Hart, SN

Abstract Background: Clinical germline genetic testing of cancer predisposition gene panels is used to identify women at increased risk for breast cancer. The identification of pathogenic mutations in established high and moderate predisposition genes may result in improved risk management of breast cancer for tested patients and their family members through tailored screening, prophylactic surgeries, or chemoprevention. However, the risks of breast cancer associated with mutations in these genes have likely been overestimated for many women in the general population because previous studies have focused on individuals with a family history of breast and/or ovarian cancer, early onset disease, or triple negative breast cancer. The goal of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study is to estimate breast cancer risks associated with mutations in hereditary cancer panel genes in the general population. Methods: Germline DNA samples from blood or saliva were obtained from 39,439 breast cancer patients and matched unaffected controls from six US-based cohorts (BWHS, CPSII, CTS, MEC, NHS1, NHS2, WHI). DNA was subjected to dual bar-coded QIAseq multiplex PCR-based amplification of 1733 target regions covering all coding regions of 37 cancer predisposition genes and sequenced. Mutation calling was conducted with Haplotype Caller and Vardict. Results: High quality sequence data was obtained for 38,990 of 39,439 samples (98.9%) and for 99.3% of target regions. Pathogenic mutations in 12 known breast cancer predisposition genes were identified 4.5% of all breast cancer cases and 2.1% of controls; and in 6.7% of African American breast cancer cases and 1.8% of controls. Differences in mutation frequencies were observed by age with mutations in 7.8% of cases diagnosed £50 years of age and 4.0% of cases diagnosed over age 50. Mutations in ATM, BRCA1, BRCA2, and PALB2 were enriched 2 to 3-fold in cases diagnosed under age 50 relative to older cases. No change in frequency of CHEK2 mutations by age was observed. In case-control analyses mutations in BRCA1, BRCA2 and PALB2 were significantly associated with a high risk of breast cancer (odds ratio (OR)>4.0). Of these, BRCA1 and BRCA2 displayed ORs of 13.5 and 16.6 in the £50 age group, but only 5.7 and 3.2 in the >50 age group. Only minor age-specific effects were observed for PALB2. Mutations in ATM and CHEK2 were associated with moderate risks of breast cancer (OR=2.0 to 4.0) in the younger age group, but not in the older age group. Conclusions: Results from the CARRIERS cohort-based study establish that mutations in known breast cancer predisposition genes are associated with only moderate risks of breast cancer in the general population. However, risks are substantially increased for BRCA1 and BRCA2 but not ATM, CHEK2 or PALB2 mutations in those £50 years of age. The age-related estimates of breast cancer risk for each of the hereditary cancer panel genes in this study may inform selection of individuals in the general population who may benefit from genetic testing and associated risk management strategies. Citation Format: Couch FJ, Hu C, Hart SN, Gnanaolivu RD, Lilyquist J, Lee KY, Gao C, Eckloff B, Samara R, Klebba J, Auer P, Bernstein L, Gaudet M, Haiman C, Palmer JR, Yao S, Domchek SM, Weitzel JN, Goldgar DE, Nathanson KL, Kraft P, Polley EC. Age-related breast cancer risk estimates for the general population based on sequencing of cancer predisposition genes in 19,228 breast cancer patients and 20,211 matched unaffected controls from US based cohorts in the CARRIERS study [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 GS2-01.

