Citations

4084 Background: Treatment of advanced CCA has changed dramatically over the past five years with the advent of molecularly targeted therapy, now approved in the 2nd line and beyond. However, real world utilization of molecular profiling and targeted therapy is still unknown and these data are critical to empower treatment decision-making. Methods: In 2019, the Cholangiocarcinoma Foundation (CCF) and Ciitizen (a wholly owned subsidiary of Invitae Corporation) collaboratively launched a registry platform that directly consents patients and collects comprehensive medical records. De-identified data including clinical characteristics, molecular testing, interventions, and outcomes are extracted and standardized for research use. The data is longitudinal with regularly planned updates; registry participants can be re-engaged to obtain additional data and communicate tailored insights. Results: We quantified the rate of molecular testing, the presence of targetable biomarkers, and the utilization and outcomes on matched targeted therapies for 372 individuals with CCA. 328 (88.2%) individuals had molecular testing, with the identified targetable mutations and matched therapies reported. Of 328 individuals who had molecular testing, 111 (33.8%) individuals had one or more targetable mutations (116 mutations total). Only 46% (51) of individuals with targetable mutations received targeted therapy. Of the 54% (60) individuals with targetable mutations that did not receive any matched therapy, the majority (61.7%, 37) were in early disease or first line of treatment and therefore not yet eligible for targeted therapy. These individuals will be informed that based on their molecular profile, a targeted therapy may be an option, and suggest they discuss with their treating physician. Conclusions: A novel prospectively-maintained database registry for CCA has been formed in collaboration between a patient advocacy organization (CCF) and industry (Invitae). Prevalence of actionable biomarkers was higher than historically expected and may reflect patient utilization bias of the registry platform. Molecular profiling and access to targeted therapeutics remains suboptimal at this time in CCA. Future directions for the registry include identifying and targeting disparities in care and supporting biopharmaceutical development and regulatory decisions. [Table: see text]

Background : Modulation of the cardiac autonomic nervous system (ANS) is a promising adjuvant therapy in the treatment of atrial fibrillation (AF). In pre-clinical models, pulsed field (PF) energy has the advantage of selectively ablating the epicardial ganglionated plexi (GP) that govern the ANS. Objective: This study aims to demonstrate the feasibility and safety of epicardial ablation of the GPs with PF during cardiac surgery with a primary efficacy outcome of prolongation of the atrial effective refractory period (AERP). Methods : In a single-arm, prospective analysis, patients with or without a history of AF underwent epicardial GP ablation with PF during coronary artery bypass grafting (CABG). AERP was determined immediately pre- and post- GP ablation to assess cardiac ANS function. Holter monitors were performed to determine rhythm status and Heart Rate Variability (HRV) at baseline and at 1 month post-procedure. Conclusions : This study demonstrates the safety and feasibility of epicardial ablation of the GP using PF to modulate the ANS during cardiac surgery. Large, randomized analyses are necessary to determine whether epicardial PF ablation can offer a meaningful impact on the cardiac ANS and reduce AF. Results : Of 24 patients, 23 (96%) received the full ablation protocol. No device-related adverse effects were noted. GP ablation resulted in a 20.7% ± 19.9% extension in AERP (P < 0.001). Post-operative AF was observed in 7 (29%) patients. Holter monitoring demonstrated an increase in mean heart rate (74.0±8.7 vs 80.6±12.3, P=0.01). There were no significant changes in HRV. There were no study-related complications.

AbstractBackgroundWe identify chronic rhinosinusitis (CRS) manifestations associated with how rhinologists assess CRS control, with a focus on patient perspectives (patient‐reported CRS control).MethodsFifteen rhinologists were provided with real‐world data from 200 CRS patients. Participating rhinologists first classified patients’ CRS control as “controlled,” “partly controlled,” and “uncontrolled” using seven CRS manifestations reflecting European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) CRS control criteria (nasal obstruction, drainage, impaired smell, facial pain/pressure, sleep disturbance, use of systemic antibiotics/corticosteroids in past 6 months, and nasal endoscopy findings) and patient‐reported CRS control. They then classified patients’ CRS control without knowledge of patient‐reported CRS control. Interrater reliability and agreement of rhinologist‐assessed CRS control with patient‐reported CRS control and EPOS guidelines were determined.ResultsCRS control classification with and without knowledge of patient‐reported CRS control was highly consistent across rhinologists (κw = 0.758). Rhinologist‐assessed CRS control agreed with patient‐reported CRS control significantly better when rhinologists had knowledge of patient‐reported CRS control (κw = 0.736 vs. κw = 0.554, p < 0.001). Patient‐reported CRS control, nasal obstruction, drainage, and endoscopy findings were most strongly associated with rhinologists’ assessment of CRS control. Rhinologists’ CRS control assessments weakly agreed with EPOS CRS control guidelines with (κw = 0.529) and without (κw = 0.538) patient‐reported CRS control. Rhinologists classified CRS as more controlled than EPOS guidelines in almost 50% of cases.ConclusionsThis study directly demonstrates the importance of patient‐reported CRS control as a dominant influence on rhinologists’ CRS control assessment. Knowledge of patient‐reported CRS control may better align rhinologists’ CRS control assessments and treatment decisions with patients’ perspectives.

