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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 Fertility can be diminished by adjuvant chemotherapy or by age-related decline in ovarian reserve in young women with breast cancer (BC). We sought to better understand the burden of concern about fertility, utilization of fertility preservation strategies, and the impact of fertility concerns on treatment decision-making among young women newly diagnosed with BC enrolled in a large multi-site study. METHODS The Young and Strong study was a cluster-randomized study that tested the effect of an educational and supportive care intervention for young women with BC (≤45) and their oncologists, at community and academic sites across the US. Patients were surveyed following diagnosis at enrollment (within 3 months of diagnosis), and at 3, 6 and 12 months thereafter. The surveys included sociodemographic and psychosocial measures (HADS anxiety and depression; Perceived Stress Scale), as well as a modified Fertility Issues Survey, which assessed fertility concerns and preservation. Treatment and tumor pathology data were abstracted from the medical record. Logistic regression was used to identify sociodemographic, clinical, and psychosocial factors that were associated with fertility concern. Variables with p ≤ 0.20 in univariable analyses were evaluated in the multivariable model using stepwise selection; variables achieving significance at p < 0.05 were included in the final model. RESULTS Of 467 women enrolled from 54 sites (14 academic, 40 community), 419 had evaluable data regarding treatment decision-making. Median age of participants at diagnosis was 40 yrs (range 22-45), 11% were African American, 80% were married/lived with a partner, and 75% had children. 35% of tumors were stage I, 51% stage II, and 14% stage III; 82% of women were treated with chemotherapy. At the time of treatment decision-making, 133 (32%) were concerned about fertility, varying by age, with fertility concern reported by 73%, 28% and 13% of those age ≤35, 36-40 and >40 (p<.01), respectively. 67 (16%) said their treatment decisions had been affected by fertility concerns, including 62 of the 133 (47%) with fertility concern. 12/419 (3%) chose one chemotherapy regimen over another, 4 (1%) chose not to take hormonal medication, and 32 (8%) chose or may choose to take it for less than 5 years. 251 (60%) reported having discussed fertility issues with their physician before starting therapy, including 117/133 (88%) of women with fertility concern. 29 (7%), including 27/133 (20%) of the concerned, took special steps to lessen the chance of infertility: 14 underwent cryopreservation of embryos, 14 cryopreservation of eggs and 12 took GnRH agonist or pursued other strategies. In the multivariable model, history of difficulty becoming pregnant (versus none, OR=3.86, 95%CI: 1.84-8.1) was associated with greater concern about fertility. Older age (OR=.75 per 1-year increase, 95%CI: 0.69-0.81) and having more than one child at diagnosis (versus never delivered, OR=0.14, 95%CI: 0.05-0.40) were associated with less concern about fertility. Race, being partnered, high-education, income, symptoms of depression, stress or anxiety at diagnosis, tumor stage, hormone receptor status and receipt of chemotherapy were not independently associated with concern about fertility in the multivariable model. CONCLUSION In a geographically and ethnically diverse study of young women with newly diagnosed BC in the U.S., many were concerned about fertility, with potential impact on their treatment decisions. For the majority of women, these concerns were discussed with their providers, though only a minority underwent fertility preservation strategies prior to treatment. Citation Format: Elisabeth Etaix, Yue Zheng, Shoshana Rosenberg, Kathryn J Ruddy, J Russel Hoverman, Karen M Emmons, Ann H Partridge. Fertility concerns and treatment decision-making among young women 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 P2-13-17.

Abstract Introduction: Amplification of chromosome 9p24.1 encoding PDL1, PDL2, and JAK2 (the PDJ amplicon) has been detected in 5-25% of triplenegative breast cancers (TNBC), and is associated with poor outcome and activation of the JAK/STAT pathway. Here, we have developed a robust multiplexed fluorescence in situ hybridization (FISH) assay for detection of 9p24.1 amplification, and assessed the frequency and cellular distribution of the PDJ amplicon in a cohort of African American (AA) women with TNBC. Methods: The FISH assay combines three chromosome 9 probes to simultaneously target JAK2 and PD-L1 (9p24.1, PDJ), chromosome 9q22, and the 9q34.1 regions. This enables discrimination of PDJ amplicons from whole chromosome 9p arm gains and from chromosome 9 ploidies that occur in the background of genomic instability in aneuploid cancer genomes. Fifty cells were scored for each probe and the average copy number was obtained. We defined PDJ amplification as PDJ>4, PDJ/9q22 ratio≥2, and/or PDJ/9q34.1 ratio≥2. The assay was benchmarked to array CGH of flow sorted TNBC tissue from Mayo Clinic Arizona (n=14). Tissue microarrays from TNBC PDX tumors (n=20) and from African American women with TNBC (n=87) were assessed. Results: Using selected TNBC tissue with known CGH data, the FISH assay tightly correlated with PDJ copy number in 13/14 cases. The discordant case was negative by CGH on a biopsy with low tumor content, but FISH positive on tissue section (PDJ >7.5 and a PDJ/9q22 ratio=4). Of 20 TNBC PDX tumors, 5 were amplified by FISH. Twelve of 87 (14%) of tumors had PDJ amplification by FISH, of which ten were from breast tissue and two were from lymph node. Of these 12, PDJ>4 (n=0), PDJ/9q22 ratio≥2 (n=6), and PDJ/9q34.1 ratio≥2 (n=10). Significant intratumoral variation was observed with the presence of single cells with >10 PDJ copies in 8/17 (47%) amplified and 0/90 non-amplified total cases. Conclusion: 9p24.1 (PDJ) amplification encoding JAK2, PD-L1, and PD-L2 is detected by three-color FISH in 14% of TNBC from African American women. Individual cells with ≥10 copies of PDJ was seen exclusively in 8/17 amplified cases. We identified 5 PDX tumors which may provide valuable preclinical models for the amplicon. The association of this biomarker with clinical outcome will be presented. Citation Format: Karen S. Anderson, Tammey Naab, Lori K Koslosky, Megan Anderson, Michael Lewis, Yasmine Kanaan, Ali Afsari, Luisel Ricks-Santi, Barbara A. Pockaj, Michael T Barrett. Tissue prevalence and cellular heterogeneity of 9p24.1 amplification in TNBC in African American women [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 P2-10-17.

