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Background: Growing evidence indicates that restrictive criteria for determining eligibility of breast cancer patients for germline genetic testing (e.g. NCCN, etc.) can missa significant number who may benefit from testing. However, the clinical utility and outcomes of patients with germline pathogenic variants (“positive patients”) who fall outside of current criteria has not been studied,and there is limited data on the clinical impact of nonBRCA pathogenic variantsin patients who fall inside testing criteria. We present longitudinal data from a previous cohort of patients, who are being followed in a new genetics registry that correlates germlinetest results with impact on clinical decision making, disease status, treatmentcourse, clinical trial enrollment and overall survival. Methods: A large multi-center IRB approved prospective Registry initiated in 2017 collected andanalyzed data on 959 breast cancer patients, newly or previously diagnosed, atthe time of genetic test result return (Beitsch et al. JCO 2018)1.This abstract presents clinical data over the intervening 18-24 months on patients with positive variants (83) both in-criteria (IC) and out-of-criteria (OOC),collected via medical record review as part of the iGAP Registry(igapregistry.org), sponsored by Medneon (Cupertino, Ca). Results: Of the 44 positive patients for whom longitudinalclinical outcomes data have been analyzed to date, 24 met guidelines fortesting and 20 did not. 6 had a history of additional primary cancers at thetime of testing. 40/44 patients are disease free; of these 20 were IC,20 were OOC. 1/44 has stable disease and was OCC. 3/44 have progressive orrecurrent breast cancer and 2 were OCC and 1 was IC. 13/44received chemotherapy; 6 IC and 7 OOC. 5 patients (with mutations in BRCA1,BRCA2, PALB2, MUTYH) received carboplatin consistent with the sensitivity toplatinum agents conferred by deficiencies in homologous recombination (HR) andbase-excision repair (BER). Longitudinal outcomes stratified by gene result arein Table 1. Conclusions:This studyprovides initial evidence for the impact of germline genetic test results onlongitudinal patient outcomes, stratified by gene. It also begins to correlategermline results and chemotherapy, as 3/5 OOC patients receiving carboplatinhad mutations in HR or BER genes. This raises the possibility that certain treatment advantages and other beneficial changes in management could bewithheld from OOC patients if restrictive criteria persist, as well as limiting the opportunities for possible preventive interventions for their at-risk family members 1. BeitschPD, Whitworth PW, Hughes K, et al. Underdiagnosis of Hereditary Breast Cancer:Are Genetic Testing Guidelines a Tool or an Obstacle?. J Clin Oncol.2019;37(6):453-460. doi:10.1200/JCO.18.01631 Table 1Positive Gene Variant# reported mutations-by geneSubject Health Status Disease FreeSubject Health Status Stable or Progressive DiseaseNCCN # ICNCCN # OOCATM22002BLM11001BRCA122020BRCA255041CHEK266033DIS3L211001FH11010MITF11010MSH611001MUTYH98127NBN22011NF110101NTLH111001PALB232121RAD5011010RAD51C22011RAD51D32112RECQL422011VHL11010 Citation Format: Peter Beitsch, Rakesh Patel, Pat Whitworth, Barry Rosen, Rick Brown, Gia Compagnoni, Linsey Gold, Ian Grady, Edward Esplin, Sarah Nielsen, Max Brown, Melissa Trudrung, Chloe Wernecke, Mary Kay Hardwick, Robert Nussbaum. Longitudinal clinical outcomes of a multi-center universal genetic testing registry [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-30.

Background:Therapeutic and risk management options have expanded for patients harboring pathogenic variants (PVs) in cancer predisposition genes. Historically, testing costs and clinical implementation challenges led to restrictive testing guidelines in many countries. Increasing evidence demonstrates that narrow criteria will miss patients with potentially actionable PVs and broader testing is a cost-effective way to identify patients (and their family members) with PVs. Here we assess the efficacy of multiple international testing guidelines in identifying breast cancer patients with clinically actionable PVs. Methods:We reanalyzed a prospective cohort of breast cancer (BC) patients referred by their providers for multigene germline genetic testing (PMID: 30526229) 50% of which met U.S. testing criteria, by design. The is a cohort of U.S.-based patients, primarily Caucasian of Northern European ancestry. We applied testing guidelines from Australia, U.K. and 2 Canadian provinces (Ontario, British Columbia) to this cohort to determine their efficacy in selecting patients with PVs. These countries were chosen because of their single-payer healthcare model and their similar ethnic distribution to the U.S. Analysis focused on yield of PVs in high risk (>4x risk compared to general population) breast/ovarian (BC/OV) cancer genes. Results:Table 1 displays the distribution of in criteria (IC) vs. out of criteria (OOC) patients by country/testing criteria. Over 75% of patients in each country/province analyzed were OOC. Rates of PVs were similar between IC and OOC patients across countries. Existing Canadian, Australian and U.K. criteria missed up to 30% of patients with high risk PVs (Table 1). The majority (>80%) of PVs in OOC patients were in genes with published management guidelines. Conclusions:In our cohort, select ex-U.S. testing criteria identified Table 1. Findings in IC vs. OOC patientsOverallIn criteria Out of criteriaCountry/providenceGuidelineTotal n of cohortIC (% of total cohort)OOC (% of total cohort)Total PV IC (% of IC cohort)Total PV OOC (% of OOC cohort)High risk^ PVs (% of total PVs)High risk^ PVs (% of total PVs)U.S.NCCN953473 (49.6)480 (50.4)43 (9.1)40 (8.3)22 (26.5)8 (9.6)OntarioMOHLTC953210 (22.0)743 (78.0)18 (8.6)65 (8.7)5 (6.0)25 (30.1)B.C.BCHCP953203 (21.3)750 (78.7)24 (11.8)59 (7.9)9 (10.8)19 (22.9)AustraliaeviQ953180 (18.9)773 (81.1)19 (10.6)64 (8.3)12 (14.5)18 (21.7)U.K.NICE*826**127 (14.7)736 (85.3)11 (8.7)64 (8.7)6 (7.2)22 (26.5)US, United States; B.C., British Columbia; UK, United KingdomNCCN, National Comprehensive Cancer Network v. 2017MOHLTC, Ministry of Health and Long Term Care BCHCP, BC Provincial Health Services Authority Hereditary Cancer Program NICE, National Institute for Health Care Excellence*testing eligibility requires >10% BRCA mutation detection rate, typically assessed by BOADICEA model in the UK but for this cohort risk estimates were only available via BRCAPro ** BRCAPro scores were not available for the full cohort ^Includes BRCA1, BRCA2, PALB2, TP53, RAD51C, RAD51D, MSH6 Citation Format: Sarah M Nielsen, Peter Beitsch, Pat Whitworth, Emily Decker, Natalie Rickers, Hana Sroka, Alekhya Narravula, Ed D Esplin, Robert L. Nussbaum. Pathogenic variants in hereditary cancer syndrome genes are prevalent among breast cancer patients not meeting various ex-U.S. genetic testing guidelines [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-14.

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: Molecular genomic profiles are increasingly used to guide treatment of refractory cancers and are on the forefront of personalized medicine for select patients. The neoadjuvant chemotherapy (NAC) setting provides a meaningful opportunity to compare genomic profiles to pathologic response. We report profiles to response in a novel multi center registry. Methods: An ongoing IRB (WIRB) approved registry at 6 community breast practices submitted tumor samples prior to treatment for genomic/proteomic analysis (Paradigm, Phoenix, AZ.) Tumor response and associated molecular profiles were analyzed. The test evaluated over 137 genomic alterations with known actionable variations including mutations, gene-fusions, copy number variations, MRNA expression and protein expression analysis by IHC. Results: 76 patients were enrolled and 42 have completed treatment including definitive surgery and have reported data as of this date. The vast majority of patients had invasive ductal carcinoma with 16% having triple negative biology and 20% having Her2 biology. Of the triple negative patients with reported surgical results, 42% had a complete response or minimal residual disease, and the remaining 58% had a partial response. Of the patients with HER2 biology, 85% had a complete response and the remaining a partial response. 17% of patients with luminal biology had a complete response; the remaining had only a partial response or progression. Overall, 15 patients had a complete response, 4 had minimal residual disease and the remaining (over 50%) had a partial response, stable or progressive disease. Patients who did not achieve a complete response had multiple molecular aberrations with unique markers not present in patients with PCR. These included markers of known or possible drug resistance (IGFR1, CAIX), poor prognostic markers (TP53, MET, PTEN), biomarkers of response to approved treatment that were not utilized and other markers of potential response and research. Conclusions: Comprehensive genomic testing may predict resistant biology and provide additional targets for treatment or clinical study. Genomic analysis earlier in the patient’s care path may improve response rates by suggesting modifications in standard protocols or identifying clinical trials as potential first line options. Repeat genomic analysis may also suggest options for targeted adjuvant therapy for residual cancer after neoadjuvant therapy. Citation Format: Peter Beitsch, Pat Whitworth, Laura Lee, Antonio Ruiz, Rick Brown, Linsey Gold, Paul Baron, Rakesh Patel. Novel use of a precision medicine tool in the neoadjuvant therapy setting [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 P2-16-21.

