concordant between primary tumor and metastases. Therefore, patients with HER-2 -negative primary tumors rarely will receive anti-Her-2 antibody (trastuzumab, Herceptin) therapy. A very sensitive blood test was used to capture circulating tumor cells (CTCs) and evaluate their HER-2 gene status by fluorescence in situ hybridization. The HER-2 status of the primary tumor and corresponding CTCs in 31 patients showed 97% agreement, with no false positives. In 10 patients with HER-2 -positive tumors, the HER-2 /chromosome enumerator probe 17 ratio in each tumor was about twice that of the corresponding CTCs (mean 6.64 ± 2.72 vs. 2.8 ± 0.6). Hence, the ratio of the CTCs is a reliable surrogate marker for the expected high ratio in the primary tumor. Her-2 protein expression of 10 CTCs was sufficient to make a definitive diagnosis of the HER-2 gene status of the whole population of CTCs in 19 patients with recurrent breast cancer. Nine of 24 breast cancer patients whose primary tumor was HER-2 -negative each acquired HER-2 gene amplification in their CTCs during cancer progression, i.e., 37.5% (95% confidence interval of 18.8–59.4%). Four of the 9 patients were treated with Herceptin-containing therapy. One had a complete response and 2 had a partial response.

Immunohistochemical staining on breast sentinel lymph nodes (SLN) is controversial.Twenty-five SLN cases were reviewed by 10 pathologists (three academic, seven private) including 5 negative by both hematoxylin and eosin (HE) and immunohistochemistry, 11 micrometastases (2 mm) negative by HE but positive by immunohistochemistry, and 8 micrometastases and 1 macrometastasis (2 mm) positive for both HE and immunohistochemistry. Answers included "positive," "negative," and "indeterminate" for each slide.The mean number of incorrect responses was 6.6 for immunohistochemistry and 5 for HE. Twelve percent of cases were correct by all 10 pathologists; 80% of positive IHC cases had at least one pathologist score it incorrectly. As tumor cells decrease in number, incorrect responses increase. When tumor cells numbered less than 10, more than 30% of pathologists answered incorrectly.As tumor cells decrease in number pathologists' ability to recognize them decreases. We propose adding "indeterminate" to "positive" and "negative" when tumor cells number less than 10.

Importance The results of the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years. Longer follow-up was necessary because the majority of the patients had estrogen receptor–positive tumors that may recur later in the disease course (the ACOSOG is now part of the Alliance for Clinical Trials in Oncology). Objective To determine whether the 10-year overall survival of patients with sentinel lymph node metastases treated with breast-conserving therapy and sentinel lymph node dissection (SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women treated with axillary dissection. Design, Setting, and Participants The ACOSOG Z0011 phase 3 randomized clinical trial enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011 (Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases. Interventions All patients had planned lumpectomy, planned tangential whole-breast irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited. Main Outcomes and Measures The primary outcome was overall survival with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was disease-free survival. Results Among 891 women who were randomized (median age, 55 years), 856 (96%) completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was 86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI, 0-1.16]; noninferiorityP = .02). The 10-year disease-free survival was 80.2% in the SLND alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17];P = .32). Between year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups. Conclusions and Relevance Among women with T1 or T2 invasive primary breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, 10-year overall survival for patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection. These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes. Trial Registration clinicaltrials.gov Identifier:NCT00003855

