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Background Breast-conserving surgery is a critical step in treatment with the goal of removing all cancer cells while minimizing the removal of healthy tissue. 15% to 25% of lumpectomy patients have positive margins and require a second surgery to achieve negative margins and reduce the risk of local recurrences. These positive margins are poorly predictive (35% PPV) of cancer left in the cavity, so most second surgeries find no residual cancer. Better detection tools are needed to guide in real-time the removal of cancer missed during the initial lumpectomy to reduce the number of second operations. The pegulicianine imaging agent is injected intravenously before surgery and its fluorescence signal is activated by proteases in tumor cells and cells at the tumor margin. The LUM Imaging System visualizes activated pegulicianine in the lumpectomy cavity via a hand-held detector and proprietary tumor detection software. This system was previously tested in multiple single-site studies and a prospective multi-site study that enrolled 234 patients and showed good ability to detect residual cancer in the lumpectomy cavity. Trial Design and Specific Aims: The current prospective, multi-center, randomized, blinded study was designed to show the clinical efficacy, system accuracy, and safety of the LUM Imaging System. It aims to demonstrate guided removal of residual cancer in the lumpectomy missed during the initial procedure and potentially reduce the rates of positive margins. This study is powered by an event-driven design that requires 70 truth-standard positive events. It is expected that approximately 390 women at fourteen medical centers across the US will be enrolled to achieve the number of events. Pegulicianine is injected 2-6 hours prior to the lumpectomy procedure. Surgeons perform standard of care (SOC) lumpectomy followed by blinded intraoperative imaging of the lumpectomy cavity with the LUM Imaging System in regions where SOC shaves will be taken. The patient is then randomized. If the random assignment is to the device arm, the surgeon is directed to excise margins that have positive LUM signal. Pathologists are blinded to the source of tissue removed (SOC vs. LUM) when conducting the pathology assessment. The amount of additional tissue volume resected is also evaluated. Patient reported outcome data is collected as a quality-of-life survey before and after the subject’s lumpectomy.Eligibility Criteria: This study seeks to enroll women with primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. Patients must not have a history of allergic reaction to polyethylene glycol, contrast agents, or have received neoadjuvant therapy to treat their current breast cancer. Use of blue dyes before imaging with the LUM System are not allowed. Additional detailed eligibility criteria are listed in the protocol. Accrual and Study Progress To date, 350 subjects have participated in this trial. This study is funded in part by the National Cancer Institute (5R44CA211013). This trial is registered as NCT03686215. Citation Format: Jorge Ferrer, David Carr, Peter Blumencranz, Irene Wapnir, Donna Dyess, Shelly Hwang, Nayana Dekhne, Daleela Dodge, Beth-Ann Lesnikoski, Kelly Hunt, Patricia Clark, Stephanie Valente, Marie Catherine Lee, Lynne Clark, Brian Schlossberg, Sean Madden, Alejandra Rodriguez, Kate Smith, Manna Chang, Barbara Smith. Pivotal study of the Lum imaging system for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer: The INCITE trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-12-03.

BACKGROUND The Current National Comprehensive Cancer Network guidelines recommend modified radical mastectomy (MRM) as the surgical treatment of choice for nonmetastatic inflammatory breast cancer (IBC). Limited studies have looked into the outcomes of breast conserving surgery (BCS) vs. MRM for IBC. METHODS National Cancer Database (NCDB) data from 2004 to 2014 were retrospectively analyzed. Patients' demographics, tumor characteristics, and overall survival (OS) trends were compared for BCS and MRM cases of nonmetastatic IBC. Univariate and multivariate analyses were performed. RESULTS A total of 413 (3.89%) BCS and 10,197 (96.11%) MRM cases were identified. Median follow-up was 58.45 months. Compared to MRM, BCS patients were more likely to be older, be African American, have Medicare/Medicaid or be uninsured, live in lower education ZIP codes, and live in a metropolitan area (all p

Positive margins following breast-conserving surgery (BCS) are often identified on standard pathology evaluation. Intraoperative assessment of the lumpectomy cavity has the potential to reduce residual disease or reexcision rate following standard of care BCS in real time.To collect safety and initial efficacy data on the novel pegulicianine fluorescence-guided system (pFGS) when used to identify residual cancer in the tumor bed of female patients undergoing BCS.This prospective single-arm open-label study was conducted as a nonrandomized multicenter controlled trial at 16 academic or community breast centers across the US. Female patients 18 years and older with newly diagnosed primary invasive breast cancer or ductal carcinoma in situ DCIS undergoing BCS were included, excluding those with previous breast cancer surgery and a history of dye allergies. Of 283 consecutive eligible patients recruited, 234 received a pegulicianine injection and were included in the safety analysis; of these, 230 were included in the efficacy analysis. Patients were enrolled between February 6, 2018, and April 10, 2020, and monitored for a 30-day follow-up period. Data were analyzed from April 10, 2020, to August 5, 2021.Participants received an injection of a novel imaging agent (pegulicianine) a mean (SD) of 3.2 (0.9) hours prior to surgery at a dose of 1 mg/kg. After completing standard of care (SOC) excision, pFGS was used to scan the lumpectomy cavity to guide the removal of additional shave margins.Adverse events and sensitivity, specificity, and reexcision rate.Of 234 female patients enrolled (median [IQR] age, 62.0 [55.0-69.0] years), 230 completed the trial and 1 patient with a history of allergy to contrast agents had an anaphylactic reaction and recovered without sequelae. Correlation of pFGS with final margin status on a per-margin analysis showed a marked improvement in sensitivity over standard pathology assessment of the main lumpectomy specimen (69.4% vs 38.2%, respectively). On a per-patient level, the false-negative rate of pFGS was 23.7% (9 of 38), and sensitivity was 76.3% (29 of 38). Among 32 patients who underwent excision of pFGS-guided shaves, pFGS averted the need for reexcision in 6 (19%).In this pilot feasibility study, the safety profile of pegulicianine was consistent with other imaging agents used in BCS, and was associated with a reduced need for second surgery in patients who underwent intraoperative additional excision of pFGS-guided shaves. These findings support further development and clinical performance assessment of pFGS in a prospective randomized trial.ClinicalTrials.gov Identifier: NCT03321929.