Background: HBOC testing guidelines were established to identify patients with clinically actionable variants and limit economic burden. We report the impact of germline results on health outcome based on clinical decision making and treatment interventions, regardless of guidelines, in a multi-center registry. Methods: 20 community-based and academic sites participated in an IRB approved registry. Patients with breast cancer were tested with an 80-gene panel and clinical information was collected. Results: Data on 912 patients has been analyzed to date. 68% were recently diagnosed and the remaining were diagnosed in the past. 50.5% met NCCN criteria; 49.5% did not. Pathogenic/likely pathogenic (P/LP) germline mutations were found in 8.65% of patients. Of all patients with P/LP findings, 85% had variants in cancer-risk genes with established management recommendations and 80% had germline variants conferring eligibility for clinical trials and precision medicine-based cancer treatments, such as PARP inhibitors. When results were evaluated based on an 11 gene panel of genes most commonly associated with breast cancer, 4.9% (or X) were found to have variants and X percent of these had variants conferring eligibility for clinical trials and precision medicine. X Patients with variants outside of the 11 gene panel had eligibility for clinical trials and precision medicine. There was no significant association between BRCAPRO scores and patients having a P/LP finding, whether in BRCA1/2 alone (p=0.42) or for any cancer gene (p=0.57). For 62% of patients with P/LP germline mutations, clinicians reported results impacted patients’ health outcome; and for 69%, results impacted the health outcome of patients’ relatives. Physician reported impact on patient outcome associated significantly with the presence of P/LP germline findings (p Conclusions: Comprehensive panel testing of breast cancer patients impacts physician assessed patient outcomes and informs changes in surgical treatment strategy, medical therapies and proactive screening. The data suggest that BRCAPRO calculators are poor predictors of germline presence of P/LP findings. Physicians in this study demonstrate the ability to discern the clinically actionable value of P/LP mutations from non-actionable VUS. Multigene panels impact breast cancer patient care by identifying precision medicine treatment interventions and guiding long-term medical management and preventive surveillance for patients and family members. More patients are provided opportunities for precision medicine when a larger panel is used. Table 1. Comprehensive panel clinical management and treatment implications. Germline variants with implications for patient management and treatment. *P/LP variants in these genes confer potential clinical trial eligibility, e.g. NCT02401347.Table 1PatientsVariantsWith breast cancer management guidelines45 (56%)46 (55%)(ATM*, BRCA1*, BRCA2*, CHEK2*, NBN*, NF1, PALB2*, TP53*)With cancer management implications31 (38%)33 (39%)(BARD1*, FH, MITF, MSH6*, MUTYH*, PTCH1, RAD50*, RAD51C*, RAD51D*, RB1, RET, VHL)Evidence of actionability accruing5 (6%)5 (6%)(BLM, DIS3L2, RECQL4)Total8184 Citation Format: Peter Beitsch, Pat Whitworth, Kevin Hughes, Ian Grady, Karen Barbosa, Rakesh Patel, Michael Kinney, Paul Baron, Barry Rosen, Gia Compagnoni, Linda ann Smith, Rache Simmons, Cynara Coomer, Dennis Holmes, Eric Brown, Linsey Gold, Lisa Curcio, Patricia Clark, Tony Ruiz, Heather MacDonald, Sadia Khan, Lee Riley, Sam Lyons, Shan Yang, Mary K Hardwick, Edward D Esplin, Robert L Nussbaum. Comprehensive germline multigene panel testing changes clinical care for patients 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 P6-08-28.

Purpose An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to identify carriers of BRCA1/ 2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing. Methods An institutional review board–approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act–compliant electronic case report forms collected information on patient demographics, diagnoses, phenotypes, and test results. Results More than 1,000 patients were enrolled, and data records for 959 patients were analyzed; 49.95% met NCCN criteria, and 50.05% did not. Overall, 8.65% of patients had a pathogenic/likely pathogenic (P/LP) variant. Of patients who met NCCN guidelines with test results, 9.39% had a P/LP variant. Of patients who did not meet guidelines, 7.9% had a P/LP variant. The difference in positive results between these groups was not statistically significant (Fisher’s exact test P = .4241). Conclusion Our results indicate that nearly half of patients with breast cancer with a P/LP variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines. We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing.

Background: Pathogenic genetic variants are estimated to occur in 10-15% of all breast cancer patients, with BRCA 1/2 accounting for 40-50% of pathogenic/likely pathogenic (P/LP) variants. However, it is estimated that Methods: An IRB-approved multicenter prospective registry was initiated with 20 community and academic sites experienced incancer genetic testing and counseling. Eligibility criteria included patients with a breast cancer diagnosis who had not been previously tested. Consecutive patients aged 18-90 were consented and underwent an 80 gene panel test (Invitae –Multi-Cancer Panel). The non-inferiority study was powered to detect a difference in P/LP variant rate of 4 percentage points with statistical significance (p HIPAA compliant electronic case report forms collected information on patient diagnosis, test results, and physician recommendations made after test results were received. Results: Over 1000 patients were enrolled and data from 910 subjects analyzed to date. 50.4% met NCCN criteria and 49.5% did not. Median age for the enrolled patients is 60.5 and ranged from 22-93. 56.0% of patients were recently diagnosed with breast cancer. 10.9% of patients had a history of a prior non breast cancer. Overall, 8.9% of patients had a pathogenicvariant. 9.6% of patients who met NCCN criteria with test results had a P/LP variant. 8.2% of patients who did not meet criteria had a P/LP variant. The difference of positive cases among the two groups is not statistically significant (P = 0.49) 4.9% of patients had pathogenic variants if only an 11 gene standard breast cancer panel was considered. The spectrum of mutated genes varied between the two groups, with some overlap. Conclusions: There was no statistically significant difference in the number of pathogenic/likely pathogenic variants between those patients who met and those who did not meet NCCN guidelines. Expanded panel testing yields more medically actionable P/LP variants than testing BRCA 1/2 alone or breast cancer panels with 11 genes. This study demonstrates that there will be a significant number of patients with P/LP variants are missed if NCCN guidelines are required for genetic testing. Current NCCN guidelines for the genetic testing of breast cancer patients are an obstacle to identifying patients with P/LP variants and should be removed. Universal BC Genetic Testing RegistryNCCN Criteria (910 patients analyzed)#/% who have P/LP variants#/% who do not have P/LP variantsPatients who meet guidelines44/459 (9.6%)415/459 (90.4%)Patients who do not meet guidelines37/451 (8.2%)414/451 (91.8%) Citation Format: Beitsch P, Whitworth P, Baron P, Rosen B, Compagnoni G, Simmons R, Smith LA, Holmes D, Brown E, Gold L, Clark P, Coomer C, Grady I, Barbosa K, Riley L, Kinney M, Lyons S, MacDonald H, Kahn S, Ruiz A, Patel R, Curcio L, Esplin E, Yang S. Underdiagnosis of HBOC in breast cancer patients: Are genetic testing guidelines a tool or an obstacle? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-06.

Background: The testing of hereditary breast and ovarian cancer (HBOC) patients for BRCA1/2 only was established years ago to identify patients with clinically actionable variants and limit the economic burden. However, the cost of genetic testing has plummeted, and the number of breast cancer-risk genes with management guidelines has expanded. We created a community-based registry to test all breast cancer patients. A primary objective of this registry included accruing and comparing patients who did and did not meet NCCN guidelines and determining if providing all breast cancer patients with comprehensive multi-gene panel testing yields additional clinical value than testing BRCA1/2 alone. Methods: An IRB-approved multicenter prospective registry was initiated with 20 community-based and academic breast sites, selected to insure geographic and ethnic diversity. Consecutive patients ages 18-90 with current or prior breast cancer were offered testing with an 80-gene panel (Invitae, San Francisco, CA). HIPAA-compliant case report forms collected patient diagnosis, test results, and physician recommendations made after test results. Results: Over 1,000 patients were enrolled and data on 911 have been analyzed to date. Median age of patients is 60.5 (range 22 to 93). 56.0% were recently diagnosed with breast cancer. Of these patients, 50.54% met NCCN criteria, and 49.5% did not. 10.9% had history of a prior non-breast cancer. The pathogenic/likely pathogenic (P/LP) variant rate for patients on a comprehensive 80-gene panel was 8.9%. When restricted to a guidelines-based 11-gene breast cancer panel (BRCA1/2, ATM, CDH1, CHEK2, NBN, NF1, PTEN, STK11, TP53, PALB2), 4.9% had P/LP variants; when limited to BRCA1/2, 1.6% had P/LP variants. Of all patients with P/LP findings, 93% had variants in cancer-risk genes with established management recommendations (Table 1) and 80% had germline variants conferring eligibility for precision medicine-based cancer treatments, such as PARP inhibitors, through actively enrolling clinical trials. Conclusions: This study demonstrates that comprehensive panel testing of breast cancer patients provides a higher yield of clinically actionable P/LP variants than BRCA1/2 testing alone. Limited panels may miss clinically relevant P/LP variants, leaving risk for preventable cancers undiscovered and unnecessarily restricting patients' treatment options. These results also suggest that variants in tumor suppressor genes, not previously thought related to breast cancer, may contribute to its etiology. A comprehensive panel strategy reveals untapped clinical utility and can impact breast cancer patient care by informing implementation of precision medicine treatment interventions and guiding long-term medical management and surveillance for patients and their family members. PatientsVariantsWith breast cancer management guidelines (including variants ATM*, BRCA1*, BRCA2*, CHEK2*, NBN*, NF1, PALB2*, TP53*)45 (56%)46 (55%)With cancer guidelines and clinical management implications (including variants BARD1*, FH, MITF, MSH6*, MUTYH*, PTCH1, RAD50*, RAD51C*, RAD51D*, RB1, RET, VHL)31 (38%)33 (39%)Evidence of actionability accruing (including variants BLM, DIS3L2, RECQL4)5 (6%)5 (6%)Totals8184*P/LP variants in these genes confer potential clinical trial eligibility, e.g. NCT02401347. Citation Format: Beitsch P, Whitworth P, Baron P, Rosen B, Compagnoni G, Simmons R, Smith LA, Holmes D, Brown E, Gold L, Clark P, Coomer C, Grady I, Barbosa K, Riley L, Kinney M, Lyons S, MacDonald H, Kahn S, Ruiz A, Patel R, Curcio L, Esplin E, Yang S, Michalski S. Expanded panel testing superior to BRCA1/2 and breast cancer panel in patients with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-03.

