Citations

Objectives: To evaluate blood–labyrinth barrier permeability using delayed gadolinium enhanced three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) in patients with untreated sporadic vestibular schwannoma (VS) to interrogate the etiopathogenesis of progressive sensorineural hearing loss. Design: Prospective case series. Setting: Single institution tertiary care center. Participants: Patients with previously untreated small to medium-sized unilateral VS undergoing 3D-FLAIR imaging 10 minutes (immediate) and 5 to 8 hours (delayed) after administration of intravenous gadolinium. Main Outcome Measures: Comparison of cochlear and vestibular signal intensity ratios (SIRs) across immediate and delayed images and across the tumor and nontumor ear. Results: Six of eight (75%) patients demonstrated asymmetric enhancement of inner ear structures on delayed contrast-enhanced imaging. Delayed mean cochlea and vestibule SIRs were significantly greater than immediate SIRs (cochlea: 1.91 versus 1.21 [p = 0.02]; vestibule 1.74 versus 1.15 [p = 0.02]). A higher vestibule SIR was statistically significantly associated with poorer pure-tone average and word recognition scores (p = 0.001). Conclusion: Ears with VS exhibited increased enhancement on delayed 3D FLAIR imaging. These findings suggest that alterations in blood–labyrinth barrier permeability may explain progressive sensorineural hearing loss in a subset of patients with untreated VS.

Importance: Predicting nasal soft tissue envelope (STE) thickness is an important component of the preoperative evaluation for rhinoplasty that presently lacks validated tools. Objective: Assess for patient facial features and factors that can help predict nasal STE thickness. Design, Setting, and Participants: Retrospective review and prospective assessment conducted at an academic tertiary referral center. This study included 190 adult patients and four expert raters. The patients had high-resolution maxillofacial CT scans and standardized facial photographs on file and did not have a history of nasal fracture, septal perforation, rhinoplasty, or other surgery or medical conditions altering nasal form. Main Outcomes and Measures: Assess each face for features that could help predict nasal STE thickness: sebaceous quality of skin, visibility of nasal tip cartilages, presence of freckles, presence of telangiectasias, Fitzpatrick skin type, patient age, sex, and body mass index (BMI). Measure actual nasal STE thickness using high-resolution CT scans. Analyze which facial features and patient factors help predict nasal STE thickness. Results: Pearson correlations were calculated between actual nasal STE thickness and patient facial features and factors. These showed that more sebaceous skin, telangiectasias, higher Fitzpatrick skin type, male sex, and higher BMI were associated with a thicker nasal STE. Increased visibility of nasal tip cartilages, freckles, lower Fitzpatrick skin type, female sex, and lower BMI were associated with a thinner nasal STE. Conclusions and Relevance: There are patient facial features and factors that can help surgeons predict nasal STE thickness before rhinoplasty. An accurate prediction of nasal STE thickness can improve preoperative planning for rhinoplasty, allowing implementation of pre-, intra-, and post-operative treatments to optimize the nasal STE, which may ultimately improve patient outcomes and satisfaction.

1506 Background: Hereditary breast and ovarian cancer (HBOC) is preventable when genetic risk is identified. We aimed to test whether pre and/or post-test genetic counseling is needed to optimally deliver online accessible genetic testing. Methods: MAGENTA (Making GENetic Testing Accessible) is a four-arm non-inferiority trial evaluating electronic genetic education and results delivery alone or combined with pre-test only, or post-test only telephone genetic counseling compared to mandatory pre- and post-test counseling (control arm) in women at risk of HBOC (NCT02993068). Regardless of assigned arm, all subjects with a pathogenic mutation received post-test telephone counseling. All subjects were enrolled electronically as part of either a family history cohort (FHC) or a cascade cohort (CC, known familial mutation). The primary outcome was cancer risk distress at 3 months and the trial was powered for the FHC. Secondary outcomes included completion of testing (i.e., received results), anxiety, depression, quality of life, and decisional regret, all measured by standardized scales. Results: Enrollment is complete and a total of 3,822 participants were randomized, 3,111 in FHC and 711 in CC. Participants were enrolled from all 50 states, but most were white/non-Hispanic (88%). Among participants that completed genetic testing, 173 (7.2%) had a mutation in a breast or ovarian cancer gene, with 114 (5.7%) of FHC and 59 (14.2%) of CC. In the primary intention-to-treat analysis of FHC, each of the three experimental arms was non-inferior to the control arm for distress at 3 months (p < 0.025/3 = 0.0083). In the CC, no and pre-test only counseling were also non-inferior (p < 0.025/3 = 0.0083). Distress was lowest in the arm with neither pre nor post-test counseling. Overall, 318 (18%) participants had very high distress at three month follow-up, and this rate was not significantly different across arms. Anxiety, depression and decisional regret did not have statistically significant differences across arms at follow-up. Test completion was highest in the no counseling arm (86.4%) and lowest in the control arm (60.6%). Conclusions: Electronic genetic education and results release without genetic counseling was non-inferior with regard to patient distress and was associated with higher test completion and lower distress. These results support use of a genetic testing paradigm providing individualized genetic counseling only for patients with positive test results. Clinical trial information: NCT02993068.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.

