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BackgroundAlcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. AH patients have intense hepatic infiltration of leukocytes. Up‐regulation of cell adhesion molecules (CAMs) upon endothelial cell (EC) activation plays an important role in leukocyte transendothelial migration. CAMs can shed from EC surface and accumulate in the blood, serving as soluble markers for EC activation. In this study, we examined the impact of heavy drinking on expression of soluble forms of EC activation markers (CD146, ICAM‐1, VCAM‐1, and VEGF‐A) and the effect of alcohol abstinence on the reversal of these abnormalities in heavy drinkers with and without AH.MethodsELISA and multiplex immunoassays were used to measure soluble EC activation markers in plasma samples from 79 AH patients, 66 heavy drinkers without overt liver disease (HDC), and 44 healthy controls (HC) at baseline, 31 AH patients and 30 HDC at 6‐month follow‐up, and 18 AH patients and 25 HDC at 12‐month follow‐up.ResultsAt baseline, the 4 soluble markers were significantly up‐regulated in AH patients compared with HDC and HC, whereas only sVCAM‐1 was elevated in HDC relative to HC. At follow‐ups, plasma levels of CD146, VCAM‐1, and VEGF‐A remained higher in AH patients, even for those who stopped drinking. These dysregulated markers correlated with AH disease severity, clinical parameters, and several soluble inflammatory factors.ConclusionsThe levels of soluble CD146, ICAM‐1, VCAM‐1, and VEGF‐A were highly elevated in AH patients, and alcohol abstinence did not completely reverse these abnormalities.

Abstract Introduction: Primary mucosa-associated lymphoid tissue (MALT) lymphomas originating in thymus is rare. And, there have been few reports of patients with MALT coexisting with amyloidosis. As far as we know, this was the first case report on MALT lymphoma associated with renal amyloidosis. Patient concerns: A 57-year-old man presented with nephrotic syndrome. Further workup revealed IgM-Lambda type monoclonal gammopathy. Bone marrow biopsy showed 8% clonal plasma cells. Renal biopsy confirmed the diagnosis of Lambda light chain AL amyloidosis. positron emission tomography/computed tomography showed thymic lesions which upon biopsy were diagnosed as MALT lymphoma of the thymus. Diagnosis: Primary thymic MALT lymphoma complicated with renal amyloidosis. Interventions: The patient underwent surgical resection of the thymus mass and 2 courses of chemotherapy. Outcomes: Follow-up data showed that the patient survived 18 months after surgical excision and chemotherapy. Conclusion: The case highlights the importance of screening for malignancy in patients with renal amyloidosis.

Abstract Background: In an adaptive randomized trial, when new treatment combinations are being tested, it is important to be able to identify patients who are progressing on treatment so that they can be changed to a different therapeutic regimen. We know that even within the molecularly high risk patients in I-SPY 2, there is considerable variation in biology. In this study, we will present results of using MRI-calculated functional tumor volume (FTV) to identify tumor progression for each breast cancer subtype. Methods: Patients (n=990) enrolled in the I-SPY 2 TRIAL who were randomized to the graduated experimental drug arms or controls from 2010 to 2016 were analyzed. Four MRI exams were performed for each patient: pre-NAC (T0), after 3 weeks of NAC (T1), between regimens (T2), and post-NAC (T3). Functional tumor volume (FTV) was calculated at each exam by summing voxels meeting enhancement thresholds. Tumor progression at T1, T2 or T3 was identified by a positive FTV change relative