This article presents a clinical screening and referral framework to enable health care professionals to guide individuals with cancer to safe and effective exercise programs.

By sequencing autozygous human populations, we identified a healthy adult woman with lifelong complete knockout of HAO1 (expected ~1 in 30 million outbred people). HAO1 (glycolate oxidase) silencing is the mechanism of lumasiran, an investigational RNA interference therapeutic for primary hyperoxaluria type 1. Her plasma glycolate levels were 12 times, and urinary glycolate 6 times, the upper limit of normal observed in healthy reference individuals (n = 67). Plasma metabolomics and lipidomics (1871 biochemicals) revealed 18 markedly elevated biochemicals (>5 sd outliers versus n = 25 controls) suggesting additional HAO1 effects. Comparison with lumasiran preclinical and clinical trial data suggested she has <2% residual glycolate oxidase activity. Cell line p.Leu333SerfsTer4 expression showed markedly reduced HAO1 protein levels and cellular protein mis-localisation. In this woman, lifelong HAO1 knockout is safe and without clinical phenotype, de-risking a therapeutic approach and informing therapeutic mechanisms. Unlocking evidence from the diversity of human genetic variation can facilitate drug development.

Objective The development of these updated clinical practice guidelines (CPGs) was commissioned by the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), American Society for Metabolic and Bariatric Surgery (ASMBS), Obesity Medicine Association (OMA), and American Society of Anesthesiologists (ASA) Boards of Directors in adherence with the AACE 2017 protocol for standardized production of CPGs, algorithms, and checklists. Methods Each recommendation was evaluated and updated based on new evidence from 2013 to the present and subjective factors provided by experts. Results New or updated topics in this CPG include: contextualization in an adiposity‐based chronic disease complications‐centric model, nuance‐based and algorithm/checklist‐assisted clinical decision‐making about procedure selection, novel bariatric procedures, enhanced recovery after bariatric surgery protocols, and logistical concerns (including cost factors) in the current health care arena. There are 85 numbered recommendations that have updated supporting evidence, of which 61 are revised and 12 are new. Noting that there can be multiple recommendation statements within a single numbered recommendation, there are 31 (13%) Grade A, 42 (17%) Grade B, 72 (29%) Grade C, and 101 (41%) Grade D recommendations. There are 858 citations, of which 81 (9.4%) are evidence level (EL) 1 (highest), 562 (65.5%) are EL 2, 72 (8.4%) are EL 3, and 143 (16.7%) are EL 4 (lowest). Conclusions Bariatric procedures remain a safe and effective intervention for higher‐risk patients with obesity. Clinical decision‐making should be evidence based within the context of a chronic disease. A team approach to perioperative care is mandatory, with special attention to nutritional and metabolic issues.

Abstract Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. Individuals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease).©2019American Society for Bone andMineral Research.

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

7020 Background: Histiocytic sarcoma (HS) is a rare and aggressive malignancy of the monocyte/macrophage lineage. There is a paucity of data on treatments and outcomes in HS. Methods: This is a retrospective study of patients with histologically confirmed diagnosis of HS from 2000-2018. Kaplan-Meier and log-rank tests were used to perform overall survival (OS) analyses. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards. Results: There were 27 patients in the study (median age 59; range 3-83) and 63% were males. Nine had unifocal involvement and 18 had multifocal disease. Common sites involved were lymph node (50%), soft tissue (40%), bone (36%), and bone marrow (22%). Two of 8 patients had the BRAF-V600E mutation. Next-generation sequencing was performed on 8 patients and showed ≥1 oncogenic alterations (DNMT3A, FLT4, KRAS, NRAS, NUP98, PTCH1, PTPN11, TP53, TSC1, PDGFR, or BRAF genes) as well as a CLIP2-BRAF fusion. The median OS for the cohort was 12 months. Factors associated with worse OS included multifocal disease (OS 10 vs. 125 months, p = 0.03; HR 5.0, CI 1.1-21.8) and marrow involvement (OS 3 vs. 43 months, p = 0.003; HR 8.9, CI 1.7-45.0). Twelve (44%) had surgery with median OS of 42 months (range 1-125). Fifteen had chemotherapy with median OS of 12 months (range 2-67; Table). Conclusions: HS is an aggressive neoplasm, with multifocal disease and bone marrow involvement portending worse outcomes. Most patients have somatic oncogenic alterations involving the MAPK-ERK pathway and other genes. Chemotherapeutic regimens have variable response rates but are not durable. More studies on targeted kinase inhibitors in HS are needed to improve outcomes. [Table: see text]