PURPOSE National guidelines recommend sentinel lymph node biopsy (SLNB) be offered to patients with > 10% likelihood of sentinel lymph node (SLN) positivity. On the other hand, guidelines do not recommend SLNB for patients with T1a tumors without high-risk features who have < 5% likelihood of a positive SLN. However, the decision to perform SLNB is less certain for patients with higher-risk T1 melanomas in which a positive node is expected 5%-10% of the time. We hypothesized that integrating clinicopathologic features with the 31-gene expression profile (31-GEP) score using advanced artificial intelligence techniques would provide more precise SLN risk prediction. METHODS An integrated 31-GEP (i31-GEP) neural network algorithm incorporating clinicopathologic features with the continuous 31-GEP score was developed using a previously reported patient cohort (n = 1,398) and validated using an independent cohort (n = 1,674). RESULTS Compared with other covariates in the i31-GEP, the continuous 31-GEP score had the largest likelihood ratio (G2 = 91.3, P < .001) for predicting SLN positivity. The i31-GEP demonstrated high concordance between predicted and observed SLN positivity rates (linear regression slope = 0.999). The i31-GEP increased the percentage of patients with T1-T4 tumors predicted to have < 5% SLN-positive likelihood from 8.5% to 27.7% with a negative predictive value of 98%. Importantly, for patients with T1 tumors originally classified with a likelihood of SLN positivity of 5%-10%, the i31-GEP reclassified 63% of cases as having < 5% or > 10% likelihood of positive SLN, for a more precise, personalized, and clinically actionable SLN-positive likelihood estimate. CONCLUSION These data suggest the i31-GEP could reduce the number of SLNBs performed by identifying patients with likelihood under the 5% threshold for performance of SLNB and improve the yield of positive SLNBs by identifying patients more likely to have a positive SLNB.

Objective To assess whether preoperative ultrasound (US) assessment of regional lymph nodes in patients who present with primary cutaneous melanoma provides accurate staging. Background It has been suggested that preoperative US could avoid the need for sentinel node (SN) biopsy, but in most single-institution reports, the sensitivity of preoperative US has been low. Methods Preoperative US data and SNB results were analyzed for patients enrolled at 20 centers participating in the screening phase of the second Multicenter Selective Lymphadenectomy Trial. Excised SNs were histopathologically assessed and considered positive if any melanoma was seen. Results SNs were identified and removed from 2859 patients who had preoperative US evaluation. Among those patients, 548 had SN metastases. US was positive (abnormal) in 87 patients (3.0%). Among SN-positive patients, 39 (7.1%) had an abnormal US. When analyzed by lymph node basin, 3302 basins were evaluated, and 38 were true positive (1.2%). By basin, the sensitivity of US was 6.6% (95% confidence interval: 4.6-8.7) and the specificity 98.0% (95% CI: 97.5-98.5). Median cross-sectional area of all SN metastases was 0.13 mm; in US true-positive nodes, it was 6.8 mm. US sensitivity increased with increasing Breslow thickness of the primary melanoma (0% for ≤1 mm thickness, 11.9% for >4 mm thickness). US sensitivity was not significantly greater with higher trial center volume or with pre-US lymphoscintigraphy. Conclusion In the MSLT-II screening phase population, SN tumor volume was usually too small to be reliably detected by US. For accurate nodal staging to guide the management of melanoma patients, US is not an effective substitute for SN biopsy.

Background: The American Society of Breast Surgeons (ASBrS) Nipple Sparing Mastectomy Registry (NSMR) is a prospective, non-randomized, IRB approved, multi-institutional registry. The purpose of this Registry is to provide a large, prospective, non-randomized database of patient characteristics, tumor characteristics, surgical technique, and outcome (both aesthetic and oncologic) of the nipple sparing mastectomy (NSM). Methods: Data is entered into the ASBrS NSMR, housed within the Mastery of Surgery Program, after patients consent to participation. Each investigator routinely offers NSM in their practice has obtained IRB approval and completed forms of agreement to participate in the ASBrS NSMR. Results: This data set represents a total of 1,935 NSMs performed on 1,170 patients by 98 investigators from 70 institutions/sites. Of the 1,935 NSMs: 833 were performed for an indication of cancer [594 invasive carcinoma and 239 for ductal carcinoma in situ (DCIS)] and 1,102 were prophylactic. Of the 1,170 total patients, 352 underwent a unilateral and 818 underwent a bilateral NSM. Recurrence at a mean follow-up of 31 months/median follow-up of 27 months, with a range of 9.7 to 58.3 months since surgery was 1.4% with no recurrences at the nipple or nipple areola complex (NAC). Cancer occurrence (0.3%) also did not involve the nipple/NAC. Overall patient satisfaction of excellent/good: 94.9% and overall cosmesis (surgeon rated) of excellent/good was 96.4%. Overall infection rates included flap infection of 4.4%, NAC complication rate of 4.5% (defined as necrosis/other or ischemia/epidermolysis requiring surgery), and a 10% rate of NAC epidermolysis with full recovery. Conclusions: NSMs were performed on breasts with a variety of sizes and degrees of ptosis, via multiple incisions, dissection and reconstruction techniques with low complication rates and high patient satisfaction and surgeon rated cosmesis.

BackgroundMost patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here.MethodsPatients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients.ResultsFor randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients ConclusionsSeviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas.Trial registration numberNCT01546571.

Background: With increased demand for hereditary cancer genetic testing, some large national health-care insurance payers (LNHPs) have implemented policies to minimize inappropriate testing by mandating consultation with a geneticist or genetic counselor (GC). We hypothesized such a restriction would reduce access and appropriate testing. Methods: Test cancellation rates (ie, tests ordered that did not result in a reported test result), mutation-positive rates, and turnaround times for comprehensive BRCA1/2 testing for a study LNHP that implemented a GC-mandate policy were determined over the 12 months before and after policy implementation (excluding a 4-month transition period). Cancellation rates were evaluated based on the reason for cancellation, National Comprehensive Cancer Network testing criteria, and self-identified ancestry. A control LNHP was evaluated over the same period for comparison. Results: The study LNHP cancellation rate increased from 13.3% to 42.1% ( P < .001) after policy implementation. This increase was also observed when only individuals who met National Comprehensive Cancer Network criteria for hereditary breast and ovarian cancer testing were considered (9.5% to 37.7%; P < .001). Cancellation rates increased after policy introduction for all ancestries; however, this was more pronounced among individuals of African or Latin American ancestry, for whom cancellation rates rose to 48.9% and 49.6%, respectively, compared with 33.9% for individuals of European ancestry. Over this same time period, control LNHP cancellation rates decreased or stayed the same for all subgroups. Conclusion: These findings demonstrate that a GC-mandate policy implemented by a LNHP substantially decreased access to appropriate genetic testing, disproportionately impacting minority populations without any evidence that inappropriate testing was decreased.