to T0. Visual inspection was used to exclude false progression due to strong background parenchymal enhancement post-contrast, prominent vessels, motion, or insufficient image quality. pCR was defined as no invasive disease in the breast and lymph nodes. Negative predictive value for pCR was defined as:NPV=number of true non-pCRs / number of patients with MRI assessed tumor progressions, where “true non-pCRs” referred to patients who were non-pCRs at surgery and were assessed as progressors by MRI. The analysis was performed in the full cohort and in sub-cohorts defined by HR and HER2 statuses. Results: Out of 990 patients, 878 had pCR outcome data (pCR or non-pCR, pCR rate = 35%). Total and non-pCR numbers for each subtype, number of patients with tumor progression assessed by MRI at T1, T2, and T3, and NPVs, are shown in Table 1. In the full cohort, the NPV increased consistently over treatment, from T1 (NPV=83%) to T2 (93%), and to T3 (100%). The HER2+ cancer subtypes showed fewer MRI-assessed tumor progressions than HER2- subtypes: e.g. 10/209 (5%) vs. 108/669 (16%) at T1. NPV was 100% for HER2+ subtypes at T1 and T2 except for a single misclassification of a HR- tumor at T1. Only 6 tumor progressors, all HER2- were identified at T3, and all were confirmed at surgery as non-pCRs (NPV=100%). For HR+/HER2-, the NPV increased slightly from 89% at T1 to 91% at T2, while triple negative subtype had a more substantial increase, from 78% to 92%. Conclusions: Our study showed strong association between tumor progressors assessed by MRI with true non-pCRs after NAC. For HER2+ tumors, although MRI progressors are rare, they strongly indicate non-pCR at all treatment time points, while HER2- subtypes show more accurate results later in treatment. We are evaluating MRI change at 6 weeks to determine if that time point is sufficient to predict progressors. Table 1 MRI assessed tumor progression at different treatment time pointN/non-pCRs/%non-pCRMRI assessed tumor progressionT1 (after 3 weeks)T2 (inter-regimen)T3 (post-NAC)NNPV (%)NNPV (%)NNPV (%)Full cohort878/572/65%11883.14192.76100%HR+/HER2-344/280/81%4588.91190.93100%HR+/HER2+134/85/63%610021000N/AHR-/HER2+75/23/31%47521000N/Atriple negative325/184/57%6377.82692.33100% Citation Format: Wen Li, Natsuko Onishi, David C Newitt, Jessica Gibbs, Lisa J Wilmes, Ella F Jones, Bonnie N Joe, Laura S Sit, Christina Yau, A. Jo Chien, Elissa Price, Kathy S Albain, Theresa Kuritza, Kevin Morley, Judy C Boughey, Kathy Brandt, Sadia Choudhery, Amy S Clark, Mark Rosen, Elizabeth S McDonald, Anthony D Elias, Dulcy Wolverton, Kelly Fountain, David M Euhus, Heather S Han, Bethany Niell, Jennifer Drukteinis, Julie E Lang, Janice Lu, Jane L Meisel, Zaha Mitri, Rita Nanda, Donald W Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K Viscusi, Anne M Wallace, Douglas Yee, Rachel Yung, Smita M Asare, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Donald A Berry, Angela DeMichele, Hiroyuki Abe, Deepa Sheth, Kirsten K Edmiston, Erin D Ellis, Richard Ha, Ralph Wynn, Erin P Crane, Charlotte Dillis, Michael Nelson, An Church, Claudine Isaacs, Qamar J Khan, Karen Y Oh, Neda Jafarian, Dae Hee Bang, Christiane Mullins, Stefanie Woodard, Kathryn W Zamora, Haydee Ojeda-Fornier, Pulin Sheth, Linda Hovanessian-Larsen, Mohammad Eghtedari, Michael Spektor, Marina Giurescu, Mary S Newell, Michael A Cohen, Elise Berman, Constance Lehman, William Smith, Kim Fitzpatrick, Marisa H Borders, Wei Yang, Basak Dogan, Sally Goudreau, Thelma Brown, Laura J Esserman, Nola M Hylton. Breast cancer subtype specific association of pCR with MRI assessed tumor volume progression during NAC in the I-SPY 2 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 PD9-04.