Abstract Background New treatment strategies for metastatic breast cancer (mBC) are mainly driven by therapies against specific targets. BRCA mutations are one of the few established actionable targets, with PARP-Inhibitors and Platinum showing high efficacy in mBC. Hereditary cancer testing panels are now broadly used for identification of individuals with BRCA1/2 mutations who may benefit from these therapies. Many of these panels also contain other predisposition genes involved in BRCA-related DNA repair pathways, but the clinical relevance of mutations in these genes remain unclear. The aim of this study was to describe the mutation rates of BRCA1/2 and panel-based predisposition genes, and the associated clinical characteristics of individuals with these mutations, in a prospective cohort of mBC patients. Methods The PRAEGNANT mBC registry (NCT02338167) is a prospective registry for metastatic breast cancer patients with a focus on molecular biomarkers. Patients receiving any therapeutic regimen are eligible for this registry. Germline DNA was collected at study entry and genotyped for 37 cancer predisposition genes including BRCA1 and BRCA2. The frequency of mutations in each gene was determined, and associations between mutations and patient and tumor characteristics, metastatic pattern, and overall survival were assessed. Results Mutations in established high (odds ratio (OR)>5.0) and moderate risk (OR>2.0) breast cancer genes (BRCA1/2, PALB2, CHEK2, ATM, RAD51D, BARD1, and MSH6) were seen in 123 of 1462 tested patients with mBC (8.4%). BRCA1 and BRCA2 mutations were seen in 1.4% and 2.9% of patients respectively. Most frequently mutated non-BRCA panel genes were CHEK2, PALB2 and ATM with 2.8%, 0.8% and 0.6% of patients. Mutation frequency varied with regard to patients who developed brain metastases, visceral metastases or bone only metastases. BRCA1 or BRCA2 mutations were seen frequently in patients with brain (5.3%) or visceral metastases (5.2%), but were present in only 2.5% patients with bone only metastases and 1.5% of patients with lesions in other locations. Panel genes were equally distributed among all metastatic patients. PALB2 mutations (n=11) were only seen in patients with brain (1.9%) and visceral metastases (0.9%), but not in patients with bone metastases or other locations. 36.4% (N=4) of all patients with PALB2 mutations developing a brain metastasis. When adjusted for other mBC prognostic factors, a mutation (all genes) was associated with an unfavorable prognosis (HR: 1.50; 95%CI: 1.04 to 2.30, p=0.03). Mutation frequencies were similar according to therapy lines. All other associations with molecular subtypes and risk factors were similar to primary breast cancer cases. Conclusion Mutations in high and moderate risk breast cancer genes were frequent in metastatic breast cancer patients. The frequency was substantially higher than the 4 to 5% mutation frequency observed among unselected primary breast cancer patients, but is consistent with recent results from studies of metastatic prostate cancer patients. Patients with brain and visceral metastases had the highest BRCA mutation rates. Results suggested that PALB2 mutations may be more frequent in patients with brain metastases. Citation Format: Fasching PA, Hu C, Hart SN, Polley EC, Lee KY, Gnanolivu RD, Lilyquist J, Hartkopf AD, Taran FA, Janni W, Hadji P, Tesch H, Haeberle L, Ettl J, Lux MP, Lueftner D, Wallwiener M, Mueller V, Beckmann MW, Belleville E, Wimberger P, Untch M, Kolberg H-C, Fehm TN, Overkamp F, Wallwiener D, Brucker SY, Schneeweiss A, Couch F. Cancer predisposition genes in metastatic breast cancer – Association with metastatic pattern, prognosis, patient and tumor characteristics [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-02.

Abstract Background: Germline cancer testing panels provide an effective method for identifying individuals at increased risk for breast cancer. However, estimates of risk for triple negative breast cancer (TNBC) (estrogen receptor-negative, progesterone receptor-negative, HER2-negative) associated with pathogenic mutations in panel genes have not been established. We sought to define the genes that contribute to TNBC. Methods:Germline hereditary cancer multigene panel testing results were obtained for 8,753 TNBCs evaluated by a clinical testing laboratory. Associations between pathogenic mutations in individual genes and TNBC were assessed by comparing mutation frequencies in TNBCs and in the Exome Aggregation Consortium, non-Finn European, non-Cancer Genome Atlas reference controls. Results: Inactivating mutations in 21 known cancer predisposition genes were identified in 14.6% of TNBCs. BRCA1, BRCA2, PALB2, BARD1, and RAD51D alterations were associated with high risks (odds ratio(OR)>5.0) of TNBC and variants in BRIP1, RAD51C, MSH6, and TP53 were associated with moderate risks (OR>2). In contrast, ATM, CHEK2, NBN, and RAD50 yielded no clinically relevant risks of TNBC. Pathogenic mutations in these established non-BRCA1/2 TNBC susceptibility genes were detected in 6.3% of TNBCs. Similar trends were observed among African American TNBCs. Overall, 5.5% of TNBCs with pathogenic mutations did not meet NCCN clinical testing criteria for BRCA1/2 due to a lack of significant family history and diagnosis over the age of 60. Conclusions: The identification of genes associated with elevated risk of TNBC will improve understanding of the etiology of this aggressive form of breast cancer and inform risk management of individuals receiving panel testing. The high frequency of pathogenic variants suggests that all patients with TNBC, regardless of age of diagnosis or family history of cancer, should be considered for multigene panel testing. Citation Format: Couch FJ, Shimelis H, LaDuca H, Hu C, Hart SN, Polley EC, Pesaran T, Tippin-Davis B, Goldgar DE, Dolinsky JS. Triple negative breast cancer predisposition genes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-01.

