Citations

Background: The American Heart Association recently published an updated algorithm for quantifying cardiovascular health (CVH)—the Life’s Essential 8 score. We quantified US levels of CVH using the new score. Methods: We included individuals ages 2 through 79 years (not pregnant or institutionalized) who were free of cardiovascular disease from the National Health and Nutrition Examination Surveys in 2013 through 2018. For all participants, we calculated the overall CVH score (range, 0 [lowest] to 100 [highest]), as well as the score for each component of diet, physical activity, nicotine exposure, sleep duration, body mass index, blood lipids, blood glucose, and blood pressure, using published American Heart Association definitions. Sample weights and design were incorporated in calculating prevalence estimates and standard errors using standard survey procedures. CVH scores were assessed across strata of age, sex, race and ethnicity, family income, and depression. Results: There were 23 409 participants, representing 201 728 000 adults and 74 435 000 children. The overall mean CVH score was 64.7 (95% CI, 63.9–65.6) among adults using all 8 metrics and 65.5 (95% CI, 64.4–66.6) for the 3 metrics available (diet, physical activity, and body mass index) among children and adolescents ages 2 through 19 years. For adults, there were significant differences in mean overall CVH scores by sex (women, 67.0; men, 62.5), age (range of mean values, 62.2–68.7), and racial and ethnic group (range, 59.7–68.5). Mean scores were lowest for diet, physical activity, and body mass index metrics. There were large differences in mean scores across demographic groups for diet (range, 23.8–47.7), nicotine exposure (range, 63.1–85.0), blood glucose (range, 65.7–88.1), and blood pressure (range, 49.5–84.0). In children, diet scores were low (mean 40.6) and were progressively lower in higher age groups (from 61.1 at ages 2 through 5 to 28.5 at ages 12 through 19); large differences were also noted in mean physical activity (range, 63.1–88.3) and body mass index (range, 74.4–89.4) scores by sociodemographic group. Conclusions: The new Life’s Essential 8 score helps identify large group and individual differences in CVH. Overall CVH in the US population remains well below optimal levels and there are both broad and targeted opportunities to monitor, preserve, and improve CVH across the life course in individuals and the population.

Abstract Previous studies have found that the prevalence of subtypes of T cells may be associated with patient outcomes, but a comprehensive analysis of the immune profile in the TM of FL has not been done. In the present study, we identified groups of FL patients with discretely unique TMEs and determined whether the T-cell phenotypes in the TME differed among groups. Using a cohort of 82 FL patients with biopsy specimens collected before treatment, we defined the type of TME based on the content of major lineages (T, B, monocytes/macrophages and NK cells) determined by CyTOF analysis. Hierarchical clustering of this cohort stratified patients into 4 groups with different TME: group 1 (G1) included patients with a high percentage of monocyte/macrophages/NK cells; patients from G2 and G3 were enriched for intratumoral T and B cells, respectively. Patients with intermediate numbers of T and B cells were included in G4. CITRUS analysis revealed that T-cell clusters with phenotypes expressing KLRG1, CD57, PD-1dim and rich in TEMRA cells were significantly more abundant in G1 when compared to G2, G3 or G4. In contrast, T-cell clusters with phenotypes containing CD127, CD45RA, CCR7 or PD-1high cells were significantly less abundant in G1 when compared to other groups. When compared to G3 or G4, 2 classes of T cell clusters, all from CD4+ T cells, were significantly more (CD127+KLRG1-) or less (CD57+PD-1high) abundant in G2, respectively. Clusters with a phenotype rich in short-lived effector cells (SLEC) (from CD8+) were upregulated in G3 when compared to G4. These results suggest that patient groups with distinct TME exhibited variable T-cell phenotypes. To determine the role of T-cell differentiation in predicting patient outcome in FL, we identified T-cell subsets using tSNE plots based on the expression of T-cell maturation markers. We identified 18 subsets (S1-S18) of T cells (11 from CD4, 6 from CD8 and 1 from CD4-CD8-) in each sample. Four subsets - S4 (CD4+TN), S5 (CD4+TCM), S7 (CD8+TN) and S10 (CD8+MEPCs) - were considered to be naïve cells or cells in the early stages of differentiation. Four additional subsets - S8 (CD57+TFH), S9 (CD4+TEXH), S13 (CD8+SLECs) and S17 (CD4+PD-1+Treg) - were memory cells with expression of surface markers indicting late-stage differentiation. We found that the 4 subsets (S4: p=0.08, S5: p=0.01, S7: p=0.04 and S10: p<0.01) with an early-stage phenotype were associated with a favorable clinical outcome. In contrast, subsets (S8: p=0.02, S9: p=0.04, S13: p=0.07 and S17: p=0.06) with a late-stage differentiation phenotype had an unfavorable survival. Supporting this finding, we observed that increased numbers of CD45RA+ T cells correlated with a favorable survival. These results indicate that the differentiation stage may determine the role of T cells in predicting patient outcome in FL. Citation Format: Zhi-Zhang Yang, Hyo Jin Kim, Hongyan Wu, Xinyi Tang, Jordan Krull, Patrizia Mondello, Jose Villasboas, Anne Novak, Stephen Ansell. T-cell phenotype and differentiation vary in the tumor microenvironment of follicular lymphoma and are associated with patient outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2529.