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: 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 fluorescent drug, 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. Methods: The Intraoperative Detection of Residual Cancer in Breast Cancer trial (NCT03321929) is a non-randomized, open-label, multi-site trial. This is a prospective, interventional feasibility study and is a pilot arm to a pivotal study which will further evaluate the safety and efficacy of the LUM Imaging System. This study enrolls 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. LUM015, a fluorescent drug, 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. In real-time, the LUM Imaging System highlights areas within the tumor bed that may contain, residual abnormal tumor tissue. Surgeons remove additional tissue based on the guidance of the LUM Imaging System. A maximum of two additional tissue shaves may be obtained. All excised tissue specimens are evaluated by routine pathology and correlated to the output of the LUM Imaging System. Results and Discussion: Sixteen medical centers across the United States enrolled 234 subjects into this study. Preliminary data on 141 subjects has been evaluated. The median age of enrolled women undergoing surgery using the Lumicell system was 61 years old. The histology of tumor type in women evaluated in this analysis is representative of the general population, with 21% diagnosed with ductal carcinoma in-situ (DCIS), 11% diagnosed with invasive lobular carcinoma, and 64% diagnosed with invasive ductal carcinoma (with or without DCIS features present). Most women (71%) presented with a palpable mass on physical examination prior to their lumpectomy surgery. Radiological imaging prior to lumpectomy showed scattered areas of fibroglandular density in 49% of the enrolled subjects and heterogeneously dense breast tissue in 42% of the enrolled subjects. The use of the LUM Imaging System positively impacted enrolled subjects; approximately 10% of subjects (N=14) had residual tumor detected and removed from the tumor bed guided by the LUM Imaging System after the standard of care surgery was completed. Without the use of this guidance technology, tumor tissue would have been left behind in this cohort of subjects, potentially requiring additional surgical intervention or other therapy, or local recurrence. The mean absolute volume of tissue removed due to guidance by the Lumicell System was 15 cc corresponding to about 15% of the total tissue removed. The LUM Imaging System correctly identified all positive margins in 28% of subjects with a positive margin after standard of care, and directed excision of additional tissue to create a wider margin. 12% of the patients with positive margins were converted to a negative margin by removing additional tissue guided by this imaging system. Future studies are planned that will measure the sensitivity and specificity of the device. Citation Format: 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, Sean Madden, Manna Chang, Kate Smith, David Strasfeld, W David Lee, Barbara Smith. Results from the 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 clinical trial [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 P1-20-06.

Background Accurate identification of the tumor bed after breast-conserving surgery (BCS) ensures appropriate radiation to the tumor bed while minimizing normal tissue exposure. The BioZorb® three-dimensional (3D) bioabsorbable tissue marker provides a reliable target for radiation therapy (RT) planning and follow-up evaluation while serving as a scaffold to maintain breast contour. Methods After informed consent, 818 patients (826 breasts) implanted with the BioZorb® at 14 U.S. sites were enrolled in a national registry. All the patients were prospectively followed with the BioZorb® implant after BCS. The data collected at 3, 6, 12, and 24 months included all demographics, treatment parameters, and provider/patient-assessed cosmesis. Results The median follow-up period was 18.2 months (range, 0.2–53.4 months). The 30-day breast infection rate was 0.5 % of the patients (n = 4), and re-excision was performed for 8.1 % of the patients (n = 66), whereas 2.6 % of the patients (n = 21) underwent mastectomy. Two patients (0.2 %) had local recurrence. The patient-reported cosmetic outcomes at 6, 12, and 24 months were rated as good-to-excellent by 92.4 %, 90.6 %, and 87.3 % of the patients, respectively and similarly by the surgeons. The radiation oncologists reported planning of target volume (PTV) reduction for 46.2 % of the patients receiving radiation boost, with PTV reduction most commonly estimated at 30 %. Conclusions This report describes the first large multicenter study of 818 patients implanted with the BioZorb® tissue marker during BCS. Radiation oncologists found that the device yielded reduced PTVs and that both the patients and the surgeons reported good-to-excellent long-term cosmetic outcomes, with low adverse effects. The BioZorb® 3D tissue marker is a safe adjunct to BCS and may add benefits for both surgeons and radiation oncologists.

The appropriateness of substituting sentinel lymph node dissection (SLND) and regional nodal irradiation (RNI) for axillary lymph node dissection (ALND) in patients with residual lymph node (LN) disease following neoadjuvant chemotherapy (NAC) is unknown. We used the National Cancer Database (NCDB) to compare survival following SLND and ALND in breast cancer patients with residual LN disease. We analyzed NCDB patients, treated between 2006 and 2014, with cT1–3, cN1, cM0 breast cancer and residual disease in 1–3 axillary LNs (ypN1) following NAC. Patients were grouped into those who received SLND (defined as removal of ≤ 4 LNs) and RNI, or ALND and RNI. Patients were matched for all patient, tumor, and treatment characteristics. We identified 1313 eligible patients in the ALND group and 304 patients in the SLND group. For the matched cohorts, SLND was associated with significantly lower survival in both univariate and doubly robust multivariable analyses (MVA) (HR 1.7, 95% CI 1.3–2.2, P

Purpose/Objective(s) There is a paucity of data regarding the use of whole breast irradiation (WBI) as part of breast conserving therapy (BCT) in women diagnosed with breast cancer who had undergone prior breast implant-based augmentation. In this population, we investigated various factors that impact radiation related toxicities, including the need for additional cosmetic surgery. Materials/Methods A retrospective review was performed for a single institution, with queries done on health-system medical records, radiation therapy medical records, radiology mammography studies, and internal radiation therapy and toxicity databases. We included patients with a prior history of breast implant-based augmentation who subsequently underwent BCT and WBI. Patient and treatment characteristics were collected and reported, and univariate analyses comparing factors correlating with toxicity endpoints were performed. Long-term cosmesis was assessed by the patient's radiation oncologist during routine follow-up visits via the Harvard grading criteria. Results 35 patients treated at our institution between 2006 and 2020 were included in our analyses, with a median follow up time of 2.4 years. Of these, 28 were treated with conventionally fractionated WBI (1.8-2 Gy/Fx) and 7 were treated with hypofractionated WBI (2.66 Gy/Fx). Good/excellent long-term cosmesis was observed in 94% of all patients. 44% of patients ultimately needed additional cosmetic surgery at some point after radiation. Indications for additional surgery included capsular contracture (10), wound complications (2), implant rupture (1), volume loss (1), and asymmetry (1). Fourteen patients (50%) treated with conventionally fractionated WBI and one patient (14%) patient treated with hypofractionated WBI required additional surgery, but this difference was not significant on UVA (P = 0.12). Other factors found not to be significantly associated with rates of additional surgery included BMI, stage, the volume of the breast receiving 105% or 110% of the prescription dose, and presence or absence of bolus during treatment. No patients experienced local or regional recurrence. Conclusion Patients with a prior history of breast implantation often experience good long-term cosmesis with a moderate risk of needing additional future surgery. The use of hypofractionated WBI was not associated with worse cosmetic outcome or an increase in need for additional cosmetic surgery.