Abstract Background: Clinical panel testing has become routine practice for patients that are diagnosed with breast cancer at a young age and/or have a personal or family history of cancer. Associations with known breast cancer genes and breast cancer subtypes have been previously identified, such as BRCA1 associations with estrogen receptor negative (ER-) and triple negative (ER-/PR-/HER2-) breast cancers. However, the cancer predisposition genes associated with each of the four clinical subtypes of breast cancer have not been fully defined. We evaluated 24,901 Caucasian female breast cancer cases receiving clinical panel testing for 23 cancer predisposition genes and assessed associations between mutations in each gene and breast cancer subtypes. Methods: Germline hereditary cancer multigene panel testing results for cancer predisposition genes were obtained for 24,901 Caucasian female breast cancer cases evaluated by a clinical testing laboratory. Information on tumor histology, personal and family history of cancer, age at diagnosis, and previous genetic testing was provided by clinical care providers of patients receiving clinical cancer genetic testing. Breast cancer cases were classified into clinical breast cancer subtypes based on estrogen/progesterone hormone receptor status (HR) and HER2 status: Luminal A (HR+/HER2-), Luminal B (HR+/HER2-), HER2 subtype (HR-/HER2+), and Triple Negative (HR-/HER2-). The frequency of pathogenic or likely pathogenic mutations observed in each subtype was compared against the Exome Aggregation Consortium (ExAC) non-TCGA non-Finnish European population to estimate risks. Results: ATM was associated with moderate risks (odds ratio (OR)>2.0) of Luminal A, Luminal B, and HER2 subtypes of breast cancer, but was not associated with the Triple Negative subtype. PALB2 was associated with moderate risk for Luminal B subtype, but high risk (OR>5.0) for Luminal A, HER2, and triple negative subtypes. TP53 was associated with high risks for Luminal B and HER2 tumors. NBN, MRE11A, and RAD50 were not associated with any subtype of breast cancer. Conclusions: Identifying associations between inherited mutations (odds ratio (OR)>2.0) and breast cancer subtypes can inform clinical risk management, treatment options, and therapeutic development efforts. Citation Format: Lilyquist J, Laduca H, Hu C, Na J, Polley EC, Hart SN, Pesaran T, Tippin-Davis B, Goldgar DE, Dolinsky JS, Couch FJ. Associations between hereditary cancer panel predisposition genes and breast cancer histological subtypes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-02.