Immunohistochemically ER-positive HER2-negative (ER+HER2−) breast cancers are classified clinically as Luminal-type. We showed previously that molecular subtyping using the 80-gene signature (80-GS) reclassified a subset of ER+HER2− tumors to molecular Basal-type. We report here that molecular reclassification is associated with expression of dominant-negative ER variants and evaluate response to neoadjuvant therapy and outcome in the prospective neoadjuvant NBRST study (NCT01479101). The 80-GS reclassified 91 of 694 (13.1%) immunohistochemically Luminal-type tumors to molecular Basal-type. Importantly, all 91 discordant tumors were classified as high-risk, whereas only 66.9% of ER+/Luminal-type tumors were classified at high-risk for disease recurrence (i.e., Luminal B) (P P P

Background: The risk of distant recurrence gene signature, MammaPrint (MP), together with the molecular subtyping gene signature, BluePrint (BP), stratifies breast tumors into Luminal A, Luminal B, HER2, and Basal subtypes, independent of immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) expression. In the Neoadjuvant Breast Registry Symphony Trial (NBRST), MP and BP identified patients likely to respond to neoadjuvant treatment with higher accuracy compared to conventional methods. Here, we report 5-year follow up (FU) data in breast cancer (BC) patients from the NBRST registry with discordant clinical and genomic subtyping.Methods: This prospective study enrolled 1072 early-stage BC patients from 2009-2014 who received MP and BP testing. Patients received neoadjuvant therapy following standard of care and consented to 5 years post-surgery FU. IHC determined hormone receptor (HR) status, including ER and PR, and IHC and/or FISH determined HER2 status. Median FU for distant metastasis free survival (DMFS) and overall survival (OS) was 4.6 and 5 years, respectively. Differences in DMFS and OS was assessed by Kaplan Meier analysis and log-rank test.Results: Overall, BP reclassified 22% of tumors into different molecular subtypes compared to IHC/FISH (Table). BP reclassified 17% of ER+HER2- tumors as BP Basal, with higher pathological complete response (pCR) rates compared to ER+/BP Luminal tumors (36% vs. 4%). ER+/BP Basal patients had similar pCR rates as triple negative BC (TNBC)/BP Basal patients (36% vs. 37%) following neoadjuvant treatment, and pCR correlated with improved survival outcomes. The 5-year DMFS and OS probabilities were lower in ER+/BP Basal patients compared to TNBC/BP Basal patients and were substantially lower compared to ER+/BP Luminal patients (P < 0.001). There were 106 HR-HER2+ patients, of whom BP reclassified 23.6% to Basal and 2.8% as Luminal B; the remaining 73.6% were confirmed HER2 by BP. The 5-year DMFS and OS probabilities were worse in HER2+/BP Basal patients compared to HER2+/BP HER2 patients. Of 142 triple positive (TP, ER+PR+HER2+) patients, BP classified 55% as Luminal, 39% as HER2, and 6% as Basal, with higher pCR rates observed in BP Basal and BP HER2 tumors compared to BP Luminal. The 5-year DMFS and OS probabilities were substantially lower in TP/BP Basal patients compared to TP/BP HER2 and TP/BP Luminal patients (P < 0.05 and P < 0.04). Of clinical HER2+ patients (HR+ or HR-) that received pertuzumab, patients that reclassified as BP Basal had worse OS compared to BP HER2 patients (P < 0.04).Conclusion: ER+HER2- and HER2+ patients that reclassified as BP Basal are more likely to achieve pCR and have improved survival, demonstrating the clinical utility of BP in the neoadjuvant setting. These patients may benefit from optimized chemotherapy used for TNBC, including novel emerging treatments such as PD-1 and PARP1 inhibitors, in addition to HER2-targeted therapy. Furthermore, HER2+ tumors that were confirmed HER2 by BP may have high response rates to regimens containing TDM-1. Lastly, BP identified a subgroup of triple positive BC patients, who reclassified as BP Luminal, that may avoid overtreatment. Overall, molecular subtyping using MP and BP is more accurate in stratifying patients and predicting treatment responses and 5-year disease outcomes than conventional methods and thus, facilitates successful treatment decisions. Clinical subtypeFrequency of BP classificationBluePrint subtypepCR%5-yr DMFS (95% CI)5-yr OS (95% CI)TNBC (n=236)0.42% (1/236)Luminal A100% (1/1)N/AN/A2.54% (6/236)Luminal B16.67% (1/6)N/AN/A1.27% (3/236)HER233.33% (1/3)N/AN/A95.76% (226/236)Basal36.73% (83/226)100% (pCR)100% (pCR)60.5% (50.5-69.1)(non-PCR)64.3%(52.1-71.2) (non-PCR)ER+HER2- (n=520)28.84% (152/520)Luminal A1.97% (3/152)91.1% (84.0-95.2)94.6% (88.3-97.6)52.37% (276/520)Luminal B5.43% (15/276)75.2% (69.0-80.4)84.5% (79.0-88.7)1.33% (7/520)HER214.29% (1/7)N/AN/A17.46% (92/520)Basal35.9%(33/92)84.1% (67.8-92.5) (pCR)86.3% (70.1-94.1) (pCR)54.6% (42.0-65.5) (non-pCR)57% (43.7-68.2) (non-pCR)HR-HER2+ (n=106)2.83% (3/106)Luminal B66.67% (2/3)100%100%73.59% (78/106)HER269% (54/78)82.8% (69.9-90.5)88.6% (76.0-94.8)23.58% (25/106)Basal40% (10/25)79.0% (52.5-91.7)79.0% (52.5-91.7)Triple Positive (n=142)12.68% (18/142)Luminal A22.22% (4/18)88.8% (76.5-94.8)94.5% (83.8-98.2)42.25% (60/142)Luminal B11.67%(7/60)38.73% (55/142)HER244.44% (24/55)87.5% (72.0-94.7)97.9% (83.8-98.2)6.34% (9/142)Basal55.56%(5/9)62.5% (22.9-86.1)70.0% (22.5-91.8)HER2+ (HR+ or HR-)treated with pertuzumab (n=105)28.6%(30/105)Luminal37% (11/30)84.7% (63.8-94.1)92.2%(71.8-98.0)57%(60/105)HER282% (49/60)91.4% (78.3-96.8)92.9%(79.2-97.7)14%(15/105)Basal40% (6/15)66.0%(31.1-86.3)64.0% (29.1-85.1) Citation Format: Pat Whitworth, James Pellicane, Jr, Paul Baron, Peter Beitsch, Laura Lee, Michael Rotkis, Angela Mislowsky, Carrie Dul, Charles Nash, Bichlien Nguyen, Mary Murray, Paul Richards, Mark Gittleman, Stephanie Akbari, Shiyu Wang, Andrea Menicucci, Erin B Yoder, Lisa Blumencranz, William Audeh. Molecular subtyping by BluePrint improves prediction of treatment responses and survival outcomes in patients with discordant clinical and genomic classification [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-04.

Background: MammaPrint (MP) is used to identify breast cancer (BC) patients who can safely forego adjuvant chemotherapy. MP combined with the BluePrint (BP) molecular subtyping signature identifies BC subtypes with distinct therapeutic response rates and survival outcomes. In the Neoadjuvant Breast Symphony Trial (NBRST), MP and BP (MP/BP) predicted rates of pathologic complete response to neoadjuvant chemotherapy (NCT) and partial response to neoadjuvant endocrine therapy (NET). Here, we report 5-year overall survival (OS) and distant metastasis-free survival (DMFS) in patients from the NBRST registry according to MP/BP molecular classification. Methods: The NBRST trial (NCT01479101) prospectively enrolled 1072 patients from 2011 to 2014, who received MP and BP testing. Patients were assigned to receive NCT or NET according to NCCN guidelines and consented to 5 years post-surgery follow-up (FU). Clinical outcomes were available for 913 patients from 67 US institutions. Median FU for OS and DMFS was 5 and 4.6 years, respectively. Tumors classified by MP as High Risk (HR) or Low Risk (LR) were further stratified into four molecular subtypes by BP: Luminal A, Luminal B, HER2, and Basal. Differences in OS and DMFS at 3 and 5 years were assessed by Kaplan Meier analysis and log-rank test. Results: MP results from neoadjuvant patients (N=913) classified 16% of tumors as MP LR and 84% as MP HR. MP and BP classified 15.7% (143/913) of tumors as Luminal A, 32.5% (297/913) as Luminal B, 17.1% (156/913) as HER2, and 34.7% (317/913) as Basal. The 5-year OS and DMFS probabilities were significantly lower in HR compared to LR patients (p < 0.001 for OS and DMFS), and lowest in Basal and Luminal B compared to Luminal A and HER2 subtypes (p < 0.001 for OS and DMFS). Most DMFS events in BP Basal tumors occurred within the first 3 years. Of 841 patients that received NCT with or without HER2-targeted therapy, 12.2% (103/841) were LR and 87.8% (738/841) were HR. MP and BP classified 11.9% (100/841) of these patients as Luminal A, 32.6% (274/841) as Luminal B, 8.3% (154/841) as HER2 subtype, and 37.2% (313/841) as Basal. The 5-year OS and DMFS probabilities were lowest in HR, Basal or Luminal B patients (p < 0.001). In 59 patients who received NET alone, 5-year OS and DMFS were significantly worse in HR patients that had Luminal B or HER2 tumors compared to LR Luminal A patients. In the 39 patients with Luminal A tumors, response to NET at the time of surgery was: 46.2% partial response, 41.0% stable disease, 5.1% progressive disease, 2.6% not reported. Five year DMFS in patients with Luminal A tumors treated with NCT or NET was not significantly different (p=0.67).Conclusions: MammaPrint remained prognostic in BC patients undergoing neoadjuvant therapy. Long -term prognosis was excellent in LR groups who received NCT or NET alone. MP and BP can accurately classify patients into specific subtypes with distinct OS and DMFS outcomes at five years, with BP Basals having the worst outcomes, followed by Luminal B, HER2, and Luminal A subtypes. BP Basal patients had the highest frequency of events within the first 3 years post-surgery, suggesting a genomic risk timeline distinct from other BP subtypes and a potential benefit from a secondary therapeutic immediately post-surgery. Additionally, Luminal A patients had a very low risk of progressive disease while on NET alone prior to surgery, with similar DMFS outcomes to Luminal A-types who received NCT. Number of patientsObserved events% at 5 year (95% CI)p-valueAll patients - MammaPrint Risk GroupOS913134p Citation Format: Pat Whitworth, James V Pellicane, Jr., Paul Baron, Peter Beitsch, Laura Lee, Michael Rotkis, Angela Mislowsky, Carrie Dul, Charles Nash, Bichlien Nguyen, Mary Murray, Paul Richards, Mark Gittleman, Stephanie Akbari, Shiyu Wang, Erin B Yoder, Andrea Menicucci, Lisa Blumencranz, William Audeh, NBRST Investigators Group. 5-year outcomes in the NBRST trial: Preoperative MammaPrint and BluePrint breast cancer subtype is associated with neoadjuvant treatment response and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD9-01.