Abstract Introduction: The risk of specific clinical subtype of breast cancer (defined by ER and HER2 status) among women in the general population who are carriers of germline pathogenic variants (PVs) in cancer predisposition genes is not well-defined. Methods: A total of 13,153 women with breast cancer (ER+/HER2-: 9381; ER+/HER2+: 1462; ER-/HER2+: 690; and ER-/HER2-: 1620) and 25,005 unaffected women (controls) from nine studies within the CAnceR RIsk Estimates Related to Susceptibility (CARRIERS) consortium that were not enriched for family history or early onset disease were included in the present analysis. A multiplex amplicon-based panel was used to perform germline sequencing for cancer predisposition genes. Case-control associations for each of the four clinical subtype of breast cancer was performed for PVs in 5 common breast cancer predisposition genes (ATM, BRCA1, BRCA2, CHEK2 and PALB2) utilizing a logistic regression model adjusting for study, age at diagnosis, race/ethnicity and family history of breast cancer. Results: The frequency of PVs in 5 genes was 3.8% for ER+/HER2-, 6.2% for ER+/HER2+, 4.2% for ER-/HER2+ and 9.3% for ER-/HER2- subtypes. PVs in BRCA1 and BRCA2 were associated with high risk (Odds Ratio (OR) >4) for all clinical subtypes of breast cancer, but the risk was highest (OR>8) for ER-/HER2- breast cancer. PVs in PALB2 were associated with high risk (OR>4) of ER-/HER2- and ER+/HER2+ subtypes and moderate risk (OR: 2-4) of ER+/HER2- breast cancer. Irrespective of the HER2 status, PVs in ATM were associated with a moderately increased risk (OR: 2-4) of ER+ breast cancer but the risk of ER- breast cancer was not elevated. In contrast, PVs in CHEK2 were associated with high risk (OR>4) of ER+/HER2+ breast cancer and moderate risk (OR: 2-4) of ER+/HER2- and ER-/HER2+ breast cancer, but the risk of ER-/HER2- breast cancer was not elevated. Conclusions: This study provides population-based estimates of risk of specific clinical subtypes of breast cancer which will be useful for genetic counseling and targeting appropriate screening strategies in PV carriers based on subtype specific risks of breast cancer. Citation Format: Siddhartha Yadav, Chunling Hu, Nicholas J. Boddicker, Eric Polley, Steven Hart, Rohan Gnanaolivu, Jie Na, Hongyan Huang, Song Yao, Celine M. Vachon, Lauren Teras, Jack A. Taylor, Dale P. Sandler, Julie R. Palmer, Janet E. Olson, Susan Neuhausen, Elena Martinez, Sara Lindstroem, Loic Le Marchand, Charles Kooperberg, Christopher Haiman, Mia M. Gaudet, James V. Lacey, Kimberly A. Bertrand, Leslie Bernstein, Paul W. Auer, Christine Ambrosone, Jeffrey N. Weitzel, Peter Kraft, David E. Goldgar, Katherine L. Nathanson, Susan M. Domchek, Fergus J. Couch, CARRIERS Consortium. Population-based risk estimates of clinical subtypes of breast cancer among carriers of germline pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-01.

Abstract The tumor microenvironment plays a crucial role in mediating the tumor immune response, thereby affecting patient outcomes in follicular lymphoma (FL). Using CyTOF, we analyzed single cell suspensions created from pre-treatment biopsies in a cohort of 82 FL patients and retrospectively extracted patient clinical parameters. Hierarchical analysis of the tumor microenvironment composition stratified these patients into 4 groups: group 1 represents patients with high percentage of monocyte/macrophages/NK cells; patients from group 2 and 3 are rich of intratumoral T and B cells, respectively. Patients with intermediate number of T and B cells are classed into group 4. Intratumoral T cells from these 4 groups exhibited distinct phenotypical characteristics. Group 1 was enriched with KLRG1 +CD8 + T cells, while group 4 showed increased number of CXCR3 - T EM and CD4 + T N cells. Patients from group 2 and 3 featured with increased number of ICOS + T reg cells and CD57 + T FH cells, respectively. We observed that higher numbers of T cells significantly correlated with early disease stage, lack of B-symptoms, event-free survival at 24 months (EFS24) and a favorable overall and EFS survival in patients with histological grade 1 and 2. However, this association was not seen in patients with histological grade 3a and b, suggesting that T cell-mediated anti-tumor immunity is preserved in low grade patients, but overridden in higher grade patients. CITRUS analysis revealed that a cluster that is CD57 + and PD-1 high was significantly more abundant in patients who had disease progression than patients who had a complete response to therapy, suggesting a role of CD57 + T FH cells in promoting malignant cell growth in FL. Consistent with this finding, we observed that higher number of CD57 + T FH cells correlated with an inferior survival in FL. Using CITE-seq technology, we found that CD57 + T FH cells exhibited a substantially different transcriptome when compared to CD57 - T FH cells. Genes that were differentially upregulated in CD57 + T FH cells when compared to CD57 - T FH cells included genes involved in cell survival, compromised inflammatory response, and metabolism activation including GZMK, CCL4, CST7, DUSP2, LGALS3, CYTOR, CHI3L2, SYNE2, CXCL13, CD27 and FABP5. Taken together, our results indicate different tumor microenvironments among FL patient groups that is associated with variable T-cell phenotype. We found that CD57 + T FH cells play an important role in predicting disease progression and patient prognosis in FL. Figure 1 Figure 1. Disclosures Novak: Celgene/BMS: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