Abstract Background: Chronic lymphocytic leukemia (CLL) can have a profound effect on the quality of life (QOL) of patients living with the illness. To our knowledge, no studies to date have evaluated the influence of the doctor-patient relationship on patient’s emotional distress or QOL. Methods: We conducted an international, web-based survey of patients with CLL using standardized instruments to evaluate QOL. Additional questions on the survey explored how often patients thought about their disease and evaluated their satisfaction with specific aspects of their relationship with the physician caring for them. Patients were also asked to indicate what phrases their physicians had used to describe/characterize CLL. Results: Between June and October 2006, 1482 patients responded to the survey. The diagnosis of CLL was validated in a randomly selected subset of patients. Over half (55.9%; n=822) of patients reported they thought about their CLL diagnosis daily. Although the proportion of patients who thought about CLL daily decreased with time, two or more years after diagnosis over 50% of patients still thought about their disease every day. When asked to indicate their satisfaction with various aspects of the physician caring for their CLL, more than 90% (n=1340) of patients felt their doctor had a good understanding of how their disease was progressing (i.e., the stage, blood counts, lymph nodes) but only 69% (n=1024) felt their physician had a good understanding of how CLL affected their QOL (anxiety, worry, fatigue, etc.). Similarly, while 90% (n=1324) of patients felt comfortable talking to their doctor about treatment and management of CLL, only 77% (n=1134) felt comfortable talking to their doctor about how CLL affected QOL. Reported satisfaction with their physician in these areas strongly related to patients’ measured emotional and overall QOL on standardized instruments (all p&lt;0.001). This effect on QOL remained (p&lt;0.002) after adjustment for age, extent of co-morbid health conditions, measured fatigue, and treatment status in a regression analysis. Finally, patients were asked to indicate whether the physician caring for them had used specific phrases to describe CLL. Thirty-three percent of patients had been told “CLL is the ‘good’ leukemia,” 24% had been told “don’t worry about your CLL,” and 35% had been told “if you could pick what cancer to have, this is what you would choose.” Overall, 52% of patients had received one or more of these characterizations of CLL by their physician. The emotional and overall QOL were worse among patients who reported their physician had used these phrases to describe CLL (all p≤0.001). This effect on QOL remained after regression analysis (p&lt;0.002). Patients whose physician had used one of these phrases to describe CLL were also less likely to feel their physician understood how CLL was effecting their QOL and to feel comfortable discussing the effects of CLL on their QOL with their physician (all p&lt;0.001). Conclusions: Physicians play an important role helping patients adjust to the physical, intellectual, and emotional challenges of CLL. The effectiveness with which physicians accomplish these tasks appears to impact the QOL of patients with CLL. Additional studies exploring how physicians can best support patients with CLL are needed.