Neoadjuvant therapy (NAT) has been shown to clinically downstage locally advanced breast cancers. This study aimed to determine whether a meaningful change in gene signatures occurs between pre- and post-NAT breast cancers for patients who do not achieve a pathologic complete response. The current analysis included women from the prospective Neoadjuvant Breast Registry Symphony Trial who had breast cancer and awaited NAT. MammaPrint and BluePrint (Agendia, Inc., Irvine, CA) assays were performed on pre- and post-NAT breast tumor samples. At the completion of NAT, 93 patients with residual disease had their remaining tumor analyzed for MammaPrint and BluePrint. Of 93 patients, 21 switched tumor classification: 16 from high risk (HR) to low risk (LR) and 1 from LR to HR (p

Purpose The Sunbelt Melanoma Trial is a prospective randomized trial evaluating the role of high-dose interferon alfa-2b therapy (HDI) or completion lymph node dissection (CLND) for patients with melanoma staged by sentinel lymph node (SLN) biopsy. Patients and Methods Patients were eligible if they were age 18 to 70 years with primary cutaneous melanoma ≥ 1.0 mm Breslow thickness and underwent SLN biopsy. In Protocol A, patients with a single tumor-positive lymph node after SLN biopsy underwent CLND and were randomly assigned to observation versus HDI. In Protocol B, patients with tumor-negative SLN by standard histopathology and immunohistochemistry underwent molecular staging by reverse transcriptase polymerase chain reaction (RT-PCR). Patients positive by RT-PCR were randomly assigned to observation versus CLND versus CLND+HDI. Primary end points were disease-free survival (DFS) and overall survival (OS). Results In the Protocol A intention-to-treat analysis, there were no significant differences in DFS (hazard ratio, 0.82; P = .45) or OS (hazard ratio, 1.10; P = .68) for patients randomly assigned to HDI versus observation. In the Protocol B intention-to-treat analysis, there were no significant differences in overall DFS (P = .069) or OS (P = .77) across the three randomized treatment arms. Similarly, efficacy analysis (excluding patients who did not receive the assigned treatment) did not demonstrate significant differences in DFS or OS in Protocol A or Protocol B. Median follow-up time was 71 months. Conclusion No survival benefit for adjuvant HDI in patients with a single positive SLN was found. Among patients with tumor-negative SLN by conventional pathology but with melanoma detected in the SLN by RT-PCR, there was no OS benefit for CLND or CLND+HDI.

Background Ideally classification by subtype predicts treatment response and overall outcome. BluePrint 80-gene functional molecular subtype is based on mRNA expression (as is intrinsic subtype) associated with intact translation to protein (unlike intrinsic subtype). BluePrint (BP) classifies patients into Luminal, Her2 or Basal-type. Presently subtype is approximated using conventional immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) ("conventional subtype") or assigned by gene expression profiling. The main objective of the prospective neo-adjuvant NBRST study is to compare drug sensitivity as defined by pathological Complete Response (pCR), using 80-gene functional subtype vs. conventional IHC/FISH subtyping. NBRST enrolled over 1,000 US patients between June 2011 and December 2014. In this analysis we present the results for IHC/FISH Her2-positive patients. Methods Here we report findings in the 260 NBRST patients who had IHC/FISH Her2+ breast cancer, according to ASCO CAP guidelines at the time of diagnosis. Treatment, including chemotherapy and HER2-targeted agents, was at the discretion of the physician adhering to NCCN approved or other peer-reviewed, established regimens over the course of the study. pCR was defined as T0/isN0. Fisher's exact test was used to compare pCR rates among IHC/FISH and functional subtypes and treatment groups. Results The 260 IHC/FISH Her2+ patients had median age 53 (range 23-81) and included T1-4, N0-3 tumors. Of 169 ER+/Her2+ tumors 49% were re-classified as BP Luminal, 43% as BP HER2, and 8% as BP Basal. The median ER% of ER+/Her2+/BP Luminal tumors was 93% (range 3-100), compared to 79% in ER+/Her2+/BP HER2 (range 1-91) and 8% in ER+/Her2+/BP Basal-type (range 2-99).The overall pCR rate in ER+/Her2+/BP Luminal was 17% (4% with chemo/trastuzumab; 39% chemo/trastuzumab/pertuzumab, p Conclusions In the NBRST study, BP 80-gene functional subtype (based on mRNA expression and translation): 1. Re-classifies over half of all IHC/FISH ER+/Her2+ patients; 2. Predicts treatment response or resistance in Her2+ patients not segregated by conventional IHC/FISH classification and 3. Identifies ER+/Her2+ tumors that are sensitive to chemo/trastuzumab/pertuzumab but resistant to chemo/trastuzumab. Citation Format: Whitworth P, Beitsch P, Baron P, Beatty J, Pellicane JV, Murray MK, Dul CL, Mislowsky AM, Nash CH, Richards PD, Lee LA, Stork-Sloots L, de Snoo F, Untch S, Gittleman M, Akbari S, Rotkis MC. Three distinct HER2 subtypes identified by BluePrint 80-gene functional subtyping predict treatment-specific response in the prospective neo-adjuvant NBRST registry. [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 P1-14-05.

Background The phase 4 Neo-adjuvant Breast Registry Symphony Trial (NBRST) enrolled over 1,000 US patients between June 2011 and December 2014. The aim of NBRST study is to compare chemo-sensitivity as defined by pathological Complete Response (pCR) using the 80-gene BluePrint (BP) functional subtype profile vs. conventional IHC/FISH subtyping. Treatment was at the discretion of the physician utilizing standard NCCN regimens. Pertuzumab, a monoclonal antibody, inhibits the dimerization of HER2 with other HER receptors. Pertuzumab received US FDA approval for the neo-adjuvant treatment of HER2-positive breast cancer in September 2013. Essentially all patients with HER2 positive cancers were treated with chemotherapy + trastuzumab and after this date pertuzumab was added, creating 2 distinct groups of Her2-treated patients. The aim of the current analysis is to compare the pCR rate of chemo-trastuzumab (c-t) vs chemo-trastuzumab plus pertuzumab (c-t-p) by conventional and 80-gene BP functional subtype. 80-gene BP functional subtype was derived by supervised cluster analysis for concordant mRNA and protein expression. Methods The current analysis includes women from the NBRST study, with histologically proven breast cancer, who received neo-adjuvant treatment, had 80-gene subtyping and provided written informed consent. Pathological assessment of HER2 was performed according to ASCO CAP guidelines at the time of diagnosis. 80-gene BluePrint (BP) classifies patients into Luminal, HER2 or Basal-type. pCR is defined as T0/isN0. All pCRs were verified with a de-identified copy of the surgical pathology report. Fisher's exact test was used to compare pCR rates within different subgroups. Results 286 IHC/FISH HER2+ patients received c-t (175) or c-t-p (111). Of these 80-gene BP subtype classified 53% as HER2-type, 33% as Luminal-type and 14% as Basal-type. 64% were ER positive. The pCR rates and p-values within different subgroups of clinical HER2+ patients are provided in the table below. c-tc-t-p (n)pCR ratep-valueTotal (n=286)41%57%0.01BP HER2 (153)58%73%0.06 BP Luminal (93) 6% 39% 0.0002BP Basal (40)45%1.0IHC/FISH HER2+/ER+ (183)31%53%0.003IHC/FISH HER2+/ER- (103)59%64%0.68 Conclusions One-third of ASCO/CAP Her2+ patients had 80-gene BP Luminal subtype and demonstrated resistance to c-t (pCR 6%). Addition of Pertuzumab overcame resistance in this group (pCR 39%). This finding in the neoadjuvant setting suggests a substantial potential benefit in the adjuvant setting and thus an urgent need to consider treatment in at-risk patients as well as confirmatory tissue analysis from independently reported trials. Citation Format: Beitsch P, Whitworth P, Baron P, Beatty J, Pellicane JV, Murray MK, Dul C, Mislowsky AM, Nash CH, Richards PD, Lee LA, Stork-Sloots L, de Snoo F, Untch S, Gittleman M, Akbari S, Rotkis MC. One-third of HER2 positive patients have 80-gene luminal subtype that is resistant to chemo-trastuzumab but sensitive to chemo-trastuzumab-pertuzumab: Critical implications for the adjuvant setting from the NBRST phase 4 neoadjuvant study. [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 P4-14-29.