Abstract Iron (Fe) overload is not rare among sickle cell disease (SCD) patients. It results from either chronic transfusions for primary or secondary stroke prevention, or more commonly sporadic, mostly unnecessary transfusions and are associated with significant morbidity, secondary to hepatic, cardiac and renal Fe deposition. Previous studies at our Center showed that 12% of the adult SCD population had Fe overload, and vast majority of these (80%) resulted from episodic transfusions (Son et al, 2013). Subsequent studies showed that the Fe regulatory peptide, hepcidin was appropriately upregulated in SCD subjects with Fe overload, and the plasma levels of the glycoprotein hormone erythroferrone (ERFE) was not as high as that found in patients with transfusion dependent beta thalassemia (TDT) due to the absence of significant ineffective erythropoiesis in SCD (Thawer et al, 2017, Mangaonkar et al, Brit. J. Haematol, 2020). We report on the utilization and outcomes in Fe overloaded SCD patients who were prescribed the oral chelating agent deferasirox. 22 patients were prescribed deferasirox; median age was 38, 12 female 10 male. 21 had Hb SS, and 1 had s-b 0 thalassemia. Deferasirox dose ranged from 720-2500 mg/day (12 to 28 mg/Kg/day). Nonadherence was ascertained by patients' own admission. Figures 1-3 show the pre and post ferritin levels in subjects who were on deferasirox, and in controls; patients who took deferasirox had a more pronounced decrease in their ferritin (p=.004 vs p=.74). Although hepatic MRI for liver iron content (LIC) was not available on all patients, in those who underwent MRI there was a correlation between LIC and serum ferritin obtained at close temporal proximity (Fig. 4). Most common side effects of deferasirox were gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), which were seen less commonly with the newer oral formulation (Jadenu). Several conclusions can be drawn from our observation on relatively small number of patients: 1) Deferasirox is effective in decreasing Fe overload as shown by serum ferritin levels 2) Second generation of oral deferasirox is better tolerated, and therefore is associated with improved adherence, 3) Documentation of a decrease in LIC with chelation will be important for the reversal of Fe induced organ damage, and 4) Parallel studies of the levels of Fe regulatory peptides hepcidin and erythroferrone (ERFE) will clarify the effect of chelation therapy on biomarkers of Fe metabolism. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

PURPOSETo determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.MATERIALS AND METHODSThe study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).RESULTSThe frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.CONCLUSIONThe study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

Background CD8+ T-lymphocyte subsets defined by killer lectin-like receptor G1 (KLRG1) and CD127 expression have been reported to have an important role in infection, but their role in the setting of lymphoid malignancies, specifically follicular lymphoma (FL), has not been studied. Methods To characterize the phenotype of KLRG1/CD127-defined CD8+ subsets, surface and intracellular markers were measured by flow cytometry and Cytometry by time of flight (CyTOF), and the transcriptional profile of these cells was determined by CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing). The functional capacity of each subset was determined, as was their impact on overall survival (OS) and event-free survival (EFS) of patients with FL. Results We found that intratumoral CD8+ cells in FL are skewed toward effector cell subsets, particularly KLRG+CD127- and KLRG1-CD127- cells over memory cell subsets, such as KLRG1-CD127+ and KLRG1+CD127+ cells. While effector subsets exhibited increased capacity to produce cytokines/granules when compared with memory subsets, their proliferative capacity and viability were found to be substantially inferior. Clinically, a skewed distribution of intratumoral CD8+ T cells favoring effector subtypes was associated with an inferior outcome in patients with FL. Increased numbers of CD127+KLRG1- and CD127+KLRG1+ were significantly associated with a favorable OS and EFS, while CD127-KLRG1- correlated with a poor EFS and OS in patients with FL. Furthermore, we demonstrated that interleukin (IL)-15 promotes CD127-KLRG1+ cell development in the presence of dendritic cells via a phosphoinositide 3-kinase (PI3K)-dependent mechanism, and treatment of CD8+ T cells with a PI3K inhibitor downregulated the transcription factors responsible for CD127-KLRG1+ differentiation. Conclusions Taken together, these results reveal not only a biological and prognostic role for KLRG1/CD127-defined CD8+ subsets in FL but also a potential role for PI3K inhibitors to manipulate the differentiation of CD8+ T cells, thereby promoting a more effective antitumor immune response.

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.