Abstract BACKGROUND: Green tea has long been touted as a health promoting substance. The active chemical compounds in green tea are called polyphenols or catechins. Epigallocatechin gallate(EGCG) is the major catechin in green tea. We previously reported the in vitro ability of EGCG to induce apoptotic cell death in chronic lymphocytic leukemia(CLL) B-cells in vitro (Blood 104:788). After publication of our findings, clinical activity in individuals using over the counter green tea extracts were reported (Leuk Res 30:707). Based on this information, we opened a phase I/II trial of green tea extracts for patients with asymptomatic, early stage CLL in fall of 2005. METHODS: The purpose of the phase I portion of this trial was to determine the optimal dose of EGCG in the Polyphenon E preparation for chronic daily administration and define tolerability in CLL patients. Previously untreated patients with asymptomatic, Rai stage 0–II CLL not currently meeting National Cancer Institute(NCI) Working Group(WG) Criteria for treatment were eligible for participation. Polyphenon E with a standardized dose of EGCG was obtained from NCI. The phase I portion of the trial was designed with 8 dose levels(range 400–2000 mg orally BID) using the standard 3 patient per dose level design. Patients remained on study up to 6 months. Grade 2 adverse events attributed to study treatment that did not respond to supportive care were considered dose limiting toxicity. The trial was designed to administer Polyphenon E in the fasting state. After accrual to dose levels 1 and 2, the U.S. FDA mandated all U.S. trials of Polyphenon E administer drug in the fed state. Accordingly, drug was administered in the fed state for dose levels 3–8. Trough plasma EGCG levels were measured 1 month after initiation of therapy. Response was classified using the NCI WG Criteria. RESULTS: As of August 2007, 33 patients have been accrued to dose levels 1–8. The maximum tolerated dose(MTD) has not been reached. Side effects have generally been mild. The most common toxicities were nausea(grade 1: 42%; grade 2: 3%), elevation in SGOT (42%; all grade 1), and abdominal pain (36%; all grade 1). To date, no patient has had a sustained 50% reduction in both absolute lymphocyte count (ALC) and lymphadenopathy that would meet the NCI WG criteria for partial response. A majority of patients have had a reduction in ALC(Table). Among the 10 patients who had palpable adenopathy at study enrollment, 7 patients experienced at least a 50% reduction in the sum of the products of all nodal areas at some point during treatment. Trough plasma EGCG levels after 1 month of treatment ranged from 2.93974 ng/mL(median 40.5 ng/mL). Plasma levels did not clearly relate to the degree of reduction in ALC suggesting sensitivity to Polyphenon E may relate more to characteristics of the leukemic clone than plasma EGCG levels. CONCLUSION: Daily oral EGCG in the Polyphenon E preparation was well tolerated by CLL patients in this phase I trial. The MTD has not been reached. As classified by the NCI WG criteria, no partial or complete remissions have been observed to date, however declines in ALC and lymphadenopathy have been observed in the majority of patients. The phase II portion of this trial will open at Mayo Clinic Fall 2007. Best reduction in ALC n % of patients At least 10% decline 25 76% At least 20% decline 14 42% At least 30% decline 8 24% At least 40% decline 4 12% At least 50% decline 2 6%

Abstract Background: CLL is still an incurable lymphoid malignancy. The current standard of care is to treat only patients with obvious clinical progression as defined by the National Cancer Institute Working Group in 1996 (NCI–WG 1996). High risk CLL can be identified at diagnosis by a variety of tests including fluorescence in situ hybridization (FISH), immunoglobulin heavy-chain variable region (IgVH) analysis, and expression of ZAP-70 or CD38. With this information we can identify patients with high risk, early stage disease who are candidates for novel low toxicity therapies that could alter the natural course of their disease. Our hypothesis was that combination monoclonal antibody (MoAb) therapy using alemtuzumab and rituximab would significantly reduce the high risk clone in early stage CLL. Methods: This phase II trial was conducted with IRB approval and accrued the planned 30 patients between January 2005 and July 2007 at Mayo Clinic Rochester. The study enrolled consenting patients with Rai stage 0–II CLL without NCI–WG 1996 criteria for treatment who had high risk CLL as defined as one or more of the following 17p13–, 11q22–, unmutated (UM) IgVH (&lt; 2%) and expression of ZAP–70 (≥ 30%) and/or CD38 (≥20%). Treatment was one 30 day cycle (alemtuzumab 3 mg, 10 mg, 30 mg days 1–3 then 30 mg 3 × week × 4 weeks with all doses subcutaneously and rituximab at 375 mg/m2/week IV × 4 doses from day 8). Patients received 7 days of allopurinol and antimicrobial prophylaxis against PCP and herpes virus infections for 7 months. CMV testing by PCR was done weekly during treatment, then monthly × 6. Results: All 30 patients have completed therapy and 27 have been evaluated for response. The median age of these 27 patients was 62 yr (range 29–77) with 8 patients &gt; 70 years. There was a male predominance (67%) with median time from diagnosis to treatment of 0.7 yr (range 0.1 – 6.1). Stage (Rai) at the start of therapy was 0 in 7 (26%), I in 19 (70%), and II in 1. High risk markers were 17p13– in 9 (33%), 11q22– in 7 (26%), UM IgV and expression of either ZAP–70 or CD38 in 11 (41%). All 27 patients completed therapy without interruption. Non hematological grade 3–4 toxicity occurred in 3 patients (2 drug reactions caused by SMX/TMP, 1 CMV reactivation responsive to IV therapy). Response evaluation at 2 months after completion of therapy using NCI–WG 1996 criteria showed an ORR of 93% with 12 (44%) CR, 8 (30%) nPR, and 5 (19%) PR. Two (7%) patients had disease progression. Median duration of follow up was 14.1 months (range 1.9 – 27.2). Median time to disease progression in the 25 responding patients was 14.4 months (95% CI 5.9 – 22.4). Seven (26%) patients have received subsequent treatment for CLL (median 5.2 months, range 2.4 – 20.1). A minimal residual disease assay using 3-color flow cytometry on peripheral blood was negative in 6 of the 7 patients with CR who had no evidence of residual CLL on immunohistochemical examination of the bone marrow. These 6 patients all remain in sustained CR (median follow up 15 months, range 2 – 27.2). Conclusion: Alemtuzumab and rituximab is an effective and tolerable therapy in patients with high risk early stage CLL. A randomized controlled trial is now required to test if this intervention is better than the standard observation approach. In addition, this combination MoAb regimen could be used as a platform to develop even more effective combination treatments for patients with CLL.