Abstract Background: Germline genetic testing of individuals with a diagnosis of triple negative breast cancer, young age at diagnosis, or a family history of breast and/or ovarian cancer has led to the identification of many unique BRCA2 missense variants of uncertain significance (VUS). VUS in BRCA2 are predominantly missense mutations that have unclear relevance to breast, ovarian, and other cancers. Thus, patients found to have a germline BRCA2 VUS do not know if the variant is associated with high risks of these cancers similar to truncating mutations, intermediate risks more similar to CHEK2 mutations, or low risks of no clinical significance. Furthermore, it is unclear if germline BRCA2 VUS, or somatic VUS identified by tumor sequencing, are associated with hypersensitivity to selected DNA damaging and cross-linking agents. Methods: We have used a homology directed repair (HDR) cell-based assay to characterize missense variants in the DNA binding domain (DBD) of BRCA2. The method has been validated using known pathogenic and known non-pathogenic BRCA2 missense variants and has 100% sensitivity (95% confidence interval (CI): 75.3%–100%) and 100% specificity (95% CI: 81.5%–100%) for pathogenic BRCA2 variants. A classifier of variant pathogenicity based on the mean and variances of the distributions of the HDR results of the known pathogenic and neutral variants has been established. We have also developed PARP inhibitor and cisplatin drug response assays for BRCA2 missense variants. Results: Assessment of 207 BRCA2 missense variants, identified in public databases such as BRCA exchange and ClinVar, by the HDR assay identified 71 deleterious variants with >99% probability of pathogenicity, 116 neutral variants with >99% probability of neutrality, and 20 with hypomorphic activity and potentially intermediate risk. A combination of the functional data and sequence-based predictors of protein activity in a Bayesian prediction model resulted in classification of the deleterious variants as pathogenic cancer predisposing variants and the neutral variants as non-pathogenic with low clinical significance. The influence of the deleterious/pathogenic variants on PARPi and cisplatin response was also assessed. Conclusion: The HDR assay is effective for characterization of BRCA2 VUS. The combination of functional data and in silico prediction models provides a robust tool for clinical annotation of BRCA2 VUS. HDR function of BRCA2 missense variants is strongly correlated with response to targeted therapy. Citation Format: Couch FJ, Shimelis H, Hart SN, Moore RM, Thomas A, Lipton GB, Iversen E. Cancer risks and response to targeted therapy associated with BRCA2 variants of uncertain significance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS4-06.

Abstract Clinical genetic testing panels are broadly used to gather information about cancer predisposition in individuals with personal and/or family history of breast cancer. However, the involvement of several of the genes on clinical testing panels in predisposition to breast cancer, such as MRE11A and RAD50, has recently come into question. In addition, accurate risk estimates for breast and other cancer are not well defined for the majority of genes on testing panels. We studied 60,000 women diagnosed with breast cancer who were tested for germline cancer predisposing mutations using hereditary cancer gene panels. Information on personal and family cancer history, age of diagnosis, and ethnicity of patients was obtained from test requisition forms. Greater than 90% met National Comprehensive Cancer Network HBOC testing criteria. To estimate gene-specific risks for breast cancer, case-control analyses were performed comparing the frequencies of pathogenic mutations from Caucasian cancer cases with frequencies from Caucasian, non-Finnish, non-TCGA controls from the Exome Aggregation Consortium (ExAC) database. Mutations were detected in 9% of breast cancer patients. Twelve genes displayed a significant association (p<0.05) with breast cancer. Nine of these genes, including ATM, RAD51D, NF1, and MSH6, were associated with moderate risk (RR>2.0) of breast cancer and three genes (BRCA1, BRCA2, PALB2) were associated with high risk (RR>5.0) of breast cancer. Cumulative age-dependent risk models were developed for each gene. This large clinical testing dataset of 60,000 women with breast cancer provides useful data for many predisposition genes previously lacking risk estimates, and should prove useful for clinical risk management of patients with inherited mutations in these genes. Citation Format: Couch FJ, Hu C, Lilyquist J, Shimelis H, Akinhanmi M, Na J, Polley EC, Hart SN, McFarland R, LaDuca H, Huether R, Goldgar DE, Dolinsky JS. Breast cancer risks associated with mutations in cancer predisposition genes identified by clinical genetic testing of 60,000 breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-01.

Abstract Approximately 15% of genetic screens for mutations in BRCA1 and BRCA2 identify Variants of Uncertain Significance (VUS). Primarily missense mutations, VUS are often difficult to interpret, leading to either uncertainty in how to properly counsel a patient or an unnecessary prophylactic surgery. Given the paucity of data for which missenses are classified as truly pathogenic, computational deleterious missense prediction (DMP) algorithms are used to predict whether a mutation is likely deleterious or neutral. Accuracy of DMPs can vary considerably and have only been calibrated on a relatively small number of missense mutations of demonstrable effect on protein function. In this study, the performance of 41 different DMPs was compared to functional data from 455 functionally characterized missense variants in BRCA1 and BRCA2. New optimized thresholds for classifying missense mutations as deleterious are presented for several existing models as well as a newly derived naïve voting method (NVM). The areas under the curve estimates for the NVM approach are between 0.889-0.922, much higher than previous methods. We estimate that the overall pathogenic potential of missense variants to be 6.8% for BRCA1 and 3.2% of BRCA2, but can be as high as 50% depending on protein location. Overall these results provide key insights into how to predict deleterious missense mutations in BRCA1 and BRCA2. Citation Format: Hart SN, Hoskin T, Shimelis H, Feng B, Lindor NM, Monteiro A, Iversen E, Goldgar DE, Suman V, Couch FJ. Optimized prediction of deleterious missense mutations in BRCA1 and BRCA2 genes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-02-03.