Abstract Background: The IMpassion130 study demonstrated prolonged overall survival when atezolizumab, a PD-L1 inhibitor, was added to nab-paclitaxel in PD-L1 positive patients with advanced triple negative breast cancer (TNBC). Approximately 40% of tumors were PD-L1 positive, utilizing a cutoff of ≥ 1% immune cell (IC) staining with the Ventana SP142 immunohistochemical (IHC) assay. The Food and Drug Administration (FDA) approved this assay as a companion test to determine patient eligibility for atezolizumab therapy. However, literature in lung cancer shows that pathologists have a high discordance in assessing PD-L1 on IC. The FDA companion test documentation for SP142 shows high inter-laboratory reproducibility with nearly 95% overall percent agreement (OPA) between 2 readers for 2 category scoring of IC (positive versus negative) in TNBC in a central laboratory. PD-L1 testing for breast cancer is now becoming widespread in pathology laboratories. The goal of this study was to assess concordance in PD-L1 scoring between 19 pathologists from 14 institutions examining the same 86 TNBC tissues stained with the SP142 and SP263 antibodies. We also present a new method to determine the minimum number for evaluators needed to estimate concordance between large numbers of readers as occurs in real life setting. Methods: Full tissue sections were stained exactly as prescribed on the label on the Ventana Benchmark with the SP142 and SP263 PD-L1 assays. Sixty-eight and 76 cases were evaluable respectively. Stained slides were scanned and digital files distributed to pathologists who independently scored cases as either negative (< 1% IC staining) or positive (≥ 1% IC staining) and estimated the % of IC staining for positive cases. We applied a method that we call Observers Needed to Evaluate Subjective Tests (ONEST). For any combination of pathologists, we can quantify the degree of overall agreement using the proportion of tissue samples upon which all selected pathologists agreed, which can lead to a plot of non-increasing trajectory of agreement as the number of pathologists increases. We computed and plotted the empirical estimate of the overall agreement with the 95% confidence interval (CI) from 1000 randomly selected permutations of the pathologists. Results: PD-L1 was interpreted as positive with SP263 in an average of 78% of cases compared to 58% with the SP142 assay (p<.0001). IC positive continuous scores ranged from 1-95% (mean=20%) and 1-90% (mean=10%) for SP263 and SP142. Complete 2 category (positive vs negative) scoring concordance across all observers was achieved in 38 cases (50%) with SP263 and 26 cases (38%) with SP142. The intraclass correlation coefficient (ICC) for 2 category scoring of SP263 and SP142 was 0.513 and 0.560 respectively. ONEST plots made for each assay for 19 pathologists showed a decrease in OPA as number of observers increased, reaching a low plateau of approximately 0.46 at 10 observers for SP263 and 0.42 at 8 observers for SP142. Conclusions: Utilizing the FDA approved SP142 assay, we found a higher prevalence of PD-L1 positive tumors than published in the IMpassion130 trial but lower prevalence than seen with the SP263 assay. The different proportion of positive cases seen with two different assays highlights the need to establish cutoffs for each assay to correspond with clinical benefit. The ICC of scoring immune cells with both PD-L1 assays showed poor reproducibility across multiple pathologists. The ONEST analysis finds a plateau with 10 pathologists, only reaching an OPA of 0.4 for immune cell assessment. This suggests that more than half of the pathologists in real world situations may mis-assign patient IC scores. This could lead to a high percentage of patients either receiving atezolizumab, when they are unlikely to benefit or not receiving atezolizumab when they may benefit. Citation Format: Emily Suzanne Reisenbichler, Gang Han, Vasiliki Pelekanou, Vesal Yaghoobi, Fahad S Ahmed, Andrew Bellizzi, Veerle Bossuyt, Jane Brock, Kimberly Cole, Oluwole Fadare, Omar Hameed, Krisztina Hanley, Beth T Harrison, M G Kuba, Amy Ly, Dylan Miller, Mirna Podoll, Anja C Roden, Mary A Sanders, Kamaljeet Singh, Shi Wei, Hannah Wen, Lajos Pusztai, David L Rimm. Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays in triple negative 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 PD5-01.