Abstract BACKGROUND: The diagnosis of monoclonal B-cell lymphocytosis (MBL) is used to characterize patients who have a circulating population of clonal B-cells, a total B-cell count of &lt;5 x 109/L, and no other features of another B-cell lymphoproliferative disorder. In most patients the immunophenotype is similar to that of chronic lymphocytic leukemia with co-expression of CD19 and CD5. The natural history of CLL-phenotype MBL is unclear. We used the Mayo Clinic hematopathology database to identify patients with CLL-phenotype MBL and abstracted clinical information on natural history and prognostic parameters from clinical and research records. METHODS: Using hematopathology records, we identified a cohort of 1820 patients seen at Mayo Clinic between August 1998 and May 2006 who underwent investigation using peripheral blood flow cytometry and who were found to have a clonal B-cell population of CLL phenotype. After elimination of patients with advanced stage (Rai I-IV), previously treated CLL, and individuals with an established diagnosis of CLL/MBL &gt;1 year prior to flow, 636 unique patients with isolated lymphocytosis were identified. Based on our prior analysis (Leukemia Research 32:1458) demonstrating that nearly all patients with an ALC &gt;10x109/L have a B-cell count &gt;5x109/L, we focused the remaining analysis on the 405/636 patients who had an ALC &lt;10x109/L and the necessary raw data from flow cytometry analysis to determine the B-cell count. RESULTS: Among the 405 individuals with an ALC &lt;10x109/L, 306 (76%) had a B-cell count &lt;5x109/L at the time of flow and met the current criteria for the diagnosis of MBL (BJH 130:325). Median age at the time of MBL diagnosis was 70 years (range 34 – 93). A slight male preponderance was observed (59% male). B-cell counts ranged from 0.02 to 4.99x109/L and ALC ranged from 0.3–9.6 x109/L. CD38 status was available for 268 (88%) MBL patients of whom 20% were CD38 positive using the 30% threshold. Cytogenetic analysis by fluorescent in situ hybridization (FISH) was available in 130 (42%) MBL patients. Using the hierarchical classification system of Dohner and colleagues, 57 (44%) were 13q-, 23 (18%) were trisomy 12, 5 (4%) were 11q-, 4 (3%) were 17p-, and 39 (30%) had no defect detected. ZAP-70 status was available for 77 (25%) patients of whom 13% were ZAP-70+ positive. Patients underwent sequential monitoring with a median follow-up of 1.7 yrs (range 0–8.1 yrs). Time from diagnosis to treatment for patients meeting criteria for MBL (n=306) as compared to Rai stage 0 CLL patients with B-cell counts between 5.0 and 10.0 x109/L (n=99) was not significantly different and is shown in Figure 1 (p=0.87). For individuals with MBL, survival free of treatment was 98% (95%CI: 96–100%) at 1 year, 93% (95%CI: 89–98%) at 2 years, and 77% (95%CI: 67–89%) at 5 years. While gender (p=0.10), and B-cell count as a continuous variable (p=0.15) were not found to be associated with time to treatment (TTT) among MBL patients, age (p=0.02, HR=0.94, 95% CI: 0.89–0.99) and CD38 status (p&lt;0.02, HR: 3.3, 95% CI: 1.2–9.2) did show a relationship with TTT. CONCLUSIONS: Although we observed a low rate of progression among individuals meeting criteria for MBL, TFS was similar to individuals meeting current criteria for Rai stage 0 CLL who had B-cell counts between 5.0 – 10.0 x109/L . Among individuals meeting criteria for MBL, younger patients and those who were CD38 positive had a shorter time to treatment. Additional studies are needed to determine what B-cell count or other characteristics should be used to distinguish between MBL and Rai stage 0 CLL. FIGURE: FIGURE:.