Abstract Background: Both HR deficiency and BRCA mutation status predict response to platinum-based therapy and BRCA mutation status predicts docetaxel resistance. However, the association of either biomarker with response to the individual elements of either AC or taxanes (T) is unknown since T is commonly given concomitantly with or after anthracyclines (A). We evaluated the association of HRD and BRCA mutation status with response to neoadjuvant weekly T followed by AC or (F)EC in high-risk breast cancer. Methods: We studied 140 high risk Stage I-III breast cancer patients (pts), enrolled in the breast cancer genome guided therapy study (BEAUTY), obtaining biopsies for DNA/RNA sequencing and MRI imaging to assess response to neoadjuvant weekly T (+trastuzumab+/-pertuzumab for HER2+ disease) followed by AC or (F)EC. Germline BRCA status and HR status of tumor samples (Myriad laboratories) were obtained. HR deficient tumor was defined as HRD score ≥42 or BRCA mutation. MRI response by changes in tumor size after 12 weeks of T was classified by WHO criteria. pCR was defined as ypT0/Tis ypN0. Both MRI response after T and pCR (after T and AC) were examined in terms of germline BRCA mutation (gBRCAmut vs. gBRCAwt) and tumor HR deficiency. Results: Of 140 pts enrolled, 8 withdrew consent and 2 carboplatin treated pts were excluded. Germline data were available for 124/130 pts. 12 patients had BRCA deleterious germline mutations (4 BRCA1, 8 BRCA2). MRI partial (PR)/complete response (CR) rate to T was 47.3% (95% CI: 37.8-57.0%) in the BRCAwt group and 66.7% (95% CI: 34.9-90.1%) in the BRCAmut group. No MRI CR's were observed in BRCA1 mut pts. In contrast, pCR rate was 50% in the 12 gBRCAmut pts (95% CI: 21.1-78.9%) and 31.3% in the 112 gBRCAwt pts (95% CI: 22.8-40.7%). HR deficiency status has thus far been determined for 74 pts: 26 pts have HD deficient tumors: 18 TNBC, 5 Luminal B, 2 ER-/HER2+; and 1 ER+/HER2+. Determination of HR deficiency is ongoing and will be reported for the full cohort in terms of 12 week MRI response to T and pCR to T+AC. HR deficientMolecular Subtypeyes (%)no (%)TBD (%)Luminal A0/112/11 (18.2)9/11 (81.8)Luminal B5/37 (13.5)13/37 (35.1)19/37 (51.3)Luminal NOS0/21/2 (50)1/2 (50)ER+/Her2+1/17 (5.8)14/17 (82.4)2/17 (11.8)ER-/Her2+2/20 (10)11/20 (55)7/20 (35)Triple Negative18/43 (41.9)6/43 (18.6)17/43 (39.5)germline BRCA statusMRI partial response after T (%)MRI complete response after T (%)pCR after T&AC (%)BRCA11/4 (25)0/42/4 (50)BRCA25/8 (62.5)2/8 (25)4/8 (50)BRCAwt35/112 (31.3)18/112 (16.1)35/112 (31.3) Conclusion: In the setting of neoadjuvant weekly T followed by AC, pCR rates were non-significantly higher in pts with BRCA1 mutations. While we observed no overall association between BRCA mutation status and response rates to taxanes; nearly all MRI responses to taxanes (partial and complete) were observed in the BRCA2 group. Prospective studies are needed to validate these findings and to determine whether BRCA status can be used to select therapy. HR deficiency is uncommon in luminal A and HER2+, frequent in TNBC, and the association of HRD with both MRI response to taxanes and pCR will be reported at the meeting. Citation Format: Boughey JC, Kalari KR, Suman VJ, McLaughlin SA, Moreno Aspitia A, Moyer AM, Northfelt DW, Gray RJ, Vedell PT, Tang X, Dockter TJ, Jones KN, Felten SJ, Conners AL, Hart SN, Visscher DW, Wieben ED, Ingle JN, Hartman A-R, Timms K, Elkin E, Jones J, Wang L, Weinshilboum RW, Goetz MP. Role of germline BRCA status and tumor homologous recombination (HR) deficiency in response to neoadjuvant weekly paclitaxel followed by anthracycline-based chemotherapy. [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 P3-07-29.