Abstract Background: The I-SPY 2 TRIAL enrolls women with locally advanced, molecular high-risk breast cancer. An integrated Residual Cancer Burden (iRCB), based on MRI volume change through treatment, is used to predict pathologic complete response (pCR) in the randomization/evaluation Bayesian engine. With the goal of effective de-escalation of treatment for patients exhibiting an early response, biomarkers are being assessed for their ability to predict pCR, alone or with MR data, during treatment. Here, we present the results of a pilot study to examine if invasive tumor cellularity in mid-treatment tissue core biopsies predicts pCR in a 40-patient cohort of I-SPY 2 patients. Other pathologic variables evaluated include Ki67, tumoral histologic features, and stromal tumor-infiltrating lymphocytes (sTILs). Methods: I-SPY 2 TRIAL pathologists (N=4) were provided images of H&E-stained and Ki67 IHC- labelled (DAKO/Agilent, clone MIB-1) core biopsy sections from 40 patients at the inter-regimen time point, ~12-weeks into treatment. Of the 40 patients, 35 had 4 cores, 3 had 3 cores, and 2 had 2 cores assessed. In total, images from 153 cores were evaluated. For each core, pathologists were asked to score the % area occupied by tumor bed (treatment changes and/or residual cancer), % of viable invasive tumor (0-100%) within tumor bed (with Nottingham grading, % Ki67 labelled, and % sTILs, using standardized guidelines). As decided by the pathologist group, only cores with identified tumor bed were included in the initial analysis. Concordance between pathologists was assessed for all scored criteria, using % agreement for dichotomous variables, and Pearson correlation (r)/standard deviation (sd) for continuous variables. The maximum and average cellularity recorded over all cores/patient, averaged over all pathologists, were analyzed for association with pCR using t- tests (significance threshold: p<0.05). Fisher’s Exact test was used for dichotomous variables, and Pearson’s correlation for association of continuous variables with the residual cancer burden (RCB) index. Results: Pathologist were in general agreement about the presence or absence of tumor bed, with greater than 82% agreement between any two (83-96%), and an overall agreement of 77%. For scoring the % of the tumor bed involved by invasive cancer, correlations between pairs of pathologists ranged from 0.79-0.95 (mean(r)=0.87, sd=5%), and agreement on a binary presence/absence of invasive cancer was 78%. Both the mean (t-test: p=7.59E-05) and maximum (t-test: p=0.0012) %invasive tumor at 12 weeks, scored as an average over all pathologists, were significantly higher in patients who did not achieve pCR than in responders. We also treated %invasive cellularity as a dichotomous variable (present/absent). 90% (9/10) of patients scored by all pathologists as 0% invasive tumor cells (absent) achieved a pCR, vs only 20% (6/30) of patients scored as >0% invasive cellularity by one or more pathologists (present) (OR=32, Fisher p=0.0005); yielding a positive predictive value for pCR of 0.9. Ki67 and sTILS at 12 weeks were fairly concordant across pathologists ((r,sd)=(0.92, 8.45%) and (0.82,5.5%), respectively), but did not associate with response (p>0.05 for pCR, RCB01, or RCB index). Tumor histologic grade at 12 weeks, assessed in 29/30 patients with non-zero cellularity, trended toward association (Fisher p=0.078): 44% (4/9) with Grade 3 went on to have a pCR, vs. 15% (2/13) with Grade 2 and 0 with Grade 1. These data demonstrate the utility of invasive tumor cellularity as a predictor of pCR in a clinical setting. Conclusion: In this pilot study we demonstrate that the absence of invasive cancer cells within identified tumor bed in mid-treatment core biopsy samples is highly predictive of pCR. Citation Format: Sara J Venters, Denise M Wolf, Lamorna Brown-Swigart, Christina Yau, Amy L Delson, Bev Parker, Ron Balassanian, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Jane Wei, I-SPY 2 TRIAL Consortium, Laura J Esserman, Laura J van't Veer, W Fraser Symmans. Assessing biomarkers to inform treatment de-escalation: Mid-treatment biopsy cellularity predicts pCR in the I-SPY 2 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 P6-10-02.