Abstract Introduction/Objectives: Purines regulate DNA repair in brain tumors through uncertain mechanisms. We sought to define the mechanisms by which purines regulate DNA repair and therapy response. Methods: Crispr/Cas9, siRNA, and CDNA overexpression and immunoblot were used to modulate and confirm protein levels. γ-H2AX and Rad51 foci were enumerated using immunofluorescence. Fluorescent reporter assays were performed to detect DNA repair activity. Phosphoproteomics was used to identify GTP-dependent (de)phosphorylation events after RT and antibodies generated against novel sites. Celltiter-glo or clonogenic assay were performed to evaluate drug/RT responses. IHC was used to detect protein expression. Animal models of glioblastoma and normal tissue (irradiation of GI system) were used to assess DNA repair and treatment responses in vivo. Results: Pharmacogenomic inhibition of GTP (but not ATP) synthesis sensitized GBM cells to RT, slowed the repair of RT-induced DSBs and inhibited the activity of non-homologous end joining (NHEJ), but not homologous recombination (HR). These effects could be rescued by GTP (but not ATP) supplementation. We found a GTP-dependent RT-induced dephosphorylation event on Abl interactor 1 (Abi-1) serine 323 (S323) using phosphoproteomics. We generated a new antibody for p-Abi-1 (S323), validated its specificity, and confirmed that RT causes a GTP-dependent dephosphorylation of Abi-1 (S323). Knockout of Abi-1 slowed RT-induced DSB repair and this was rescued by re-expression of dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D). Abi-1 canonically binds to the small GTP-activated protein Rac1. Expression of constitutively active Rac1 promoted the dephosphorylation of Abi-1 (S323) and DSB repair while these effects were blocked by dominant negative Rac1. Pharmacogenomic inhibition of protein phosphatase 5 reversed the GTP- and Rac1-mediated dephosphorylation of Abi-1 and DSB repair. These findings have therapeutic relevance. In GBM PDX samples, levels of p-Abi-1 (S323) negatively correlated with Rac1 activity and predicted favorable efficacy of genotoxic treatments. In orthotopic GBM mouse models, inhibition of Rac1 enhanced RT responses and suppressed Abi-1 S323 dephosphorylation. Abi-1 knockout enhanced efficacy of numerous genotoxic treatments and could be rescued by Abi-1 S323A (but not Abi-1 S323D) re-expression. This regulation is generalizable beyond brain cancer, as GTP supplementation promoted DNA repair and p-Abi1 (S323) dephosphorylation in normal astrocytes and enteroids and protected mice from RT-mediated gastrointestinal injury. Conclusions: GTP promotes DNA repair by activating Rac1 and PP5 to dephosphorylate Abi-1 and stimulate NHEJ. Disrupting this regulation could improve brain tumor treatment responses while augmenting it could help protect normal tissues from genotoxic injury. Citation Format: Weihua Zhou, Angelica Lin, Zitong Zhao, John Yang, Kari Wilder-Romans, Jie Xu, Sumeet Solanki, Jing Li, Annabel Yang, Andrew Scott, Ayesha Kothari, Erik Peterson, Navyateja Korimerla, Jessica Liang, Janna Jacobson, Sravya Palavalasa, Alexandra Obrien, Sean Ferris, Shuang Zhao, Jann N. Sarkaria, Meredith Morgan, Theodore S. Lawrence, Costas A. Lyssiotis, Yatrik Shah, Daniel R. Wahl. GTP-dependent signaling links metabolism, non-homologous end joining and treatment responses in cancer and normal tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3498.