Background Ideally classification by subtype predicts treatment response and overall outcome. BluePrint 80-gene functional molecular subtype is based on mRNA expression (as is intrinsic subtype) associated with intact translation to protein (unlike intrinsic subtype). BluePrint (BP) classifies patients into Luminal, HER2 or Basal-type. Presently subtype is approximated using conventional immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) ("conventional subtype") or assigned by gene expression profiling. The aim of the prospective NBRST study was to compare chemosensitivity as defined by pathological Complete Response (pCR), or endocrine sensitivity as defined by partial response (PR) using 80-gene functional subtype vs. conventional IHC/FISH subtyping. In this analyses we present the results of all IHC/FISH Hormone Receptor (HR) positive/Her2 negative patients. Methods The neo-adjuvant NBRST study enrolled over 1000 US patients between June 2011 and December 2014. Women aged 18–90 with histologically proven breast cancer, who were scheduled to start neo-adjuvant chemotherapy (NCT) or neo-adjuvant endocrine therapy (NET), and who provided written informed consent were included. Additional inclusion criteria were no excision biopsy or axillary dissection, no confirmed distant metastatic disease, and no prior therapy for breast cancer. Treatment was at the discretion of the physician adhering to NCCN approved or other peer-reviewed, established regimens. BluePrint in combination with MammaPrint classifies patients into four molecular subgroups: Luminal A, Luminal B, HER2 and Basal. pCR is defined as T0/isN0 and PR is according to RECIST and defined as at least a 30% decrease in the tumor bed. Results 418 IHC/FISH HR+/Her2- T1-4, N0-3, patients were enrolled (median age 54, range 22-87). MammaPrint and BluePrint (MP/BP) classified 28% as Luminal A, 54% as Luminal B, and 18% as Basal-type. The distribution of locally assessed ER% in BP Luminal tumors was 2% ER 0-10%; 3% ER 11-50%; and 95% ER>50% compared to 45% ER 0-10%; 28% ER 11-50%; and 27% ER >50% in BP Basal tumors. Tumors classified as BP Luminal 370 (89%) received NCT and the overall pCR rate was 9%. There was a significantly higher (p Conclusions Molecular subtyping using MammaPrint and BluePrint classified 1 out of 5 pathological luminal patients as BP Basal-type with a significant higher response rate to NCT compared to BP Luminal patients. BP Luminal patients have an excellent partial response rate to NET. Citation Format: Pellicane JV, Whitworth P, Beitsch P, Baron P, Beatty J, Murray MK, Dul CL, Mislowsky AM, Nash CH, Richards PD, Lee LL, Stork-Sloots L, de Snoo F, Untch S, Gittleman M, Akbari S, Rotkis MC. Chemosensitivity and endocrine sensitivity predicted by MammaPrint and BluePrint in clinical luminal patients in the prospective NBRST study. [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 P3-07-67.

10017 Background: Seviprotimut-L is a vaccine prepared from antigens of 3 human melanoma cell lines, administered with alum. Prior formulations induced T cell and antibody responses and improved survival in a small phase II clinical trial. Part B1 of MAVIS (Melanoma Antigen Vaccine Immunotherapy Study, a three part, Phase III clinical program), was a multicenter, double-blind, placebo-controlled trial to assess efficacy of seviprotimut-L, with the primary endpoint of relapse-free survival (RFS). The goal of Part B1 was to guide design of the pivotal Part B2. Methods: Patients with AJCC v7 stage IIB-III cutaneous melanoma, after surgical resection, age 18-75, ECOG PS 0-1, were randomized 2:1 to seviprotimut-L 40 mcg or placebo, injected subcutaneously every 2 weeks x 5, then monthly x 4, then every 3 months x 9. Patients were stratified by stage (IIB/C, IIIA, IIIB/C). Target enrollment was 325. The study was powered for assessment of RFS, with target hazard ratio (HR) of 0.625, one-sided alpha of 0.10, and power 80%. Final data are presented. Results: 347 patients were randomized. Arms were well-balanced. Treatment-related adverse events (AEs) led to discontinuation in 0.4% and 0%, respectively, for vaccine and placebo arms. There were no treatment-related SAEs. By intent-to-treat (ITT) analysis, RFS was not significantly longer for seviprotimut-L in the full study population but trended toward benefit (HR 0.88). Subgroup analysis based on planned stratification revealed the hazard ratio (HR) for the Stage IIB/IIC subset (randomization stratum, n=111) to be 0.65 (95% CI [0.37, 1.17]), favoring seviprotimut-L. Age can decrease immune competence: RFS was longer with vaccine for patients age

Sentinel lymph node biopsy (SLNB) is a highly accurate method for staging the axilla in early breast cancer. Superparamagnetic iron oxide mapping agents have been explored to overcome the disadvantages of the standard SLNB technique, which uses a radioisotope tracer with or without blue dye. One such agent, Sienna+, was shown to be non-inferior to the standard technique for SLNB in a number of studies. The SentimagIC trial was designed to establish the non-inferiority of a new formulation of this magnetic tracer, Magtrace (formerly SiennaXP). Patients with clinically node-negative early-stage breast cancer were recruited from six centers in the US. Patients received radioisotope and isosulfan blue dye injections, followed by an intraoperative injection of magnetic tracer, prior to SLNB. The sentinel node identification rate was compared between the magnetic and standard techniques to evaluate non-inferiority and concordance. Data were collected for 146 procedures in 146 patients. The per patient detection rate was 99.3% (145/146) when using the magnetic tracer and 98.6% (144/146) when using the standard technique, while the nodal detection rate was 94.3% (348/369 nodes) when using the magnetic tracer and 93.5% (345/369) when using the standard technique (difference 0.8%, 95% binomial confidence interval lower bound − 2.1%). Of the 22 patients with positive sentinel lymph nodes (SLNs), 21 (95.4%) were detected by both the magnetic tracer and the standard technique. All malignant nodes detected by standard technique were also identified by the magnetic technique. The magnetic technique is non-inferior to the standard technique of radioisotope and blue dye for axillary SLN detection in early-stage breast cancer. The magnetic technique is therefore a viable alternative.

The Breast Cancer Test (BCT) score has been validated for its ability to predict the risk of distant metastasis in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. This study aimed to examine the value of the BCT score for predicting the benefit of adjuvant chemotherapy for Korean women with hormone receptor-positive, HER2-negative, lymph node-negative breast cancer. The study included 346 patients treated with either hormone therapy alone (n = 203) or hormone therapy plus chemotherapy (n = 143), and compared patient survival between the two treatment groups. The effect of BCT score on patient survival by treatment group was assessed using Cox proportional hazards models. Based on the results, the BCT score was prognostic for distant metastasis-free survival and breast cancer-specific survival in the hormone therapy alone group. There was no significant difference between the treatment groups in terms of 10-year distant metastasis-free survival in the overall patient population. However, when patients were classified as low risk (n = 266) and high risk (n = 80) according to the BCT score, addition of adjuvant chemotherapy to hormone therapy for patients classified as BCT high-risk group led to a significant improvement in 10-year distant metastasis-free survival, from 65.4% to 91.9% (hazard ratio, 0.18; 95% confidence interval, 0.05-0.64; P = 0.003); in contrast, there was no benefit for the BCT low-risk group. The stratification of patients according to the BCT score also identified clinically high-risk patients who may not benefit from chemotherapy. Results were similar for breast cancer-specific survival. In conclusion, the BCT score was not only of prognostic value but was also a predictor of chemotherapy benefit for Korean patients with hormone receptor-positive, HER2-negative, lymph node-negative breast cancer.

Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P

Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping. Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment. In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) (p = 0.00001) and the 45 tumors (15%) classified as basal (44%) (p = 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%). The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients.