Background Breast-conserving surgery is a critical first step in treatment with the goal of removing all cancer cells while minimizing the removal of healthy tissue. 15% to 25% or more of lumpectomy patients have positive margins and require a second surgery to achieve negative margins and reduce the risk of local recurrences. These positive margins are poorly predictive (35% PPV) of cancer left in the cavity, so most second surgeries find no residual cancer. Better detection tools are needed to identify residual cancer in real time during the initial lumpectomy to reduce the number of second operations. LUM015 is a protease-activated fluorescent imaging agent that accumulates in tumor cells and tumor associated macrophages. The LUM Imaging System camera visualizes the intravenously injected LUM015 in the lumpectomy cavity via a hand-held wide field detector and proprietary tumor detection software. This imaging system was previously tested in multiple single-site studies and a large, prospective multi-site study that enrolled 234 patients and showed good ability to detect residual cancer in the lumpectomy cavity. Trial Design The current prospective, multi-center, randomized, blinded study was designed to demonstrate the clinical efficacy, system accuracy, and safety of the LUM Imaging System. It aims to identify residual cancer in the lumpectomy cavity to reduce the rates of positive margins. This study seeks to enroll women with primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. Approximately 310 women at 14 US medical centers will be enrolled. This study is powered by an event-driven design that requires 70 patients to be enrolled that have a ‘truth-standard positive' event, which is the identification of cancer in a protocol defined tissue type. To be eligible, patients must not have a history of allergic reaction to polyethylene glycol, intravenous contrast agents, or systemic therapies to treat their cancer. Use of blue dyes before imaging with the LUM System are not allowed. LUM015 is injected prior to the lumpectomy procedure. Surgeons perform standard of care (SOC) lumpectomy and perform blinded intraoperative imaging of the lumpectomy cavity with the LUM Imaging System in regions where SOC shaves will be taken. The patient is then randomized. If the random assignment is to the device arm, the surgeon is directed to excise margins that the LUM System indicates are positive for cancer. Pathologists are blinded to the type of tissue removed when conducting the pathology assessment. Patient reported outcome data is collected as a quality-of-life survey before and after the subject's lumpectomy. Additional detailed eligibility criteria are in the protocol. To date, 166 patients have participated in this trial. This trial is registered as NCT03686215. Citation Format: Jorge Ferrer, David Carr, Peter Blumencranz, Irene Wapnir, Donna Dyess, Shelly Hwang, Nayana Dekhne, Daleela Dodge, Beth-Ann Lesnikoski, Kelly Hunt, Patricia Clark, Stephanie Valente, M. Catherine Lee, Lynne Clark, Brian Schlossberg, Sean Madden, Alejandra Rodriguez, Kate Smith, Manna Chang, Barbara Smith. Pivotal Study of the LUM Imaging System for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT259.

Background: For many women with breast cancer, breast-conserving surgery is a critical first step in treatment with the goal of removing all cancer cells while minimizing the removal of healthy tissue. 15% to 25% or more of lumpectomy patients have positive margins and require a second surgery to achieve negative margins and reduce the risk of local recurrences. These positive margins are poorly predictive (35% PPV) of cancer left in the cavity, so most second surgeries find no residual cancer. Better detection tools are needed to identify residual cancer in real time during the initial lumpectomy to reduce the number of second operations. LUM015 is a protease-activated fluorescent imaging agent that accumulates in tumor cells and tumor associated macrophages. The LUM Imaging System camera visualizes the intravenously injected LUM015 in the lumpectomy cavity via a hand-held wide field detector and proprietary tumor detection software. This imaging system was previously tested in multiple single-site studies and a large, prospective multi-site study that enrolled 234 patients and showed good ability to detect residual cancer in the lumpectomy cavity. Trial Design: The current prospective multi-center, two-arm randomized, blinded study was designed to demonstrate the clinical efficacy, system accuracy, and safety of the LUM Imaging System. It aims to identify residual cancer in the lumpectomy cavity in order to reduce the rates of positive margins. This study seeks to enroll women with confirmed primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy. The planned enrollment is 170 women being treated at fifteen medical centers across the US. To be eligible, patients must not have a history of allergic reaction to polyethylene glycol, intravenous contrast agents, or systemic therapies to treat their cancer. Use of blue dyes before imaging with the LUM System are not allowed. LUM015 is injected prior to the lumpectomy procedure. Surgeons perform standard of care (SOC) lumpectomy and perform blinded intraoperative imaging of the lumpectomy cavity with the LUM Imaging System in any regions where SOC shaves will be taken. The patient is then randomized either the further use of device or not. If the random assignment is to the device arm, the surgeon is directed to excise margins that the LUM System indicates are positive for cancer. Pathologists are blinded to the type of tissue removed when conducting the pathology assessment. Patient reported outcome data is collected as a quality of life survey before and after the subject's surgery. Additional detailed eligibility criteria are listed in the protocol. To date, 22 subjects have participated in this trial. This trial is registered as NCT03686215. Citation Format: Jorge Ferrer, David Carr, Irene Wapnir, Kelly Hunt, Peter Blumencranz, Nayana Dekhne, Daleela Dodge, Donna Lynn Dyess, Shelley Hwang, Stephanie Valente, Lynne Clark, Beth-Ann Lesnikoski, Anees Chagpar, Paticia Clark, Marie Catherine Lee, Brian Schlossberg, Sean Madden, Livia Gjylameti, Manna Chang, Kate Smith, Barbara Smith. Pivotal study of the LUM Imaging System for assisting intraoperative detection of residual cancer in the tumor bed of female patients with breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT281.

// Bryan J. Thibodeau 1 , Vincent Lavergne 2 , Nayana Dekhne 3 , Pamela Benitez 3 , Mitual Amin 4 , Samreen Ahmed 1 , Jean L. Nakamura 2 , Philip R. Davidson 5 , Alice O. Nakamura 5 , Inga S. Grills 6 , Peter Y. Chen 6 , Jessica Wobb 6 and George D. Wilson 1, 6 1 Beaumont BioBank, Beaumont Health, Royal Oak, MI, USA 2 Department of Radiation Oncology, University of California, San Francisco, CA, USA 3 Department of Surgery, Beaumont Health, Royal Oak, MI, USA 4 Department of Pathology, Beaumont Health, Royal Oak, MI, USA 5 Department of Finance and Statistical Analysis, University of Alberta, Edmonton, Alberta, Canada 6 Department of Radiation Oncology, Beaumont Health, Royal Oak, MI, USA Correspondence to: George D. Wilson, email: george.wilson@beaumont.edu Keywords: angiosarcoma; radiation-associated; breast; mutational signature; next generation sequencing Received: September 15, 2017 Accepted: October 13, 2017 Published: January 19, 2018 ABSTRACT Purpose: Radiation-associated breast angiosarcomas are a rare complication of radiation therapy for breast carcinoma. With relatively little is known about the genetic abnormalities present in these secondary tumors, we examined genomic variation in biospecimens from radiation-associated breast angiosarcomas. Experimental Design: Patients were identified that had a previous breast cancer diagnosis, received radiation therapy, and developed angiosarcoma in the ipsilateral breast as the earlier cancer. Tumor regions were isolated from archival blocks using subsequent laser capture microdissection. Next generation sequencing was performed using a targeted panel of 160 cancer-related genes. Genomic variants were identified for mutation and trinucleotide-based mutational signature analysis. Results: 44 variants in 34 genes were found in more than two thirds of the cases; this included 12 variants identified as potentially deleterious. Of particular note, the BRCA1 DNA damage response pathway was highly enriched with genetic variation. In a comparison to local recurrences, 14 variants in 11 genes were present in both the primary and recurrent lesions including variants in genes associated with the DNA damage response machinery. Furthermore, the mutational signature analysis shows that a previously defined IR signature is present in almost all of the current samples characterized by predominantly C→T substitutions. Conclusions: While radiation-associated breast angiosarcomas are relatively uncommon, their prognosis is very poor. These data demonstrate a mutational pattern associated with genes involved in DNA repair. While important in revealing the biology behind these tumors, it may also suggest new treatment strategies that will prove successful.