Abstract BACKGROUND: The diagnosis of CLL among asymptomatic patients without lymphadenopathy or cytopenias has historically been based on documenting a characteristic lymphocyte clone and the presence of lymphocytosis. Currently, there are no data regarding what lymphocyte type (absolute lymphocyte count [ALC] or B-cell count) or threshold should be used for this diagnosis. We analyzed the relationship of these lymphocyte counts to clinical outcome in a cohort of 459 patients to determine whether the CLL diagnosis: should be based on ALC or B-cell count what lymphocyte threshold should be used for diagnosis whether any lymphocyte counts has independent prognostic value after accounting for molecular prognostic markers. METHODS: We used the Mayo Clinic CLL database to identify all Rai stage 0 patients diagnosed with CLL between 1/1/00 and 12/31/07 who were evaluated and had flow cytometry at Mayo within 12 months of diagnosis. All patients had lymphocytosis (ALC ≥5 x 109/L) and fulfilled the 1996 criteria for CLL. Raw data from the peripheral blood flow analysis was used in conjunction with blood counts to determine ALC and absolute B-cell count at diagnosis. Estimates of survival were calculated using the Kaplan-Meier method. RESULTS: To assess whether B-cell count or ALC more strongly related to clinical outcome, we evaluated the relationship of these variables with treatment free survival (TFS) and overall survival (OS; n=459). When treated as continuous variables (i.e. measuring risk of each 1.0 x 109/L increase in cell count), both ALC and B-cell count were related to TFS (hazard ratio [HR] ALC=1.02; p&lt;0.0001; HR B-cell count=1.02; p&lt;0.0001) and OS (HR ALC=1.02; p=0.04; HR B-cell count=1.02; p=0.02). Because B-cell count and ALC related to TFS and OS as a continuous variables, we next evaluated what threshold (nearest 1.0 x109/L) at diagnosis best related to an individual’s risk of requiring chemotherapeutic treatment and/or dying of CLL using the HR (log rank statistic) and c-statistic [c=1 indicates perfect discrimination between poor survivors and good survivors; c=0.5 equivalent to chance]. The B-cell threshold that best predicted OS was 11 x 109/L (HR=2.36, p=0.01; c=0.60). This threshold also predicted TFS (HR=3.02; p&lt;0.0001; c=0.64). With respect to ALC, a threshold of 12 x 109/L was able to predict TFS (HR=2.28, p=0.003; c=0.62) but not OS (HR=1.62, p=0.12; c=0.56). The B-cell threshold used in the current diagnostic criteria (5 x 109/L) was able to predict TFS (HR=3.24, p&lt;0.0001; c=0.63), but not OS (HR=1.64, p=0.13; c=0.55) Finally, we evaluated the ability of B-cell count to predict TFS independent of IGHV mutation status, ZAP-70 status, CD38 status, and FISH. Since not all patients had all prognostic tests performed, the predictive value of B-cell count (&lt; or ≥11 x 109) independent of the other prognostic variable was assessed for each variable independently. B-cell count retained prognostic value independent of IGHV mutation status, ZAP-70 status, CD38 status, and FISH (all p≤0.001) [Table]. CONCLUSIONS: Although B-cell count and ALC have similar ability to predict TFS and OS as continuous variables, B-cell count may be a better predictor of TFS and OS when a defined lymphocyte threshold is used. These findings provide evidence to justify the recent proposal by Hallek et al (Blood 111:5446) to base the diagnosis of CLL on B-cell count rather than ALC. The results also provide justification for retaining the size of the B-cell count as part of the diagnostic criteria even in the era of molecular/biologic prognostic markers, but imply a threshold of 11 x 109 is the B-cell count that best predicts patient’s TFS and risk of death. Differentiating between CLL and MBL based on a patient’s likelihood of developing clinical symptoms and dying of disease could minimize unnecessary psychologic distress caused by labeling asymptomatic individuals at low risk for adverse clinical consequences as having leukemia. TABLE: TREATMENT FREE SURVIVAL HR p-value CD38 + 3.20 0.0002 B-cell ≥11 3.10 0.0001 ZAP + 8.33 &lt; 0.0001 B-cell ≥11 6.86 &lt; 0.0001 Unmutated 5.26 &lt; 0.0001 B-cell ≥11 3.06 0.001 FISH (17p- or 11q-) 3.97 0.01 B-cell ≥11 3.67 &lt; 0.0001