Abstract Multiple studies including ours have shown that the interaction of chronic lymphocytic leukemia (CLL) B cells with the bone marrow (BM) microenvironment promotes cell survival and protects these cells from the cytotoxic effects of therapy. A detailed understanding of this interaction will help better understand CLL leukemic cell survival and drug resistance mechanisms. We performed RNA-seq in paired CLL B cells isolated from untreated blood and BM (n=6) and in untreated CLL B cells (n=4) cultured alone or co-cultured with bone marrow stromal cells (BMSCs) derived from either normal individuals (n=2) or CLL patients (n=2). We found upregulation of 232 and 917 genes in CLL B cells from BM and in co-cultured CLL B cells compared to the CLL B cells from the same patient’s blood and CLL B cells cultured alone respectively (p&lt;0.05, fold change &gt;1.5). However we found only 13 genes overlapped between BM CLL B cells and co-cultured CLL B cells. To explore the functional importance of these 13 genes, we analyzed the expression of these genes in CLL blood B cells from an additional 169 untreated patients by RNA-seq and found a positive relationship between 5 of these 13 genes (MKI67, PNP, C16orf54, MOB3A, CDK2AP2) with CLL patient’s clinical outcome including overall survival (OS), progression free survival (PFS), and time to first treatment (TTFT) [univariate Cox regressions analysis (UCRA) p&lt;0.05]. Out of 5 genes, purine nucleotide phosphorylase (PNP) which is an enzyme in the purine salvage pathway, showed the significant association for patient’s OS, PFS, and TTFT using UCRA [hazard ratio (HR) {95% CI}: 2.8 {1.8-4.3}, 2.7 {1.9-3.8}, 2.9 {2.0-4.2}, respectively, p&lt;.0001], suggesting purine metabolism plays an important role in BM induced CLL B cell survival. We also observed an increase in PNP protein levels in CLL B cells co-cultured with BMSCs or from BM using Western blot analysis. Untargeted metabolomic profiling (LC-MS+GC-MS) showed an increased level of purine salvage pathway metabolites adenosine, inosine, and hypoxanthine in co-cultured CLL B cells. Consistent with this altered nucleotide metabolism data, we also found increased pyrimidine pathway enzyme thymidylate synthase (TYMS) at RNA and protein levels in co-cultured CLL B cells and in BM CLL B cells. We further analyzed the RNA-seq data generated from the 169 CLL patients and it also showed a positive association of TYMS gene with their OS, PFS and TTFT using UCRA [HR (95% CI): 1.35 (1.0-1.8), 1.3 (1.0-1.6), 1.63 (1.3-2.1) respectively, p&lt;0.05]. In conclusion, these results indicate that active purine/pyrimidine metabolism in CLL B cells may be augmented by the BM environment to support CLL B cell survival. Future studies to understand the exact mechanism of PNP and TYMS mediated CLL B cell survival for both untreated and treated CLL B cells will uncover unique approaches for therapy. Citation Format: Sutapa Sinha, Zhiquan Wang, Weiguo Han, Kari G. Rabe, Susan L. Slager, Chantal E. McCabe, Daniel R. O'Brien, Sameer A. Parikh, Esteban Braggio, Neil E. Kay. Role of purine and pyrimidine metabolism in CLL B cell survival and drug resistance mediated via interaction with bone marrow microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1252.

Objective: We aimed to characterize seasonal variation in US population-based blood pressure (BP) control and BP-related metrics and evaluate the association between outdoor temperature and BP control variation. Methods: We queried electronic health records (EHRs) from 26 health systems, representing 21 states, to summarize BP metrics by quarters of 12-month periods from January 2017 to March 2020. Patients with at least one ambulatory visit during the measurement period and a hypertension diagnosis during the first 6 months or prior to the measurement period were included. Changes in BP control, BP improvement, medication intensification, average SBP reduction after medication intensification across quarters and association with outdoor temperature were analyzed using weighted generalized linear models with repeated measures. Results: Among 1 818 041 people with hypertension, the majority were more than 65 years of age (52.2%), female (52.1%), white non-Hispanic (69.8%) and had stage 1/2 hypertension (64.8%). Overall, BP control and process metrics were highest in quarters 2 and 3, and lowest in quarters 1 and 4. Quarter 2 had the highest percentage of improved BP (31.95 ± 0.90%) and average SBP reduction after medication intensification (16 ± 0.23 mmHg). Quarter 3 had the highest percentage of BP controlled (62.25 ± 2.55%) and lowest with medication intensification (9.73 ± 0.60%). Results were largely consistent in adjusted models. Average temperature was associated with BP control metrics in unadjusted models, but associations were attenuated following adjustment. Conclusion: In this large, national, EHR-based study, BP control and BP-related process metrics improved during spring/summer months, but outdoor temperature was not associated with performance following adjustment for potential confounders.

Abstract TP53 aberrations, including mutations and deletion of 17p13, are important adverse prognostic markers in chronic lymphocytic leukemia (CLL) but are less studied in high count monoclonal B-cell lymphocytosis (HCMBL), an asymptomatic pre-malignant stage of CLL. Here we estimated the prevalence and impact of TP53 aberrations in 1,230 newly diagnosed treatment-naïve individuals (849 CLL, 381 HCMBL). We defined TP53 state as: wild-type (no TP53 mutations and normal 17p), single-hit (del(17p) or one TP53 mutation), or multi-hit (TP53 mutation and del(17p), TP53 mutation and loss of heterozygosity, or multiple TP53 mutations). Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time to first treatment and overall survival by TP53 state. We found 64 (7.5%) CLL patients and 17 (4.5%) HCMBL individuals had TP53 mutations with variant allele fraction &gt;10%. Del(17p) was present in 58 (6.8%) of CLL and 11 (2.9%) of HCMBL cases. Most individuals had wild-type (N=1,128, 91.7%) TP53 state, followed by multi-hit (N=55, 4.5%) and then single-hit (N=47, 3.8%) TP53 state. The risk of shorter time to therapy and death increased with the number of TP53 abnormalities. Compared to wild-type patients, multi-hit patients had 3-fold and single-hit patients had 1.5-fold increased risk of requiring therapy. Multi-hit patients also had 2.9-fold increased risk of death compared to wild-type. These results remained stable after accounting for other known poor prognostic factors. Both TP53 mutations and del(17p) may provide important prognostic information for HCMBL and CLL that would be missed if only one were measured.

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p&lt; 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was &gt;20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was &lt; 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.