The purpose of the study was to show that delayed axillary lymph node dissection (ALND) has higher rates of lymphedema compared with immediate ALND, using data from NSABP-B32 at Beaumont Hospital.NSABP B-32 at Beaumont had 207 patients with follow-up data on 199 patients, randomizing clinically negative axilla to sentinel lymph node biopsy (SLNB)+ALND (GrA N=98), and SLNB+cytology±ALND (GrB N=101). All patients had preoperative volumetric arm measurements and only node negatives had routine postoperative measurements assessing lymphedema for 36 months. We contacted node-positive patients for postoperative measurements for this study. Twenty-four and 15 cytology-positive patients had SLNB+ALND in GrA and GrB, respectively (SubGrA1 N=24; SubGrB1 N=15). Fourteen hematoxylin and eosin-positive patients had delayed ALND (SubGrB2a N=14).Lymphedema rate for node-positive SLNB+ALND was 10.3% [SubGrA1 (3/24)+SubGrB1 (1/15)=4/39] and node-negative SLNB+ALND was 6.8% (SubGrA2=5/74). Lymphedema was 14.3% for delayed ALND in SubGrB2a (2 of 14) and 0% for 72 SLNBs in SubGrB2b. Our study comparing immediate and delayed ALND lymphedema was not statistically significant (10.3% vs. 14.3%, P=0.65). Comparing node-negative ALND (SubGrA2= 5/74=6.8%) to node-positive ALND (A1+B1+B2a=6/53=11.3%) was not statistically significant (P=0.52). Comparing lymphedema for node-negative ALND (SubGrA2) to SLNB (SubGrB2b) only approached significance (6.8% vs. 0%, P=0.058).The rate of lymphedema was higher in delayed ALND but not statistically significant. Comparison, however, is difficult, given the limited sample size. We urge the other centers of NSABP-B32 to validate this, by contacting the node-positive patients for measurements. The lymphedema rate for SLNB alone was 0% and approached statistical significance when compared with node-negative ALND.

Background This study reports the rate of breast reconstruction failure and cosmetic outcomes after postmastectomy radiation therapy (PMRT) with temporary tissue expanders (TEs) or implants in place. Patients and Methods Ninety-four patients underwent mastectomy (93 unilateral, 1 bilateral; 95 cases total) and immediate TE reconstruction followed by PMRT. Ninety TEs and 5 permanent implants were irradiated. All patients received a dose of 5400 cGy given in 180-cGy fractions to the reconstructed breast. Twenty-one patients (22%) received tangents alone and 74 patients (78%) were treated with tangents and a supraclavicular field using a monoisocentric technique. Bolus was used in 91 patients (96%). Eighty-eight patients (93%) received chemotherapy and 78 patients (82%) received endocrine therapy. Results With a median follow-up of 24.1 months, 19 patients (20%) experienced failure of reconstruction. The 1-, 2-, and 3-year actuarial rate of reconstruction failure was 9.7%, 19.3%, and 25.5%, respectively. Infection was the most common cause of failure. Of the 19 failures, 8 patients underwent salvage procedures with flap reconstruction. Univariate analysis was performed examining age, chemotherapy use, hormone therapy use, use of a supraclavicular field, smoking status, diabetes, hypertension, and menopausal status. No risk factors were found to be associated with reconstruction failure. In patients who did not experience reconstruction failure, good/excellent cosmesis was observed in 75% of patients. Conclusion In the current series of women with a high risk of locoregional recurrence, PMRT with a TE/implant in place provides good cosmesis in the majority of women, with an acceptable risk of expander or implant loss.

Limited data are available on the implementation of a high-risk assessment program in the construct of a community clinical oncology program. The development of a high-risk breast cancer screening program at our institution identified 15%-20% of patients screened as high risk, with limited increases in structural or personnel requirements. Identification of patients as high risk could potentially improve outcomes by allowing for individualized prevention strategies and more appropriate high-risk surveillance.The implementation of a program that incorporates a risk assessment questionnaire (RAQ) to identify high-risk patients in a community-based health system was evaluated.Women with no history of breast cancer or ductal carcinoma in situ who were undergoing annual screening mammography were offered an RAQ. Cases determined to be high risk (Gail lifetime risk ≥20% or as indicated through personal and/or family history) were offered referral to our High-risk Breast Cancer Program. A retrospective data review was conducted on completed questionnaires.A total of 5878 women underwent evaluation with the RAQ between September 2009 and August 2010. The mean age of the cohort was 55 years old, with 84.9% (4990) of participants being white, and 6.8% (400) African American. In the entire population, 45.7% (2446) had at least 1 first-degree relative with breast cancer (BC), and 923 (17.2%) women were found to be high risk by the Gail model. Beyond the Gail model, 53 (0.9%) women had undergone prior chest radiation, 34 (0.6%) had a male relative with BC, 200 (3.4%), had 3 or more relatives with BC on one side of their family, 308 (5.2%) had a relative with breast and ovarian cancer on one side of the family, and 105 (1.8%) noted 2 relatives with BC with onset under age 50 years on the same side of the family.Our experience indicates that the identification of women at high risk for BC can be easily incorporated into an annual screening mammography visit. Identification of these patients as high risk can allow for individualized, more-appropriate surveillance and prevention.

To compare outcomes after accelerated partial breast irradiation (APBI) between node-negative and node-positive patients.A total of 534 patients with early-stage breast cancer received APBI including 39 node-positive (N+) cases. Clinical, pathologic, and treatment-related factors were compared between node-negative (N-) and N+ cohorts. Local recurrence (LR), regional recurrence (RR), axillary failure (AF), distant metastases (DM), disease-free survival (DFS), cause-specific survival (CSS), and overall survival (OS) were analyzed.N+ patients were younger (p = 0.04), had larger tumors (p0.001), and were more likely to receive chemotherapy (p0.001). Mean follow-up was 7.8 years for N+ patients and 6.3 years for N- patients (p = 0.06). No differences were seen in 5-year actuarial rates of LR (2.2% vs. 2.6%, p = 0.86), AF (0% vs. 0%, p = 0.69), DFS (90.0% vs. 88.0%, p = 0.79), or OS (91.0 vs. 84.0%, p = 0.65) between the two groups, whereas higher rates of RR (0% vs. 6.1%, p0.001) and DM (2.2% vs. 8.9%, p = 0.005) were noted in N+ patients. A trend for improved CSS (p = 0.06), was seen in N- patients. Age, tumor size, receptor status, T-stage, chemotherapy, APBI technique, and nodal status (p = 0.86) were not associated with LR, while a trend for an association with LR was noted with close/positive margins, (p = 0.07), and failure to receive adjuvant hormonal therapy (p = 0.06).No differences were seen in the rates of LR or AF between N- and N+ patients after APBI. These results support the continued enrollment of node-positive patients in Phase III trials evaluating the efficacy of APBI including the National Surgical Adjuvant Breast and Bowel Project-B39/Radiation Therapy Oncology Group 0413.