Abstract Background: Based upon the association between pathologic response and disease free survival, the neoadjuvant setting is increasingly being used for drug development. NGS has identified unique and recurrent genetic alterations in breast cancer (BC) that are potentially targetable; however, the clinical implications are mostly unknown. We developed a prospective neoadjuvant study (BEAUTY) in high risk BC patients (pts) using weekly T followed by anthracycline-based chemo wherein percutaneous tumor biopsies (PTB) are obtained before/during/after chemo for NGS and PDX. Our goal is to identify novel biomarkers/pathways and develop PDX to test new therapeutic approaches. Methods: Pts underwent PTB at baseline and after 12 wks of T. Response to T was defined based upon 12 week Ki-67: responder (<15%) vs non-responder (≥15%). Pts with histologic response and absence of invasive BC at 12 wks were classified as responders. NGS was performed using PTB/blood DNA (exome) and PTB (RNA seq). MRI response was classified using RECIST criteria. NGS data were used to identify somatic copy number variants (cnvs) and expressed single nucleotide variants (eSNVs). Non-SCID mice (estrogen supplemented) were implanted ≤ 30 minutes with PTB samples. Results: Of the first 78 pts, 44 have completed T. Here we focus on 18 pts with either triple negative or luminal B BC. Clinical characteristics according to Ki-67 response are shown in Table 1. Comparison of genomic alterations in BEAUTY pts with TCGA identified a greater overlap with copy number gains (73%) compared to deletions (40%), along with similar observations of mutations in TP53, PTEN, RYR2, and AKT1 genes. Association analysis of CNVs and eSNVs between responders/non-responders identified 33 genes (predominantly located in chromosomes 1, 8, 13) and 580 eSNVs (corresponding to 497 genes) with a p < 0.05. Differential gene expression (DGE) analysis of responders/non-responders identified 198 genes with a p-value < 0.05. Integrated analysis of 539 genes (CNVs, eSNVs and DGE) identified pathways such as TGF-beta, Jak-Stat, WNT and NOTCH signalling. PDX take rate was 44% [triple negative (6/10); Luminal B (2/8)]. PDX growth rate was significantly associated with clinical baseline Ki-67 (p = 0.00014). Conclusion: This is the first prospective study to demonstrate the feasibility of using PTB to obtain both NGS data and PDX in the neoadjuvant setting. PDX take rate is associated with BC subtype and baseline Ki-67. Studies are ongoing to 1) validate genes/pathways associated with treatment response in subsequent BEAUTY pts; 2) genomically characterize and assess PDX in vivo response to T and 3) Use NGS data to prioritize new drugs/drug combinations in PDX. Funded by Mayo Clinic Center for Individualized Medicine and MC Cancer Center. Clinical CharacteristicsOverallResponders: 12 week Ki-67 < 15% (n = 9)Non-Responders: 12 week Ki-67 ≥ 15% (n = 9)Median Age495345T stage T2/T314 (78%)7 (78%)7 (78%)Node Positive8 (44%)4 (44%)4 (44%)Triple negative10 (56%)6 (67%)4 (44%)Luminal B8 (44%)3 (33%)5 (56%)Ki-67 after 12 Weeks of T Median 5% (0-11%)Median 35% (17-60%)Complete/Partial MRI Response after T 6 (67%)2 (22%) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-10.