Background: Sentinel lymph node biopsy (SLNB), performed using radioisotope tracer with or without blue dye, is a highly accurate method for staging the axilla in early breast cancer. A radioisotope tracer with or without blue dye is the most commonly used technique for SLNB. Superparamagnetic iron oxide mapping agents detected by a handheld magnetic probe have been explored to overcome the disadvantages of the standard technique which include the short half-life, availability, handling and disposal issues for radioisotope, and the risk of allergic reactions to blue dye. Iron oxide mapping agents have been shown to be non-inferior to the standard technique in European studies. The SentimagIC trial was designed to establish the non-inferiority of a new formulation of the magnetic tracer, SiennaXP, to the combination of radioisotope and blue dye and was required to support a US regulatory submission. Methods: Between January and December 2015, 160 patients with clinically node negative early stage breast cancer were recruited from six centers in the United States. Subjects received radioisotope injection then an intraoperative subareolar injection of SiennaXP and isosulfan blue dye prior to SLNB being performed. The sentinel node identification rate was compared between SiennaXP and the standard technique to evaluate concordance and non-inferiority. Results: 147 procedures were completed in 147 subjects. A total of 369 histologically confirmed nodes were excised. The nodal detection rate was 94.3% (348/369) with SiennaXP and 93.5% (345/369) with the standard technique (difference 0.8%, 95% binomial confidence interval lower bound -2.1%). The per-subject detection rate was 99.3% (145/146) with SiennaXP and 98.6% (144/146) with the standard technique (one subject excluded due to not contributing any analyzable nodes). There were 22 subjects with positive SLNs, of whom 21 (95.4%) were detected by both SiennaXP and the standard tracers. In one subject, a positive node was not identified by any tracer, but was removed as clinically suspicious. The number of nodes excised per subject was 2.4 for both SiennaXP and for the standard combined technique. Conclusion: This study showed SiennaXP is non-inferior to the standard dual technique of radioisotope and blue dye for axillary sentinel lymph node detection in early stage breast cancer and this provides a potential alternative to radioisotope and blue dye. Citation Format: Alvarado M, Bold R, Gittleman M, Beitsch P, Blair S, Harmer Q, Kivilaid K, Teshome M, Thompson A, Mittendorf E, Hunt K. SentimagIC: A non-inferiority trial comparing super paramagnetic iron oxide vs. Tc99 and blue dye in the detection of axillary sentinel nodes in patients with early stage breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-11.

The 70-gene signature (MammaPrint (TM)) has been developed to predict the risk of distant metastases in breast cancer and select those patients who may benefit from adjuvant treatment. Given the strong association between locoregional and distant recurrence, we hypothesize that the 70-gene signature will also be able to predict the risk of locoregional recurrence (LRR). 1,053 breast cancer patients primarily treated with breast-conserving treatment or mastectomy at the Netherlands Cancer Institute between 1984 and 2006 were included. Adjuvant treatment consisted of radiotherapy, chemotherapy, and/or endocrine therapy as indicated by guidelines used at the time. All patients were included in various 70-gene signature validation studies. After a median follow-up of 8.96 years with 87 LRRs, patients with a high-risk 70-gene signature (n = 492) had an LRR risk of 12.6 % (95 % CI 9.7-15.8) at 10 years, compared to 6.1 % (95 % CI 4.1-8.5) for low-risk patients (n = 561; P

Accelerated partial breast irradiation (APBI) is a technique of post-lumpectomy adjuvant radiation therapy for patients with early-stage breast cancer. The basis for treating just the lumpectomy cavity walls is derived from previous research examining local recurrence data that clearly shows most local recurrences occur within the area surrounding the lumpectomy (as opposed to elsewhere in the breast). Patient selection is critically important and several specialty societies have provided guidelines to choose appropriate patients. Many APBI techniques are available, including interstitial brachytherapy, applicator-based brachytherapy, intraoperative radiotherapy, and 3D-CRT. There is little prospective randomized data comparing APBI to whole breast irradiation, but there are numerous single-institution publications with some having follow-up to 12 years. Worldwide there are several phase III trials accruing patients, including the NSABP B-39/RTOG 0413 trial, which will evaluate APBI versus whole breast irradiation.

59 Background: There are limited tools to guide clinicians regarding the risk of locoregional recurrence (LRR) in patients wishing to pursue APBI. The purpose of this study was to develop a nomogram taking into account clinicopathologic features to predict LRR in patients treated with APBI for early stage breast cancer. Methods: A total of 2,000 breasts (1,990 women) were treated with APBI at William Beaumont Hospital (N=551) or on the ASBrS MammoSite Registry Trial (N=1,449). Techniques included multiplanar interstitial catheters (N=98), balloon-based brachytherapy (N=1,689), and 3D conformal radiotherapy (N=213). Clinicopathologic variables were gathered prospectively. A nomogram was formulated utilizing the Cox Proportional Hazards Regression model to predict for LRR. This was validated by generating a bias-corrected index and cross-validated with a C-index. Results: Median follow-up was 5.5 years (0.9 to 18.3). Of the 2,000 cases, 435 were excluded due to missing data. Univariate analysis found that age