Purpose: To examine the rate of breast reconstruction failure and cosmetic outcomes following post-mastectomy radiation therapy (PMRT) with temporary tissue expander or implant in place. Methods and Materials: Ninety-four patients with 95 primary breast malignancies underwent mastectomy and immediate tissue expander reconstruction followed by PMRT. Ninety tissue expanders and five implants were irradiated. All patients received a dose of 5,400 cGy given in 180 cGy fractions. Twenty-one patients (22%) received tangents alone and seventy-four patients (78%) were treated with tangents and a supraclavicular field via a mono-isocentric technique. Bolus was used in 91 patients (96%). Eighty-eight patients (93%) received chemotherapy and 78 patients (82%) received endocrine therapy. Results: With a median follow up of 22.4 months, nineteen patients (20%) developed a reconstruction failure. Ten patients lost their tissue expanders with a median time to reconstruction failure of 7 months (range 3–9 months) while ten patients lost their permanent implant with a median time to loss of 19 months (range 9–31 months) following PMRT. The one and two-year actuarial rate of reconstruction failure was 11.2% and 24.9%, respectively. The most common cause of failure was infection (37%), followed by skin break down (21%), extrusion of expander or implant (16%), fibrosis/eschar (11%), trauma (11%) and pain (5%). Out of the 19 failures, eight patients were salvaged with an autologous flap reconstruction. Univariate analysis was performed to examine the association between age, chemotherapy, hormonal therapy, smoking status, hypertension, diabetes, menopause status, weight and the use of a third supraclavicular RT field on reconstruction failure. However no risk factors were found to be associated with reconstruction failure. In patients who did not have reconstruction failure, good/excellent cosmesis was observed in 79% of patients and fair/poor cosmesis was observed in 21% of patients. Conclusions: In our series of women with a high risk of recurrence, PMRT with a tissue expander in place followed by a prosthetic implant provides good cosmesis in the majority of women with an acceptable risk of expander or implant loss. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-04.

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: Data on patients who received breast-conserving therapy (BCT) for early stage breast cancer were examined to detect differences in disease presentation, management techniques, long-term treatment outcomes, and toxicities based on race. METHODS: Six hundred ninety-nine women with breast cancer (39 African-American [AA] women and 660 Caucasian [C] women) who received BCT were analyzed on race, clinical and pathologic characteristics at presentation, management techniques, treatment-related toxicities, recurrence, and survival. The median follow-up was 12.2 years. RESULTS: At diagnosis, AA women were younger (aged

The goal of the current study is to help refine guidelines for the need for re-excision and the appropriate amount of breast tissue to re-excise in patients with early breast cancer following excisional breast biopsy when treated with breast-conserving therapy (BCT).The study population consisted of 441 patients derived from a dataset of 607 consecutive cases of stage I and II breast cancer treated with BCT, in which patients underwent primary excisional diagnostic biopsy and subsequent re-excision prior to the initiation of radiation therapy (RT). A single pathologist reviewed all specimens. Re-excision was indicated because tumor was found close to or involving the resection margin. In 333 of the 441 cases, it was possible to measure the extension of carcinoma into the re-excision specimen. Margins were classified as negative (carcinoma4.2 mm from the margin), near (4.2 mm from the margin) or positive. Any carcinoma identified near the final margin was quantified by width of invasive carcinoma and number of ductal carcinoma in situ (DCIS) ducts near the margin and subdivided into three distinct groups: least, intermediate, and greatest amount. These factors were then analyzed to determine the likelihood and extent of residual carcinoma in re-excision specimens. Statistical analysis was performed using Systat version 10 (SPSS Inc., Chicago, IL).The quantity of carcinoma near the initial biopsy margin and the invasive carcinoma-to-specimen dimension ratio demonstrated a significant association with increasing amounts of residual carcinoma at re-excision. Combination of these two variables allowed for a statistically significant (P0.001) calculation of risk index for identifying significant residual invasive carcinoma or DCIS in the adjacent breast parenchyma at re-excision, and yielded stratification into low- (6%), intermediate- (27%), and high-risk (44%) groups. In re-excision specimens, the observed distance of carcinoma extension into adjacent breast tissue was associated with a statistically significant decrease in the ratio of the initial excisional biopsy specimen dimensions and invasive carcinoma dimensions. Combining the initial margin status with the specimen-to-invasive carcinoma maximum dimension ratio yielded an accurate predictor of the maximum distance of tumor extension.Evaluation of the initial excisional biopsy margin status in correlation with the invasive carcinoma-to-specimen maximum dimension ratio may be helpful for (1) identifying patients who require re-excision prior to RT and (2) predicting the quantity of additional breast tissue to excise to ensure adequate surgical margins with BCT.

The authors reviewed changes in the initial clinical presentation, management techniques, and patterns of disease recurrence over time (1981-1996) in patients with breast carcinoma treated with breast-conserving therapy (BCT) at a single institution. The goals of the current study were to determine the frequency and use of optimal local and systemic therapy techniques and to evaluate the impact of these changes on treatment efficacy.Six hundred seven patients with American Joint Committee on Cancer Stage I or II invasive breast carcinomas treated with BCT at William Beaumont Hospital (Royal Oak, MI) constituted the study population. All patients received at least an excisional biopsy of the primary tumor, an axillary lymph node staging procedure, and postoperative radiotherapy (RT) (a median tumor bed dose of 61 Gray [Gy] was administered). All sides were reviewed by one pathologist. Numerous clinicopathologic and treatment-related factors were analyzed to monitor changes that occurred over time. Changes in patterns of disease recurrence and treatment efficacy over time also were analyzed.Over the time period analyzed, changes at initial presentation included an increase in the mean age at diagnosis (age 56.1 years vs. 61.4 years; P0.001), a decrease in the number of patients with clinically palpable tumors (78% vs. 36%; P0.001), a decrease in the mean tumor size (2.2 cm vs. 1.6 cm; P0.001), but no change in the percentage of patients with negative lymph nodes (79% vs. 78%; P = 0.83). No differences over time were observed in mean tumor grade (2.0 vs. 1.9; P = 0.2) or the presence of angiolymphatic invasion (27% vs. 26%; P = 0.25). Changes in surgical management and pathologic assessment included the more frequent use of reexcision (46% vs. 81%; P0.001), larger mean total volumes of breast tissue specimens excised (115 cm3 vs. 189 cm3; P = 0.001), a larger percentage of patients with final negative surgical margins (74% vs. 97%; P0.001), and a small increase in the mean number of lymph nodes excised (13.8 lymph nodes vs. 14.1 lymph nodes; P = 0.01). The only other significant change in the pathologic management of patients over time included a doubling in the mean number of slides examined (10.6 slides vs. 21.1 slides; P0.001). Changes in adjuvant local and systemic therapy included an increase in the percentage of patients treated with60 Gy to the tumor bed (66% vs. 95%; P0.001), a doubling in the mean number of days from the last surgery to the start of RT (24 days vs. 50 days; P0.001), and a decrease in the use of regional lymph node RT (24% vs. 8%; P0.001). The use of adjuvant tamoxifen increased from 10% to 61% (P0.001). Finally, improvements were observed in the 5-year and 12-year actuarial rates of local disease recurrence (8% vs. 1% and 21% vs. 9%, respectively; P = 0.001) and distant metastases (12% vs. 4% and 22% vs. 9%, respectively; P = 0.006). No changes in the mean number of years to ipsilateral (6.5 years vs. 6.4 years; P = 0.59) or distant disease recurrence (4.6 years vs. 3.8 years; P = 0.73) were observed.The impact of screening mammography and substantial changes in surgical, pathologic, RT, and systemic therapy recommendations were observed over time in the study population. These changes were associated with improvements in 5-year and 12-year local and distant control rates and suggested that improvements in outcome can be realized through adherence to best practice guidelines and continuous monitoring of treatment outcome data.