Purpose The purpose of the NBRST study is to compare a multigene classifier to conventional immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) subtyping to predict chemosensitivity as defined by pathological complete response (pCR) or endocrine sensitivity as defined by partial response. Methods The study includes women with histologically proven breast cancer, who will receive neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy. BluePrint in combination with MammaPrint classifies patients into four molecular subgroups: Luminal A, Luminal B, HER2, and Basal. Results A total of 426 patients had definitive surgery. Thirty-seven of 211 (18 %) IHC/FISH hormone receptor (HR)+/HER2− patients were reclassified by Blueprint as Basal (n = 35) or HER2 (n = 2). Fifty-three of 123 (43 %) IHC/FISH HER2+ patients were reclassified as Luminal (n = 36) or Basal (n = 17). Four of 92 (4 %) IHC/FISH triple-negative (TN) patients were reclassified as Luminal (n = 2) or HER2 (n = 2). NCT pCR rates were 2 % in Luminal A and 7 % Luminal B patients versus 10 % pCR in IHC/FISH HR+/HER2− patients. The NCT pCR rate was 53 % in BluePrint HER2 patients. This is significantly superior (p = 0.047) to the pCR rate in IHC/FISH HER2+ patients (38 %). The pCR rate of 36 of 75 IHC/FISH HER2+/HR+ patients reclassified as BPLuminal is 3 %. NCT pCR for BluePrint Basal patients was 49 of 140 (35 %), comparable to the 34 of 92 pCR rate (37 %) in IHC/FISH TN patients. Conclusions BluePrint molecular subtyping reclassifies 22 % (94/426) of tumors, reassigning more responsive patients to the HER2 and Basal categories while reassigning less responsive patients to the Luminal category. These findings suggest that compared with IHC/FISH, BluePrint more accurately identifies patients likely to respond (or not respond) to NCT.

Whether breast cancer surgeons are adequately trained, skilled, and experienced to provide breast cancer genetic assessment, testing, and counseling came under debate in September 2013 when a major third-party payer excluded nongenetics specialists from ordering such testing. A literature search having failed to uncover any study on breast surgeons' skill and practice in this area, the American Society of Breast Surgeons (ASBrS) surveyed its members on their experience with the recognized crucial components of such testing.In late 2013, ASBrS e-mailed a link to an online questionnaire to its U.S. members (n = 2,603) requesting a self-assessment of skills and experience in genetic assessment, testing, interpretation, and counseling. After approximately 6 weeks, the results were collated and evaluated.By January 2, 2014, 907 responses (34.84 %) had arrived from breast surgeons nationwide working in academic settings (20 %), solo or small group private practice (39 %), large multispecialty groups (18 %), and other settings. More than half said they performed 3-generation pedigrees, ordered genetic testing, and provided pre- and posttest counseling. Most noted that they would welcome continuing educational support in genetics.Currently the majority of breast surgeons provide genetic counseling and testing services to their patients. They report practices that meet or exceed recognized guidelines, including the necessary elements and processes for best practices in breast cancer genetics test counseling. Because breast cancer genetic testing is grossly underutilized relative to the size of the U.S. BRCA mutation carrier population, these appropriate services should not be restricted but rather supported and expanded.

1583 Background: HBOC testing guidelines were established to identify patients with clinically actionable variants and limit economic burden. We report the impact of germline results on health outcome based on clinical decision making and treatment interventions, regardless of guidelines, in a multi-center registry. Methods: 20 community-based and academic participated in an IRB approved registry. Patients with breast cancer were tested with an 80-gene panel; clinical information was collected. Results: Data on 912 patients has been analyzed to date. 50.5% met NCCN criteria; 49.5% did not. Pathogenic/likely pathogenic (P/LP) germline mutations were found in 8.65% of patients. Of all patients with P/LP findings, 85% had variants in cancer-risk genes with established management recommendations and 80% had germline variants conferring eligibility for clinical trials and precision medicine-based cancer treatments, such as PARP inhibitors. For 62% of patients with P/LP germline mutations, clinicians reported results impacted patients’ health outcome. And for 69%, results impacted the health outcome of patients’ relatives. There was no significant association between BRCAPRO scores and patients having a P/LP finding, whether in BRCA1/2 alone (p = 0.42) or for any cancer gene (p = 0.57). Physician reported impact on patient outcome associated significantly with the presence of P/LP germline findings (p < 0.00001). There was no significant difference in the clinician reported clinical utility of variants of uncertain significance (VUS) compared to negative results (p = 0.467). Conclusions: Comprehensive panel testing of breast cancer patients impacts physician assessed patient outcomes and informs changes in surgical treatment strategy, medical therapies and proactive screening. The data suggest that BRCAPRO calculators are poor predictors of germline presence of P/LP findings. Physicians in this study demonstrate the ability to discern the clinically actionable value of P/LP mutations from non-actionable VUS. Multigene panels impact breast cancer patient care by identifying precision medicine treatment interventions, and guiding long-term medical management and preventive surveillance for patients and family members.

Background Classification by molecular subtype can aid in the selection of therapy for patients with breast cancer. However at present, the methodology for molecular subtyping is not standardized and the methodology and interpretation of results vary between different laboratories. Subtype is being assigned using conventional immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) ("conventional subtype") or molecularly using gene expression profiling. The aim of the current prospective NBRST study is to compare chemosensitivity as defined by pathological Complete Response (pCR), or endocrine sensitivity as defined by partial response (PR) using the 80-gene BluePrint functional subtype profile vs. conventional IHC/FISH subtyping. Methods MINDACT is an international, prospective, randomized, phase III trial investigating the clinical utility of MammaPrint in selecting patients with early BC for adjuvant chemotherapy (CT), which enrolled 6,694 patients. Molecular subtyping data were obtained by MammaPrint and BluePrint (Agendia, Amsterdam, the Netherlands) on frozen samples (n=6,694) classifying patients in the following subtypes: Luminal A (Luminal-type/MammaPrint Low Risk); Luminal B (Luminal-type/MammaPrint High Risk); HER2-type; and Basal-type. ER, PgR, HER2 and Ki67 protein status were centrally assessed on FFPE blocks by IHC and/or FISH in the European Institute of Oncology, Milan, Italy (n=5,740; 86%). Patients were also classified according to the St. 2013 Gallen recommendations [Goldhirsch et al. 2013], which recognizes an additional category (Luminal B-like HER2+). Results Ki67 is often used as biomarker to distinguish Luminal A from Luminal B subgroups. The concordance between MammaPrint and centrally assessed Ki67 in Luminal-type patients is 60%, with a κ score of 0.26 (95% CI 0.24–0.28) indicating that Ki67 and MammaPrint cannot reliably substitute for each other. When using a cut-point of 20% instead of 14% the concordance increased to 78%, with a κ score of 0.44 (95% CI 0.41–0.47). There is a relatively large group of clinical HER2+ cases that are BluePrint Luminal-type (208 out of 541; 38%) indicating that tumor expression of the Luminal profile is dominant compared with expression of the HER2 profile. These patients have high IHC ER results and all except for 1 fall into the group that St Gallen separately defines as Luminal B-like HER2-positive. These patients may have lower response to trastuzumab [von Minckwitz et al. JCO 2012]. 98 out of 622 BluePrint Basal-type patients are clinical Luminal HER2-. 2/3 of these patients have low centrally assessed IHC PR expression and 1/3 have low centrally assessed ER expression (≥1% and Conclusions Molecular subtyping using BluePrint and MammaPrint leads to a reclassification of 22% (113/515) of tumors. The re-classification of patients leading to re-assignment to more responsive vs. less responsive groups is most prominent in classically assessed triple positive patients where 46% of patients are re-assigned to the less responsive BP Luminal-type group (pCR rate of 7%) vs. 46% of patients assigned to the responsive BP HER2-type group (pCR rate of 49%). These findings confirm the more accurate identification of molecular subgroups for treatment decision by BluePrint functional subtype classifier which may therefore serve as a better guide for neo-adjuvant treatment than standard, local IHC/FISH assay. Citation Format: Pat Whitworth, Jennifer Beatty, Paul Baron, Paul Richards, James Pellicane, Angela Mislowsky, Charles Nash, Laura Lee, Mary Murray, Femke de Snoo, Lisette Stork-Sloots, Sarah Untch, Mark Gittleman, Stephanie Akbari, Peter Beitsch. Functional subtyping with BluePrint 80-gene profile identifies two distinct triple positive subtypes with and without trastuzumab/chemo-sensitivity: Implications for treatment from the NBRST registry [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-22.