Breast cancer surgery is headed for radical changes. Genomic tumor analysis will soon replace sentinel node biopsy for prognosis and determination of systemic therapy. Primary tumor analysis will identify pathways that are driving the cancer. Neoadjuvant treatment targeting these pathways will be administered until there is no evidence of the cancer within the breast. Local/regional therapy will be dictated by the tumor genomics and may just require targeted radiation without open resection. Breast cancer surgery will become obsolete in many cases. The breast cancer surgeon must adapt. Informed breast cancer surgeons will incorporate risk assessment, tissue acquisition, genetic counseling, and survivor advocacy to continue their current leadership role. We will evolve from the breast cancer extirpative surgeon into the local–regional therapy ‘‘director’’ with an even more collaborative model with our colleagues in radiation and medical oncology. Breast cancer surgeons will need to learn about targeted systemic therapy, which will be more often orally administered. This may lead to breast cancer surgeons treating with systemic targeted therapy as the medical oncology workforce reaches critically low levels. Open surgical resections will not disappear but will move toward the extremes; prophylactic nipple-sparing mastectomies will become more prevalent as genetic testing expands, as will salvage surgery for unresponsive tumors and those patients who refuse traditional therapy but accept surgical extirpation. The future will be bright for surgeons with the vision to adapt. Presidential address video access link: http://vimeo.com/ 95138064.

Background A subset analysis of the American Society of Breast Surgeons (ASBS) Registry Trial of patients with ductal carcinoma-in-situ (DCIS) was performed to compare results to patients receiving accelerated partial breast irradiation (APBI) for invasive tumors and to results in patients with DCIS receiving whole breast irradiation. Methods One hundred ninety-four cases of DCIS were identified from a total of 1,449 cancers treated on the ASBS Registry Trial. Details of the trial are previously published. Analysis of the entire group of cases was performed in regards to toxicity and local control. Results Median age was 62.1 years with 40.1% and 10.9% younger than 60 years and 50 years, respectively. Nuclear grade distribution was 35.6%, 31.4%, 17%, and 16% high, intermediate, low grade, and unknown, respectively. Necrosis was known to be present 42.3% of cases. Comedo/solid architecture was known to be present in 68% of cases. Median tumor size was 8.0 mm (range .1–45 mm, 15.5% unknown). Median margin was 2 mm; 2 cases had positive margins and 56 cases had less than 1-mm margins. The median follow-up time was 46.7 months. Five isolated ipsilateral breast failures occurred. The actuarial isolated ipsilateral breast failure rate was 2.45% at 4 years. The total in-breast 4-year actuarial failure rate was 3.0%. Three of the patients had a failure elsewhere (1.69% 4-year actuarial rate). Three of the failures were true recurrences (1.33% 4-year actuarial rate). Infection occurred in 16 patients for an 8.2% rate. Seroma formation was reported in 31%, with 13% and 12% symptomatic and requiring intervention, respectively. Seroma formation was statistically higher in open versus closed cases for all seromas. Cosmetic outcome was good to excellent in 90.3% of patients with evaluation at 36 months. Conclusions The ASBS Registry Trial includes the largest published collection of DCIS treated with APBI. Four-year follow-up shows result similar to those with invasive cancer treated with APBI, as well as DCIS treated with whole breast irradiation.