52 Background: Our tertiary care hospital addressed recent survivorship care initiatives by implementing a Nurse Practitioner (NP)-led Breast Care Survivorship Clinic (BCSC). The monthly, NP-led multidisciplinary clinic (MDC) integrated the unique needs of Breast Cancer Survivors (BCS). After 14 months, an internal evaluation prompted three significant changes to the NP-led BCSC. First, the new BCBS would become a Nurse Navigator (NN)-led risk-based model that would allow survivorship care to be individually tailored to each BCS’s needs. Secondly, patients would not meet with rest of MDC team (i.e. social work, nutrition, physical therapy) during this visit. Patients were instead referred to the Survivorship Care Workshop Series (SCWS), a bi-monthly educational program developed to complement the NN-led BCSC and address common BCS needs; needs falling outside of the SCWS content were handled individually by MDC referrals. Lastly, the NN-led BCSC was conducted at follow-up visit with surgeon to avoid an additional appointment. The NN administers a questionnaire that addresses medical and psychosocial concerns, refers BCS to relevant SCWS lecture and/or MDC referrals based on questionnaire results, and finally, delivers the SCP. Methods: A comparison of the NP-led versus the NN-led BCSC was performed on the following factors: average total time and effort (T&E) for preparation and delivery of SCPs; number of actual SCPs delivered to BCS; and cost analysis of each model. Results: There were 58 SCPs completed, and 37/58 were successfully delivered to patients during the NP-led BCSC (9/2014-10/2015). There were 95 SCPs completed, and 91/95 were successfully delivered during the NN-led BCSC (2/2016-7/2016). The average total time spent by NP was two hours (n = 37) per patient compared to the average total time of 45 minutes spent by NN (n = 91) for preparation and delivery of SCPs. The estimated annual cost of the NP-led model includes T&E for NP and MDC team, is $273,946 compared to cost of the NN-model, which includes NN T&E as well a full-time SCWS program coordinator, is $86,651. Conclusions: The NN-led risked-based BCSC model is less resource-intensive, less expensive and allows for increased delivery of SCPs to BCS.

Objective Use of routine sentinel lymph node biopsy (SLNB) in contralateral prophylactic mastectomy (CPM) is controversial. This retrospective study was undertaken to determine the frequency of SLNB in CPM at a community hospital and its utility as a guide to patient decision making. Methods Between 2007 and 2009, 170 patients underwent CPM at a suburban, tertiary care facility. The CPM was either immediate or delayed, or was for ipsilateral recurrent breast cancer. Thirty-seven (21.8%) of 170 patients had SLNB performed with CPM. The mastectomy specimens underwent standard pathologic evaluation by using intraoperative touch preparation cytology and postoperative hematoxylin and eosin staining and immunohistochemistry. Results No patients who underwent SLNB had positive nodes on touch preparation or final hematoxylin and eosin staining (0/37 [0%]). Fourteen (8.2%) of 37 patients had additional nodes identified in the specimens. These were either axillary tail or intramammary nodes. The median number of SLNs removed was 2 (range, 1-5), none of these were positive. There were 3 incidental cancers diagnosed on final pathology. Two invasive cancers (T1a and grade I) and 1 ductal carcinoma in situ were identified. SLNB was only performed on the patient with DCIS. Neither SLNB nor subsequent axillary lymph node dissection was performed in the invasive cancers. Conclusions SLNB was performed in 37 (21.8%) of patients who underwent CPM in a community hospital. Only 3 (1.76%) of 170 patients who underwent CPM had findings on final pathology that would have justified axillary staging. This correlates with other published data regarding SLNB in CPM. Because SLNB is associated with significant morbidity, guidelines for SLNB in prophylactic mastectomy need to be established so to avoid overtreatment.

Purpose To determine the rates of breast cancer–related lymphedema (BCRL) in patients undergoing whole-breast irradiation as part of breast-conserving therapy (BCT) and to identify clinical, pathologic, and treatment factors associated with its development. Methods and Materials A total of 1,861 patients with breast cancer were treated at William Beaumont Hospital with whole-breast irradiation as part of their BCT from January 1980 to February 2006, with 1,497 patients available for analysis. Determination of BCRL was based on clinical assessment. Differences in clinical, pathologic, and treatment characteristics between patients with BCRL and those without BCRL were evaluated, and the actuarial rates of BCRL by regional irradiation technique were determined. Results The actuarial rate of any BCRL was 7.4% for the entire cohort and 9.9%, 14.7%, and 8.3% for patients receiving a supraclavicular field, posterior axillary boost, and internal mammary irradiation, respectively. BCRL was more likely to develop in patients with advanced nodal status (11.4% vs. 6.3%, p = 0.001), those who had a greater number of lymph nodes removed (14 nodes) (9.5% vs. 6.0%, p = 0.01), those who had extracapsular extension (13.4% vs. 6.9%, p = 0.009), those with Grade II/III disease (10.8% vs. 2.9%, p p = 0.02). Regional irradiation showed small increases in the rates of BCRL ( p = not significant). Conclusions These results suggest that clinically detectable BCRL will develop after traditional BCT in up to 10% of patients. High-risk subgroups include patients with advanced nodal status, those with more nodes removed, and those who receive chemotherapy, with patients receiving regional irradiation showing a trend toward increased rates.

Data on the risk of axillary failure (AF) after accelerated partial breast irradiation (APBI) are limited. In this study, the authors determined the rate of AF and regional lymph node failure (RNF) in patients who received various forms of APBI and identified factors that were associated with its occurrence.In total, 534 patients with early stage breast cancer were treated at William Beaumont Hospital with APBI, including 466 patients (87%) with invasive breast cancer and 68 patients (13%) with ductal carcinoma in situ. Clinical variables (patient age, tumor location), pathologic variables (tumor size, grade, estrogen receptor status, margin status, lymph node status), and treatment-related variables (receipt of hormone and systemic chemotherapy) were analyzed to determine which factors were associated with AF and RNF. The median length of follow-up was 63 months (range, 1-201 months).The 5-year actuarial AF rate was 0.19%. Three patients (0.56%) developed RNF (all patients initially had invasive breast cancer) with a 5-year actuarial rate of 0.37%. Two of the regional recurrences were in the supraclavicular fossa, and 1 was in the axilla. No variables were associated with AF. However, patient numbers were very small. The median survival after RNF was 0.8 years (range, 0.3-1.7 years), and 2 of the 3 patients died of disease.The rate of AF and RNF after APBI was low and appeared to be similar to the rate observed with whole-breast irradiation. No variables were associated with a higher rate of AF after APBI.

Purpose To examine 10-year results of a single institution's experience with radiotherapy limited to the region of the tumor bed (i.e., accelerated partial breast irradiation, [APBI]) in selected patients treated with breast-conserving therapy (BCT) and compare them with results of matched BCT patients who underwent whole-breast irradiation (WBI). Patients and Methods A total of 199 patients with early-stage breast cancer were treated prospectively with BCT and APBI using interstitial brachytherapy. To compare potential differences in local recurrence rates on the basis of the volume of breast tissue irradiated, patients in the APBI group were matched with 199 patients treated with WBI. Match criteria included tumor size, nodal status, age at diagnosis, margins of excision, estrogen receptor status, and use of adjuvant tamoxifen therapy. Local–regional control, disease-free survival, and overall survival were analyzed between treatment groups. Results Median follow-up for surviving patients was 9.6 years (range, 0.3–13.6 years). Eight ipsilateral breast tumor recurrences (IBTRs) were observed in patients treated with APBI. The cumulative incidence of IBTR at 10 years was 5%. On matched-pair analysis, the rate of IBTR was not statistically significantly different between the patient groups (4%, 95% confidence interval [CI] 1.3–6.7% for WBI therapy patients vs. 5%, 95% CI 1.5–8.5% for APBI patients; p = 0.48). Conclusions Radiation therapy limited to the region of the tumor bed (APBI) produced 10-year local control rates comparable to those from WBI in selected low-risk patients.