Abstract Background: Strong background parenchymal enhancement (BPE) may cause overestimation in tumor volume measured from dynamic contrast-enhanced (DCE) MRI, which may adversely affect the ability of MR tumor volume to predict treatment outcome for patients undergoing neoadjuvant chemotherapy (NAC). Specifically, an overestimation of tumor volume can result in misclassification of patients with complete pathologic response (pCR) as non-responders, leading to less confidence in MRI prediction. As well, overestimation of extent of disease might lead to more aggressive surgical therapy than necessary. This study investigated whether high BPE in the contralateral breast influences the predictive performance of MRI-measured functional tumor volume (FTV) for patients with locally advanced breast cancer undergoing NAC. Methods: patients (n=990) enrolled in the I-SPY 2 TRIAL who were randomized to the graduated experimental drug arms or controls from 2010 to 2016 were analyzed. Each patient had 4 MRI exams: pre-NAC (T0), after 3 weeks of NAC (T1), between NAC regimens (T2), and post-NAC (T3). FTV was calculated at each MRI exam by summing voxels meeting enhancement thresholds. Background parenchymal enhancement (BPE) in the contralateral breast was calculated automatically as mean percentage enhancement on the early (nominal 150sec post-contrast) image in the fibroglandular tissue segmented from 5 continuous axial slices centered in the inferior-to-superior stack. For each treatment time point, patients having both FTV and BPE measurements were included in the analysis. The area under the ROC curve (AUC) was estimated as the association between FTV and pCR at T1, T2, and T3. The analysis was conducted in the full patient cohort and in sub-cohorts defined by hormone receptor (HR) and HER2 status. In each patient cohort, a cut-off BPE value was selected to classify patients with high vs. low BPE by testing AUCs estimated with low-BPE patients reached maximum when the cut-off value varied from median to maximum in steps of 10%. Results: Out of 990 patients, 878 had pCR outcome data (pCR or non-pCR, pCR rate = 35%). Table 1 shows the number of patients, pCR rate, and AUC of FTV for predicting pCR using all patients available vs. a subset patients with low BPE (< BPE cut-off). In the full cohort, AUC increased slightly across all time points after patients with high BPE were removed. In the HR+/HER2- subtype, AUC increased at T1 after removal of cases with high BPE (0.65 vs. 0.71). For HR-/HER2+, AUC increased substantially after removal of high BPE cases (0.65 to 0.86 at T1, 0.71 to 0.87 at T2, and 0.71 to 0.89 at T3), with greater improvement at the early time point (T1) compared to later time points (T2 and T3). Only a slight improvement in the AUC was observed in the HR+/HER2+ and HR-/HER2- subtypes across all time points. Conclusions: High background parenchymal enhancement adversely affected the predictive performance of functional tumor volume measured by DCE-MRI, at early treatment time point for HR+/HER2- and across all time points for HR-/HER2+ cancer subtype. The adverse effect might be offset using subtype-optimized enhancement threshold in calculating functional tumor volume. Table 1 Effect of BPE on the prediction of pCR using FTV at various treatment time pointsT1T2T3npCR rateAUCBPE cut-offnpCR rateAUCBPE cut-offnpCR rateAUCBPE cut-offFullAll64734%0.662762334%0.701761134%0.6925Subset45334%0.6831133%0.7230534%0.72HR+/HER2-All26218%0.651924918%0.718225518%0.7519Subset13118%0.7124818%0.7120419%0.76HR+/HER2+All10636%0.642110538%0.62269634%0.7120Subset5332%0.668438%0.665740%0.73HR-/HER2+All5175%0.65204774%0.71204973%0.7116Subset3073%0.862871%0.872475%0.89HR-/HER2-All22842%0.682822243%0.751821143%0.6916Subset15940%0.7111137%0.7810540%0.75 Citation Format: Wen Li, Natsuko Onishi, David C Newitt, Roy Harnish, Ella F Jones, Lisa J Wilmes, Jessica Gibbs, Elissa Price, Bonnie N Joe, A. Jo Chien, Donald A Berry, Judy C Boughey, Kathy S Albain, Amy S Clark, Kirsten K Edmiston, Anthony D Elias, Erin D Ellis, David M Euhus, Heather S Han, Claudine Isaacs, Qamar J Khan, Julie E Lang, Janice Lu, Jane L Meisel, Zaha Mitri, Rita Nanda, Donald W Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K Viscusi, Anne M Wallace, Douglas Yee, Rachel Yung, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Christina Yau, Smita M Asare, Angela DeMichele, Sally Goudreau, Hiroyuki Abe, Deepa Sheth, Dulcy Wolverton, Kelly Fountain, Richard Ha, Ralph Wynn, Erin P Crane, Charlotte Dillis, Theresa Kuritza, Kevin Morley, Michael Nelson, An Church, Bethany Niell, Jennifer Drukteinis, Karen Y Oh, Neda Jafarian, Kathy Brandt, Sadia Choudhery, Dae Hee Bang, Christiane Mullins, Stefanie Woodard, Kathryn W Zamora, Haydee Ojeda-Fornier, Mohammad Eghedari, Pulin Sheth, Linda Hovanessian-Larsen, Mark Rosen, Elizabeth S McDonald, Michael Spektor, Marina Giurescu, Mary S Newell, Michael A Cohen, Elise Berman, Constance Lehman, William Smith, Kim Fitzpatrick, Marisa H Borders, Wei Yang, Basak Dogan, Laura J Esserman, Nola M Hylton. The effect of background parenchymal enhancement on the predictive performance of functional tumor volume measured in MRI [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 P6-02-01.