The purpose of this study was to examine data on treatment efficacy, cosmesis and toxicities for the final analysis of the American Society of Breast Surgeons MammoSite(®) breast brachytherapy registry trial.A total of 1,449 cases of early-stage breast cancer underwent breast conserving therapy. The single-lumen MammoSite(®) device was used to deliver accelerated partial breast irradiation (APBI) (34 Gy in 3.4 Gy fractions). Of these, 1,255 cases (87 %) had invasive breast cancer (IBC) and 194 cases had DCIS. Median follow-up was 63.1 months with 45 % of all patients having follow-up of 6 years or longer.There were 41 cases (2.8 %) that developed an ipsilateral breast tumor recurrence (IBTR) for a 5-year actuarial rate of 3.8 % (3.7 % for IBC and 4.1 % for DCIS). Tumor size (odds ratio [OR] = 1.1, p = 0.03) and estrogen receptor negativity (OR = 3.0, p = 0.0009) were associated with IBTR, while a trend was noted for positive margins (OR = 2.0, p = 0.06) and cautionary/unsuitable status compared with suitable status (OR = 1.8, p = 0.07). The percentage of patients with excellent/good cosmetic results at 60, 72, and 84 months was 91.3, 90.5, and 90.6 %, respectively. The overall rates of fat necrosis and infections remained low at 2.5 and 9.6 % with few late toxicity events beyond 2 years. The overall symptomatic seroma rate was 13.4 and 0.6 % beyond 2 years.The final analysis of treatment efficacy, cosmesis, and toxicity from the American Society of Breast Surgeons MammoSite(®) breast brachytherapy registry trial confirms previously noted excellent results and compares favorably with other forms of APBI with similar follow-up and to outcomes seen in selected patients treated with whole breast irradiation.

Study Background: Previously, we demonstrated safety and correlated induced immune response with survival in a Phase I study of FANG immunotherapy in advanced cancer patients. We now report long term follow-up (FU) of Phase I treated patients including assessment of relationships of dose, γIFN-ELISPOT response, and patient demographics to safety and survival. Methods: Safety, γIFN-ELISPOT response, and survival have been followed through 3+ years in advanced cancer patients who received ≥ 2-12 intradermal monthly injections of 1×107 or 2.5×107 cells/injection. Clinical and serological assessments were performed monthly, radiographic evaluations bimonthly, and γ-IFN-ELISPOT at baseline, and start of Cycle 2, 4, 6, 9, 12 then sequentially at FU. Results: Previously, we reported results on 45 patients with successful FANG construction followed for 1 year (28 treated (designated FANG); 17 not treated based on availability of other alternative treatments or failed manufacturing (designated No FANG)). We now report FU results through year 3 on those patients and an additional 29 patients (7 FANG, 22 No FANG) subsequently entered into Phase I study (total N=35 FANG; total N=39 No FANG). The median survival of the current expanded Phase I trial population is 562 days vs. 122 days (p=0.00001). This is similar to the originally published data from two years earlier. The γ-IFN-ELISPOT reaction was positive in 14 of the current FANG treated patients and negative in 12 FANG treated patients at Month 3 or less post first injection. Survival correlated with γ-IFN-ELISPOT reaction; median 836 days vs. 440 days with positive and negative ELISPOT respectively, (p=0.04). No long term adverse toxicity has been seen and there was no significant correlation of immune response or survival with either dose or demographics. Conclusions: Treatment with FANG vaccine continues to show long term safety and evidence of benefit in patients with many types of advanced cancer thereby justifying further efficacy testing.