BACKGROUND. The molecular classification system categorizes invasive breast carcinomas according to their key driving biomarkers. In the current study, the authors evaluated whether response to neoadjuvant chemotherapy was correlated with the molecular classification groups. METHODS. Using immunohistochemistry, the molecular classification group (luminal-A, luminal-B, HER-2–variant, HER-2–classic, and basal phenotype) was retrospectively determined in 68 breast cancer patients who received neoadjuvant treatment. RESULTS. A total of 28 carcinoma patients (41.2%) achieved a compete pathologic response (CPR), including 2 of 15 patients classified as having luminal-A (13.3%), 4 of 16 patients classified as having luminal-B (25.0%), 10 of 12 patients classified as having HER-2–classic (83.3%), none of the 4 patients classified as having HER-2–variant, and 12 of 21 patients classified as having basal phenotype (57.1%) neoplasms. The CPR rate among patients with the HER-2–classic and basal neoplasms was 67% (22 of 33 neoplasms), compared with 17.1% (6 of 35 neoplasms) in the non-HER-2–classic/basal combined group (P < .001). Eleven carcinomas were initially diagnosed as invasive lobular carcinomas (pleomorphic and classic), 4 of which were luminal-A, 4 of which were luminal-B, 2 of which were HER-2–classic, and 1 of which was basal. On review, only 3 of these 11 cases remained classified as classic lobular carcinoma, all of which were classified as luminal-A, and none of these patients achieved a CPR. Four of the other 8 patients achieved a CPR. CONCLUSIONS. The molecular classification system is useful for identifying carcinoma patients who are most likely and those who are least likely to achieve a CPR. In the current study, all the morphologically classic lobular carcinomas were classified as luminal-A neoplasms, which may explain the low rate of CPR reported. Cancer 2007. © 2007 American Cancer Society.

45 Background: To assess if partial vs whole breast irradiation (RT) in treatment of the various biological (bio-) subtypes of breast cancer would lead to differing clinical results, a match pair analysis of APBI vs WBI was undertaken. Methods: Between 3/1993 and 9/2013 all breast CA patients (pts) treated at one institute with either APBI or WBI were matched 1:1 by follow-up (FU) +/- 15 yrs, stage and bio-subtype. This yielded 772 pts of whom 640 were luminal A, 42 luminal B, 58 triple neg (TNBC), 6 HER2+, and 26 triple +. Outcomes were analyzed across the various bio-subtypes for all the pts (APBI + WBI), APBI alone and WBI alone. The endpoints assessed were local recurrence (LR), true recurrence/marginal miss (TR/MM), elsewhere failure (EF), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), and contralateral breast failure (CLBF). Results: Mean age was 66 (32-94) with a mean FU of 5.2 years (0.1-18.3). Regarding systemic therapy, 75% received endocrine Rx, while chemotherapy was documented in 21%. For all pts (APBI+WBI) there was no significant difference across the various bio-subtypes with respect to 5, 10 and 15 yr actuarial LR, TR/MM, EF, RR, DM, DFS and CLBF. Likewise, for the 386 APBI-alone treated pts, no significant difference was found between the various bio-subtypes for all the same endpoints reported. However, for the 386 WBI pts, a significant difference was seen in the 15-year actuarial LR between luminal A and TNBC (1.5% vs 7.4%, p = 0.007). Significance was also found in the 15-year actuarial DFS between luminal A/B and TNBC (98.0%, 95.2%; 86.0%, respectively, p = 0.009). Conclusions: In comparing partial to whole breast RT across the various biological subtypes of breast CA, APBI is at least as effective as WBI. However, the retrospective nature of this study along with the limited numbers of pts in the HER2+ and triple + subsets are weaknesses which are acknowledged to exist in this dataset. The addition of further pts in all the biological subtypes, particularly the HER2+ and triple + subsets, along with results from randomized trials incorporating biomarker data will be needed to substantiate these findings.

40 Background: In response to many recent publications and mandates to assure referrals to genetic counseling for oncology patients, the Royal Oak (RO) Breast Care Center (BCC) at Beaumont Health System (BHS) evaluated the surgical outcomes of genetic referral(GR) in breast cancer (BC) patients. The goal of this study was to determine the impact of GR on surgical decision making and evaluate outcomes in this population. Methods: A retrospective chart review was performed, to identify patients who had a BC diagnosis and met criteria for GR from July 2012- July 2014. Age, histology, laterality of cancer, prior history of cancer, neoadjuvant chemotherapy, plastic surgery consultation, MRI, reason for MRI, additional testing, type of surgery, laterality of surgery, reconstruction, lymph node surgery, and time from diagnosis to surgery were evaluated using Chi Square analysis. Results: A total of 506 patients with a new BC diagnosis seen at the RO BCC at BHS within the inclusion dates were analyzed. There were 191 patients referred to the GP for counseling and possible genetic testing. Eighty percent of the referred patients underwent genetic testing. Twelve patients tested positive for deleterious mutations in BRCA 1 or 2. A statistically significant difference was found in the BC patients referred to the GP with respect to age, MRI usage, neoadjuvant chemotherapy, type and laterality of surgery, ALND, plastic surgery consult & reconstruction, and time from diagnosis to surgery. MRI usage in patients referred to GP was 43.5% vs. 12.7% in those not referred. Mastectomy rate in patients referred to GP was 51.3% vs. 25.5% (p

70 Background: To assess outcomes of ER-negative breast CA pts treated with APBI, a matched-pair analysis was performed to determine efficacy of APBI vs whole breast RT (WBRT) from a single institution. Methods: From over 1650 pts treated with BCT from 1980-2013, a cohort of ER[-] pts treated with APBI or WBRT were investigated. Matched-pair analysis with a 1:1 ratio paired 79 APBI with 79 WBRT pts, all ER[-] (total:158). Match criteria included follow-up (FU) > 1.0 yr, stage, & age +/- 5 yrs. Outcomes analyzed included local recurrence (LR), true recurrence/marginal miss (TRMM), regional recurrence (RR), distant metastases (DM), disease-free (DFS), cause-specific (CSS), and overall survivals (OS). Results: As for clinical-pathological traits, no significant differences were noted for age (p=0.302), T-stage (p=1.000), tumor size (p=0.721), N-stage (p=0.062), use of chemoRx (p=0.747), endocrine Rx(p=0.408) or Herceptin (p=1.00). Per ASTRO Guidelines, no differences were seen in cautionary or unsuitable [UnS] groups between APBI & WBRT (p=0.333). With a mean FU of 8.0 yrs (10.1 yrs APBI; 8.4 yrs WBRT p

Brachytherapy-Based Accelerated Partial Breast Irradiation Versus Canadian Whole Breast Hypofractionation: A Matched-Pair Analysis of Comparative Effectiveness P.Y. Chen, J. Wilkinson, C.S. Shah, J. Wobb, M. Wallace, H. Ye, P. Benitez, N. Dekhne, D. Brabbins, and F. Vicini; Beaumont Health System, Royal Oak, MI, Summa Akron City/St. Thomas Hospitals, Akron, OH, Michigan Healthcare Professionals/21st Century Oncology of Michigan, Farmington Hills, MI