Abstract Background: Recent studies have demonstrated independent validation of the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. However, a pooled subject-level analysis of multiple cohorts is needed to determine estimates of long-term prognosis for each class of RCB in each phenotypic subtype of breast cancer (BC) to better inform on patient outcomes. Also, a pooled subject-level analysis allows more detailed analyses of generalizability of the prognostic meaning of RCB assessments in a broader experience of practice settings. Method: Subject-level RCB results, with relevant clinical and pathologic stage, tumor subtype and grade, demographic, treatment and follow-up data from 11 institutes/trials are being collected for combined analysis. The association between the continuous RCB index and event-free survival (EFS), and distant recurrence free survival (DRFS) were assessed using mixed effect Cox models with the incorporation of random RCB coefficients to account for between-study heterogeneity. We will also allow for differences in baseline hazard across biological BC subtypes and, if needed, across studies as well. In addition to this stratified mixed effect model, a multivariate analysis adjusting for age, T-category, nodal status and grade was performed within each subtype. In addition, mixed effect Cox models will be employed to evaluate association between RCB index with EFS and DRFS within each HR/HER2 subtype. Kaplan Meier estimates of EFS and DRFS at 5 and 10 years were computed for each RCB class within subtype. Results: We analyzed subject-level data from 9 institutes/trials representing 4077 patients currently available from an anticipated final total of 4,800 patients (to be presented at the meeting). There were 950 EFS and 876 DRFS events during follow up (median 65 months, IQR: 70 months). RCB index (continuous) was independently prognostic within each subtype: HR+/HER2- (EFS HR (per unit increase in RCB index) =1.64, 95%CI 1.48-1.82; DRFS HR=1.68, 1.51-1.87), HR+/HER2+ (EFS HR=1.80, 1.57-2.05; DRFS HR=1.93, 1.67-2.24), HR-/HER2+ (EFS HR=2.15, 1.76-2.62; DRFS HR=2.10, 1.77-2.50), and HR-/HER2- (EFS HR=2.05, 1.89-2.22; DRFS HR=2.16, 1.90-2.46); and remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis. Table 1 contains the response rate and estimated EFS at 5 years and 10 years for each RCB class within each HR/HER2 phenotype (DRFS results were similar). Conclusions: Long-term prognosis after pCR was similarly excellent in all phenotypic subtypes. RCB index and classification was independently and strongly prognostic in all subtypes, and generalizable to multiple practice settings. Prognostic differences by RCB class occurred within 5 years in HR- BC, but extended to 10 years in HR+ BC. RCB-I had slightly worse EFS than pCR in HR- BC and HR+/HER2+ BC (after 5 years), but the same EFS as pCR in HR+/HER2- BC. Complete analysis of all subjects, including neoadjuvant treatments, will be presented at the meeting. PhenotypeOutcomepCRRCB-IRCB-IIRCB-IIIHR+/HER2-Frequency (%)11%10%52%27%(N=1467)5 yr EFS (95% CI)91% (86-96)93% (89-98)82% (79-85)70% (65-75)10 yr EFS (95% CI)84% (75-93)88% (82-95)71% (67-75)52% (46-58)HR+/HER2+Frequency (%)38%18%35%9%(N=762)5 yr EFS (95% CI)94% (91-97)93% (88-98)78% (73-84)49% (37-65)10 yr EFS (95% CI)91% (86-96)79% (70-90)65% (59-73)42% (29-60)HR-/HER2+Frequency (%)66%11%18%5%(N=550)5 yr EFS (95% CI)93% (90-96)88% (79-97)60% (50-71)45% (30-69)10 yr EFS (95% CI)90% (86-94)84% (74-95)56% (46-68)45% (30-69)HR-/HER2-Frequency (%)41%13%33%13%(N=1293)5 yr EFS (95% CI)92% (90-94)85% (79-91)68% (63-72)28% (21-36)10 yr EFS (95% CI)87% (82-91)80% (72-88)63% (58-68)24% (18-33) Citation Format: Christina Yau, Marieke van der Noordaa, Jane Wei, Marie Osdoit, Fabien Reyal, Anne-Sophie Hamy, Marick Lae, Miguel Martin, Maria del Monte, I-SPY 2 TRIAL Consortium, Judy C Boughey, Rebekah Gould, Jelle Wesseling, Tessa Steenbruggen, Maartje van Seijen, Gabe Sonke, Stephen Edge, Stephen-John Sammut, Elena Provenzano, Jean Abraham, Peter Hall, Ashley Graham, Lorna Mackintosh, David Cameron, Alice Wang, Priyanka Sharma, Kimberly Cole, Lajos Pusztai, Mi-Ok Kim, Laura van ‘t Veer, Laura Esserman, W. Fraser Symmans. Residual cancer burden after neoadjuvant therapy and long-term survival outcomes in breast cancer: A multi-center pooled analysis [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 GS5-01.

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P < 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P < 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

Abstract To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV , 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person‐years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow‐up of 24 months, the estimated median event‐free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.