Breast sentinel node biopsy (SNB) is a well-established procedure that has supplanted traditional axillary dissection for most clinically node-negative breast cancer patients. Techniques to identify the draining lymph nodes include colored dyes and radioactive compounds. The Sentimag system uses a non-radioactive magnetic tracer and a handheld magnetic probe to identify sentinel nodes (SNs). The Sentimag Intraoperative Comparison (SentimagIC) study compares the magnetic technique with the standard combination of radioisotope and isosulfan blue dye. Methods: SiennaXP is a nano device composed of coated iron oxide nanoparticles designed to optimize lymphatic uptake and SN retention. The Sentimag breast SNB technique involves injection of 2cc of SiennaXP fluid into Sappey's subareolar plexus followed by 5 minutes of breast massage and an additional 15 minutes of time to optimize drainage prior to beginning the procedure. The Sentimag hand held probe is then used to identify a magnetic 'hotspot' through the skin of the axilla. The usual transverse axillary incision is made and the magnetometer is used to identify the SNs. The SentimagIC study involves utilizing the Sentimag technique in combination with the 'standard' techniques of isosulfan blue dye and 99technetium sulfur colloid. All blue, radioactive and magnetic SNs are removed and identified as stained blue (from isosulfan blue dye) or black/brown (from SiennaXP) or not, and both radioactive and magnetic counts are taken ex vivo on each node. Currently there are 6 active sites with a total of 60 patients enrolled. Trial design: This is a pivotal, prospective, open label, multicenter, paired comparison of the magnetic technique with the standard of care for lymph node localization in patients with breast cancer. Primary endpoints: The lymph node detection rate with SentiMag / SiennaXP and the detection rate with the standard of care; and the safety of Sentimag / SiennaXP as indicated by adverse events. Eligibility: Diagnosis of primary breast cancer or pure ductal carcinoma in situ (DCIS); Scheduled for sentinel lymph node biopsy; Clinical negative node status (i.e. T0-3, N0, M0). Statistical methods: The primary hypothesis is that the magnetic technique is non-inferior to the standard technique. Based on an expected detection rate of 95% for both techniques and a non-inferiority margin of 5%, 140 subjects will be required to show non-inferiority with 85% power. Discussion: SNB for breast cancer is a robust procedure, able to identify the draining lymph nodes of the breast in essentially all patients. Many techniques have been used including radioactive tracers (utilized on most cases) and colored dyes. SentiMag utilizes a unique nano device that can identify the same draining nodes but without the radioactivity used in most procedures. Radioactive dyes must be handled carefully to minimize radiation exposure to healthcare providers and the patient from the manufacturing process, delivery to facility, injection under a nuclear physician license, and the surgical procedure. This novel technique may supplant radioactive tracers allowing SNs to be removed without the patient/healthcare providers being exposed to radiation or the scheduling inconvenience of pre-procedure injection. Citation Format: Beitsch PD, Hunt KK, Bold RJ, Gittleman MA, Blair SL, Alvarado MD, Harmer QJ. Magnetic nano-device for identification of the breast sentinel nodes – A novel method. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-02-03.

To determine factors important in local-regional recurrence (LRR) in patients with negative sentinel lymph nodes (SLNs) by hematoxylin and eosin (HE) staining.Z0010 was a prospective multicenter trial initiated in 1999 by the American College of Surgeons Oncology Group to evaluate occult disease in SLNs and bone marrow of early-stage breast cancer patients. Participants included women with biopsy-proven T1-2 breast cancer with clinically negative nodes, planned for lumpectomy and whole breast irradiation.Women with clinical T1-2,N0,M0 disease underwent lumpectomy and SLN dissection. There was no axillary-specific treatment for HE-negative SLNs, and clinicians were blinded to immunohistochemistry results. Systemic therapy was based on primary tumor factors. Univariable and multivariable analyses were performed to determine clinicopathologic factors associated with LRR.Of 5119 patients, 3904 (76.3%) had HE-negative SLNs. Median age was 57 years (range 23-95). At median follow-up of 8.4 years, there were 127 local, 20 regional, and 134 distant recurrences. Factors associated with local-regional recurrence were hormone receptor-negative disease (P = 0.0004) and younger age (P = 0.047). In competing risk-regression models, hormone receptor-positive disease and use of chemotherapy were associated with reduction in local-regional recurrence. When local recurrence was included in the model as a time-dependent variable, older age, T2 disease, high tumor grade, and local recurrence were associated with reduced overall survival.Local-regional recurrences are rare in early-stage breast cancer patients with HE-negative SLNs. Younger age and hormone receptor-negative disease are associated with higher event rates, and local recurrence is associated with reduced overall survival.