65 Background: Given the initial report of the RAPID trial with greater morbidity for 3-D conformal external beam APBI [3D-APBI] vs. Canadian Hypofractionation [CHfx], a propensity-score matched-pair analysis of brachytherapy-based APBI [B-APBI] vs. CHfx was performed to assess efficacy, toxicities, and cosmesis. Methods: Early-stage breast cancer patients treated with B-APBI or CHfx were reviewed. With ≥ 1y follow-up [FU], B-APBI (n=108) pts were matched 1:1 to CHfx (n=108) by age, T-stage, nodal/ER status, endocrine or chemotherapy and laterality. Ipsilateral breast tumor recurrence (IBTR), regional recurrence (RR), distant metastasis (DM), contralateral breast cancer (CLBC), cause-specific survival (CSS), overall survival (OS) and disease-free survival (DFS) were compared by Kaplan-Meier (log-rank test). Toxicities were graded per CTCAE v3 and comesis per Harvard criteria. Results: Median FU was 5.7 y (1.0-17.8) for B-APBI and 2.1 y (1.0-5.7) for CHfx [p < 0.001]. Patients did not differ by match criteria. In comparing B-APBI to CHfx, median age was 69.0 vs. 70.0 [p = 0.72]; for laterality, T-stage, nodal/ER status, endocrine or chemotherapy, no significance [NS] was noted between the 2 groups [p = 0.79, 1.0, 0.60, 0.09, 0.15, and 0.16 respectively]. Comparing B-APBI to CHfx, NS was seen in 5-y actuarial rates of IBTR [1% vs. 0% p = 0.35], RR [0% both], DM [3.4% vs. 0% p = 0.25], CLBC [2.3% vs. 2% p = 0.63], CSS [94.3% vs. 100% p = 0.47], OS [87.7% vs. 88.3% p = 0.71] & DFS [97.5% vs. 100% p = 0.52]. The majority of maximal late toxicities were Gr 1-2. Of toxicities analyzed, including pigmentary changes, edema, pain, induration, volume reduction, telangiectasia, fat necrosis and seroma, only Gr 2-3 hyperpigmentation was significantly higher in the CHfx [8% B-APBI vs. 22% CHfx p = 0.017]. Good/excellent cosmesis was seen in > 93% in both groups. Conclusions: With FU of >5 yrs, B-APBI has similar efficacy and cosmesis but less morbidity vs. CHfx; the lesser toxicity of B-APBI vs. CHfx is in contradistinction to the RAPID results comparing 3D-APBI vs. CHfx. Further FU and more patients are needed to substantiate these findings.

148 Background: This analysis compares the efficacy of a 2-day vs. 5-day accelerated partial breast irradiation (APBI) schedule in treatment of early-stage breast cancer. Methods: Patients were treated between 6/2000 and 1/2011 with balloon-based brachytherapy using a 2-day (700 cGy x 4 BID) or a 5-day (340 cGy x 10 BID) fractionation. The CTV was a 1cm expansion from the balloon surface with a single-lumen device used in all cases. To compare efficacy between the two treatment groups, a matched-pair analysis was performed using a 1:2 ratio which paired 38 two-day with 76 five-day patients. Match criteria included minimal follow-up (FU) > 1.0 yr, clinical stage, age (+/- 3 yrs), and ER status. Clinical outcomes analyzed include local-regional recurrence [LR, RR] distant metastases (DM), disease-free, cause-specific and overall survival [DFS, CSS, and OS]. Results: No significant differences were noted for age (p=0.838), clinical stage (p=1.000), ER (p=1.000), tumor size (p=0.236), margin status (p=0.556), nodal stage (p=0.381), PR (p=0.749), use of chemotherapy (p=0.927) or endocrine therapy (p=0.129). Per the ASTRO Consensus Guidelines, no differences were noted in the clinical groups between the 2-and 5-day treatments with the majority categorized as suitable or cautionary (2-day: 92% vs. 5-day: 87% p=0.436). With a mean FU of 4.7 yrs (4.9 yrs for 2-day vs. 4.5 yrs for 5-day, p=0.279), no differences were seen in the 5-year actuarial rates of LR (0.0% vs. 2.6%, p=0.359), DFS (94.4% vs. 96.1%, p=0.618), CSS (100% vs. 94.9 %, p=0.207), or OS (97.3% vs. 92.5%, p=0.811) between the 2-and 5-day groups, respectively. There was no RR in either group. DM rates were similar for both (5.6% vs. 1.3 %, p=0.456). Conclusions: With near 5-year FU for the 2-day schedule, APBI with the 2-day regimen yielded outcomes equivalent to the 5-day schema. Reduced on-treatment days by such hypofractionation offers flexibility in clinical and patient scheduling. Further FU and more patients will be needed to substantiate equivalence of hypofractionated APBI. An HIC-approved protocol randomizing patients between the 2 vs. 5-day treatments is currently open for accrual at our institution.

111 Background: We present the results of an analysis of high-risk breast cancer patients as defined by the NSABP B-39/RTOG 0413 phase III trial, all treated with accelerated partial breast irradiation (APBI) from a single institution. Methods: Between July 1993 and August 2010, 130 patients with any combination of at least one of the high-risk features of estrogen receptor (ER) negativity, age < 50, and/or axillary nodal positivity were treated with 1 of 3 forms of APBI. Sixty-seven patients were treated with interstitial needle-catheter brachytherapy, 44 balloon-based brachytherapy and 19 with 3D conformal external beam radiation therapy. Aside from the high-risk features, general eligibility criteria included infiltrating ductal carcinoma, with inclusion of invasive lobular and DCIS since 2003, margins > 2 mm, and surgically staged axilla. One-hundred eighteen patients had one high-risk factor, 11 had two, and 1 had all three factors. The median tumor size was 12.0 mm with margins > 2 mm in 80% of patients. Greater than 75% had T1 tumors and 50% were ER negative. Thirty-one percent of patients were node positive. Based upon the ASTRO Consensus Guidelines for use of APBI (2009) none of these patients were suitable, 38% cautionary and 62% were unsuitable. Results: Median age was 56.5 yrs (range 40-90). With a median follow-up of 5.3 yrs (0.02-16.9) the 5-yr actuarial local recurrence rate (LR) was 4.2%; regional recurrence (RR) was 2.1%. Median time to LR and RR were 1.2 and 2.8 yrs, respectively. On univariate analysis, the only factor significant for LR was a close/positive margin (p=0.031), as ER/PR, age, nodal status, tumor size, histology, grade, hormonal or chemotherapy were all NS. The 5-yr actuarial cause specific, disease-free, and overall survivals as well as distant metastasis were 94%, 91%, 90%, and 6.4%, respectively. Conclusions: This cohort of NSABP B-39/RTOG 0413 identified high-risk patients who have undergone APBI has yielded local-regional control rates and survival outcomes comparable to standard risk patients undergoing partial breast irradiation. Continued follow-up will be needed to assess the long-term efficacy of such high-risk breast cancer patients treated with APBI.

1562 Background: Women are seldom offered breast cancer risk assessment and information regarding risk reducing interventions at the time of their annual physical examination. Routinely assessing r...