Abstract Background: It has become increasingly clear that effective treatment of metastatic breast cancer (MBC) requires an in-depth understanding of the molecular differences between primary tumors and metastases. The AURORA US Network was established to collect primary breast cancer-metastasis pairs for multi-platform genomic profiling in order to identify the molecular drivers of metastatic disease. AURORA US has both a retrospective and prospective phase. This is the first report of the retrospective phase. Methods: Archived tissue samples from the primary tumor and at least one distant metastasis were retrospectively collected from 83 MBC patients. Following internal quality assessment, samples from 55 pts, including 105 distinct metastatic lesions, were subject to DNA low pass whole genome and exome sequencing, DNA methylation arrays, and RNA sequencing. Early analyses of these multi-platform data include: DNA methylation, tumor gene expression and microenvironmental signatures, somatic and germline variants, DNA copy number changes, and structural variants between breast primaries and matched metastases. Results: Median age at diagnosis was 49 years (25-76); 32 (58%) were Stage I or II at presentation, 27 (49%) had a family history of breast cancer, and 20 (36%) had a second breast primary. Median disease-free interval before developing MBC was 2 years (range 0-36, 5 patients presented with Stage IV). Median overall survival from initial presentation was 4 years (range 0-37). Median survival after developing MBC was 1 year (range 0-13), with a median of three treatments. Primary tissue samples were banked from 1977-2017 and metastases were banked from 1999-2017. Clinical phenotypes of the primaries included 27 HR+ (49%), 15 triple negative (TNBC, 27%), and 11 HER2+ (20%, 12 missing HER2 status). Intrinsic subtype distribution of the primaries included 17 Basal-like (31%), 17 Luminal A (31%), 7 Normal-like (13%), 5 HER2-enriched (9%), and 1 Luminal B, with 8 pending. All metastases from the Basal-like cases remained Basal-like, while metastases from luminal primaries tended to gain HER2-Enriched subtype features (5/18, p = 0.01). Overall, we identified significant metastasis-enriched alterations in metabolism pathways, an increase in proliferation, and the loss of differentiation signatures and immune infiltrates with progression; the latter being the most pronounced in brain metastases. The most frequent somatic mutations in this cohort were in TP53, NCOR1, and RUNX1. Interestingly, ERBB2, EGFR, and ATM were also mutated in ≥10% of the tumors sequenced. In almost all cases, CpG island hypermethylation was clonally present in the primary tumor and persisted stably in the majority of metastatic lesions. Promoter CpG island hypermethylation was also identified in some metastatic lesions at JAM3, an important cellular adhesion molecule,and this was accompanied by reduced mRNA expression. CONCLUSIONS: Collection of banked primary and metastatic tissue pairs identified a young MBC cohort with a high frequency of breast cancer family history and second breast primaries. Molecular characterization of luminal tumor pairs highlighted acquisition of aggressive traits including increased proliferation and loss of differentiation in the metastases. In contrast, basal-like pairs remained relatively unchanged, except for the loss of immune activation. Ongoing analyses to be presented include clonal heterogeneity and phylogeny, novel metastasis signature discovery, gene fusion, and endogenous retrovirus detection. Citation Format: Tari A King, Minetta C Liu, Marni B McClure, Toshinori Hinoue, Benjamin J Kelly, Chad J Creighton, Jay Bowen, Kristen Leraas, Robyn T Burns, Sara Coppens, Salma Rezk, Amy L Garrett, Justin M Balko, Joel S Parker, Ben H Park, Ian Krop, Carey Anders, Katherine A Hoadley, Julie Gastier-Foster, Mothaffar F Rimawi, Rita Nanda, Nancy U Lin, Claudine Isaacs, P. Kelly Marcom, Anna Maria Storniolo, Fergus J Couch, Elaine R Mardis, Adrian V Lee, Uma Chandran, Peter W Laird, Susan G Hilsenbeck, Larry Norton, Andrea L Richardson, W. Fraser Symmans, Lisa A Carey, Antonio C Wolff, Nancy E Davidson, Charles M Perou, the AURORA US Network. Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network [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 GS3-08.