Background Classification into molecular subtypes may be important for the selection of therapy for patients with early breast cancer. Previous analyses had shown that breast cancer subtypes have distinct clinical outcome (Sorlie, PNAS 2001; Esserman, BCRT 2011). The aim of the prospective NBRST study is to measure chemosensitivity as defined by pathological Complete Response (pCR), or endocrine sensitivity as defined by partial response (PR) and metastasis-free survival in molecular subgroups using MammaPrint and BluePrint. Methods The study includes women aged 18–90 with histologically proven breast cancer, who are scheduled to start neo-adjuvant chemotherapy (CT) or neo-adjuvant endocrine therapy (ET), and who provide written informed consent. Additional inclusion criteria include no excision biopsy or axillary dissection, no confirmed distant metastatic disease, and no prior therapy for breast cancer. Treatment is at the discretion of the physician adhering to NCCN approved regimens. pCR is defined as no invasive or noninvasive residual disease in the breast or axillary lymph nodes. Results 191 Patients (median age 53, range 22-82), T1-4 N0-3, had definitive surgery and the overall pCR rate was 18%. 31 (16%) patients are classified as Luminal A-type (BluePrint Luminal/MammaPrint Low Risk) of whom 24 received neo-adjuvant CT; 1 patient (4%) had a pCR. While 7 patients received neo-adjuvant ET and 5 (71%) had a PR. 64 (34%) Patients are classified as Luminal B-type (BluePrint Luminal/MammaPrint High Risk). All but 1 patient received neo-adjuvant CT and 2 (3%) had a pCR. 30 (16%) Patients are classified as BluePrint HER2-type and all received neo-adjuvant CT and trastuzumab (except for 3 patients who did not receive trastuzumab); 11 (37%) had a pCR. 66 (31%) Patients are classified as BluePrint Basal-type and received neo-adjuvant CT; 19 (29%) had a pCR. Comparison of IHC/FISH classification with molecular subtyping: 24/102 (24%) IHC/FISH ER+/Her2- patients are not classified as Luminal-type by BluePrint (4 Her2, 20 Basal). 22/48 (46%) IHC/FISH Her2+ patients are not Her2-type by BluePrint (4 Luminal A, 11 Luminal B, and 7 Basal). All IHC/FISH triple negative patients are BluePrint Basal-type. Conclusions Molecular subtyping using MammaPrint and BluePrint leads to a reclassification of 24% (46/191) of tumors. We observed differences in pCR to neo-adjuvant treatment in groups stratified by BluePrint and MammaPrint. Patients with Luminal A-type breast cancer have a high response to neo-adjuvant endocrine therapy (71% PR) and low pCR (4%) to neo-adjuvant CT. While patients with BluePrint HER2-type and Basal-type breast cancer have a high pCR rate to neo-adjuvant CT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-02.

Objectives: The American Society of Breast Surgeons (ASBS) Nipple Sparing Mastectomy Registry (NSMR) is a prospective, IRB approved, non-randomized, multi-institutional registry assessing surgical techniques, utilized metrics, oncologic outcome, and aesthetic outcome of nipple sparing mastectomies. The registry has been open for enrollment for 26 months. The target accrual is 1000 individuals. This abstract specifically analyzes rates of post-operative infection in NSMs. Methods: Fifty two investigators from 41 institutions are participating in the ASBS NSMR. A total of 373 patients underwent 631 mastectomies, with indications of prophylaxis (365), cancer (248), and unknown (18). We assessed a sub group of 449 mastectomies, with indications of prophylaxis (253) and cancer (196) that had all data sets completed. We assessed infection rates(characterized as needing oral or iv antibiotics with or without removal of implant/expander and/or debridement) in the entire group as well as by indication (cancer vs. prophylaxis). Factors such as smoking history, previous radiation therapy, previous surgery, incision type, reconstruction technique, and flap dissection technique were analyzed. Results: In a subgroup of 449 mastectomies (253 prophylactic and 196 cancer): Post operative infections were reported in 22 (4.9%) of patients: 7 (3.6%) of mastectomies with an indication of cancer and 15 (5.9%) of prophylactic mastectomies (p-value 0.3140). Infections were characterized as: treatment with oral antibiotics alone, treatment with i.v. antibiotics alone, iv antibiotics with washout or debridement, or antibiotics and implant/ tissue expander removal. No correlation was found in smoking history (p-value 1.000), previous breast surgery (p-value 0.1277) or previous radiation (p-value 0.6024). No correlation was found in incision utilized, reconstruction technique, or method of flap dissection either. Conclusion: The rate of postoperative infections in nipple sparing mastectomies is comparable if not lower than non-nipple sparing mastectomies. No statistically significant difference in infection rate was found between mastectomies completed for prophylaxis or cancer. No correlation was found between factors such as smoking history, history of radiation therapy, prior breast surgery, incision utilized, reconstruction technique, or method of flap dissection. Improved aesthetics with a nipple sparing approach (technically more demanding and typically through a smaller incision) does not come at the cost of a higher rate of infectious complications. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-07.

Background Recent retrospective, claims-based analyses have suggested a potential increased rate of toxicities associated with brachytherapy-based accelerated partial breast irradiation (APBI). The purpose of this analysis was to examine cosmesis and toxicity data from the prospective American Society of Breast Surgeons (ASBS) breast brachytherapy registry trial to compare to the findings from the claims analyses. Methods The ASBS breast brachytherapy registry is a prospective nonblinded multi-institutional registry trial. Patients with Stage 0–II breast cancer undergoing breast conserving therapy were eligible. A total of 1665 patients were enrolled and 1449 treated between 2002 and 2004 with a median followup of 63 months. All patients were treated with the MammoSite (Hologic, Inc.) single-lumen device to deliver adjuvant APBI (34 Gy in 3.4 Gy fractions). Results The rate of excellent/good cosmesis was 90.6% at 84 months. The rate of a complication (symptomatic seroma, infection, fat necrosis, telangiectasias) at 1 year/any time point was 24.2%/38.5%, whereas the rate of noninfectious complications at 1 year/any time point was 14.8%/28.9%. The rate of symptomatic seroma, fat necrosis, infection, and telangiectasia at any time was 13.4%, 2.5%, 9.6%, and 13.0%, respectively. Conclusions The final toxicity analysis from ASBS breast brachytherapy registry trial confirms the previously noted excellent cosmesis and toxicity profiles and fails to confirm retrospective claims analyses that have suggested higher rates of toxicity for brachytherapy-based APBI.

The American Society of Breast Surgeons (ASBrS) Nipple Sparing Mastectomy Registry (NSMR) is designed to facilitate compiling information on metrics utilized, techniques utilized, aesthetic outcomes, as well as oncologic outcomes of the nipple-sparing mastectomy. We aim to provide a large prospective collection of data points specifically gathered to provide evidence based medicine on outcome measures and metrics utilized for the nipple sparing mastectomy.

The early results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in locoregional recurrence for patients with positive sentinel lymph nodes (SLNs) randomized either to axillary lymph node dissection (ALND) or sentinel lymph node dissection (SLND) alone. We now report long-term locoregional recurrence results.ACOSOG Z0011 prospectively examined overall survival of patients with SLN metastases undergoing breast-conserving therapy randomized to undergo ALND after SLND or no further axillary specific treatment. Locoregional recurrence was prospectively evaluated and compared between the groups.Four hundred forty-six patients were randomized to SLND alone and 445 to SLND and ALND. Both groups were similar with respect to age, Bloom-Richardson score, Estrogen Receptor status, adjuvant systemic therapy, histology, and tumor size. Patients randomized to ALND had a median of 17 axillary nodes removed compared with a median of only 2 SLNs removed with SLND alone (P0.001). ALND, as expected, also removed more positive lymph nodes (P0.001). At a median follow-up of 9.25 years, there was no statistically significant difference in local recurrence-free survival (P = 0.13). The cumulative incidence of nodal recurrences at 10 years was 0.5% in the ALND arm and 1.5% in the SLND alone arm (P = 0.28). Ten-year cumulative locoregional recurrence was 6.2% with ALND and 5.3% with SLND alone (P = 0.36).Despite the potential for residual axillary disease after SLND, SLND without ALND offers excellent regional control for selected patients with early metastatic breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

Purpose Hormone receptor-positive (HR+) tumors have heterogeneous biology and present a challenge for determining optimal treatment. In the Neoadjuvant Breast Registry Symphony Trial (NBRST) patients were classified according to MammaPrint/BluePrint subtyping to provide insight into the response to neoadjuvant endocrine therapy (NET) or neoadjuvant chemotherapy (NCT). Objective The purpose of this predefined substudy was to compare MammaPrint/BluePrint with conventional ‘clinical’ immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) subtyping in ‘clinical luminal’ [HR+/human epidermal growth factor receptor 2-negative (HER2−)] breast cancer patients to predict treatment sensitivity. Methods NBRST IHC/FISH HR+/HER2− breast cancer patients (n = 474) were classified into four molecular subgroups by MammaPrint/BluePrint subtyping: Luminal A, Luminal B, HER2, and Basal type. Pathological complete response (pCR) rates were compared with conventional IHC/FISH subtype. Results The overall pCR rate for ‘clinical luminal’ patients to NCT was 11 %; however, 87 of these 474 patients were reclassified as Basal type by BluePrint, with a high pCR rate of 32 %. The MammaPrint index was highly associated with the likelihood of pCR (p

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.