Purpose To determine whether the American Society for Radiation Oncology (ASTRO) Consensus Statement (CS) recommendations for accelerated partial breast irradiation (APBI) are associated with significantly different outcomes in a pooled analysis from William Beaumont Hospital (WBH) and the American Society of Breast Surgeons (ASBrS) MammoSite® Registry Trial. Methods and Materials APBI was used to treat 2127 cases of early-stage breast cancer (WBH, n=678; ASBrS, n=1449). Three forms of APBI were used at WBH (interstitial, n=221; balloon-based, n=255; or 3-dimensional conformal radiation therapy, n=206), whereas all Registry Trial patients received balloon-based brachytherapy. Patients were divided according to the ASTRO CS into suitable (n=661, 36.5%), cautionary (n=850, 46.9%), and unsuitable (n=302, 16.7%) categories. Tumor characteristics and clinical outcomes were analyzed according to CS group. Results The median age was 65 years (range, 32-94 years), and the median tumor size was 10.0 mm (range, 0-45 mm). The median follow-up time was 60.6 months. The WBH cohort had more node-positive disease (6.9% vs 2.6%, P P =.06). The 5-year actuarial ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), and distant metastasis (DM) for the whole cohort were 2.8%, 0.6%, 1.6%. The rate of IBTR was not statistically higher between suitable (2.5%), cautionary (3.3%), or unsuitable (4.6%) patients ( P =.20). The nonsignificant increase in IBTR for the cautionary and unsuitable categories was due to increased elsewhere failures and new primaries ( P =.04), not tumor bed recurrence ( P =.93). Conclusions Excellent outcomes after breast-conserving surgery and APBI were seen in our pooled analysis. The current ASTRO CS guidelines did not adequately differentiate patients at an increased risk of IBTR or tumor bed failure in this large patient cohort.

The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in overall survival or local-regional recurrence rates between patients planned for breast conservation therapy including whole breast irradiation (WBI) with one or two positive sentinel lymph nodes (SLNs) randomly selected to undergo axillary lymph node dissection (ALND) versus no further surgery. The current study was undertaken to evaluate the impact of Z0011 on surgical practice nationally.A survey was sent by e-mail to 2,759 members of the American Society of Breast Surgeons (ASBrS). Questions assessed the respondents' practice, familiarity with Z0011, and preferences for treating patients with one or two positive SLNs.Of those surveyed, 849 (30.8 %) responded. The majority (97 %) indicated familiarity with the data. Of those respondents, 468 (56.9 %) would not routinely perform ALND in patients planned to receive WBI, while 279 (36.0 %) would consider omission of completion ALND in patients planned to receive accelerated partial breast irradiation (APBI), and 218 (26.6 %) would consider omission of ALND in patients not planned to receive radiation. Academic and private practice surgeons were equally likely to incorporate Z0011 into practice.ACOSOG Z0011 has changed surgical practice. ASBrS respondents have embraced Z0011 and have changed their practice, omitting ALND in patients with one or two positive SLNs who will undergo WBI. However, many also omit ALND in patients undergoing surgery without radiation or with APBI. As these clinical scenarios were not studied in Z0011, further evaluation is required prior to changing clinical practice.

Purpose The American Society of Breast Surgeons enrolled women in a registry trial to prospectively study patients treated with the MammoSite Radiation Therapy System breast brachytherapy device. The present report examined the outcomes in women aged >70 years enrolled in the trial. Methods and Materials A total of 1,449 primary early stage breast cancers were treated in 1,440 women. Of these, 537 occurred in women >70 years old. Fisher's exact test was performed to correlate age (≤70 vs. >70 years) with toxicity and with cosmesis. The association of age with local recurrence (LR) failure times was investigated by fitting a parametric model. Results Older women were less likely to develop telangiectasias than younger women (7.9% vs. 12.4%, p = 0.0083). The incidence of other toxicities was similar. Cosmesis was good or excellent in 92% of the women >70 years old. No significant difference was found in LR as a function of age. The 5-year actuarial LR rate with invasive disease for the older vs. younger population was 2.79% and 2.92%, respectively ( p = 0.5780). In women >70 years with hormone-sensitive tumors ≤2 cm who received hormonal therapy ( n = 195), the 5-year actuarial rate of LR, overall survival, disease-free survival, and cause-specific survival was 2.06%, 89.3%, 87%, and 97.5%, respectively. These outcomes were similar in women who did not receive hormonal therapy. Women with small, estrogen receptor-negative disease had worse LR, overall survival, and disease-free survival compared with receptor-positive patients. Conclusions Accelerated partial breast irradiation with the MammoSite radiation therapy system resulted in low toxicity and produced similar cosmesis and local control at 5 years in women >70 years compared with younger women. This treatment should be considered as an alternative to omitting adjuvant radiotherapy for older women with small-volume, early-stage breast cancer.