Citations

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

3072 Background: The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) previously demonstrated that a blood-based multi-cancer early detection (MCED) test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin. Cancer classes were defined within the CCGA study for sensitivity reporting. Separately, cancer types defined by the American Joint Committee on Cancer (AJCC) criteria, which outline unique staging requirements and reflect a distinct combination of anatomic site, histology and other biologic features, were assigned to each cancer participant using the same source data for primary site of origin and histologic type. Here, we report CCGA ‘cancer class’ designation and AJCC ‘cancer type’ assignment within the third and final CCGA3 validation substudy to better characterize the diversity of tumors across which a cancer signal could be detected with the MCED test that is nearing clinical availability. Methods: CCGA is a prospective, multicenter, case-control, observational study with longitudinal follow-up (overall population N = 15,254). Plasma cfDNA from evaluable samples was analyzed using a targeted methylation bisulfite sequencing assay and a machine learning approach, and test performance, including sensitivity, was assessed. For sensitivity reporting, CCGA cancer classes were assigned to cancer participants using a combination of the type of primary cancer reported by the site and tumor characteristics abstracted from the site pathology reports by GRAIL pathologists. Each cancer participant also was separately assigned an AJCC cancer type based on the same source data using AJCC staging manual (8th edition) classifications. Results: A total of 4077 participants comprised the independent validation set with confirmed status (cancer: n = 2823; non-cancer: n = 1254 with non-cancer status confirmed at year-one follow-up). Sensitivity was reported for 24 cancer classes (sample sizes ranged from 10 to 524 participants), as well as an “other” cancer class (59 participants). According to AJCC classification, the MCED test was found to detect cancer signals across 50+ AJCC cancer types, including some types not present in the training set; some cancer types had limited representation. Conclusions: This MCED test that is nearing clinical availability and was evaluated in the third CCGA substudy detected cancer signals across 50+ AJCC cancer types. Reporting CCGA cancer classes and AJCC cancer types demonstrates the ability of the MCED test to detect cancer signals across a set of diverse cancer types representing a wide range of biologic characteristics, including cancer types that the classifier has not been trained on, and supports its use on a population-wide scale. Clinical trial information: NCT02889978.

3071 Background: Disparities in cancer screening and outcomes based on factors such as gender, socioeconomic status, and race/ethnicity are well documented.1 The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was designed to develop and validate a blood-based multi-cancer early detection (MCED) test analyzing plasma cell-free DNA (cfDNA) to detect cancer signals across multiple cancer types and simultaneously predict cancer signal origin. Findings stratified by race/ethnicity from the third and final CCGA validation sub-study are reported. Methods: CCGA is a prospective, multicenter, case-control, observational study with longitudinal follow-up (overall N = 15,254). In this pre-specified exploratory analysis from the third substudy, key objectives were to evaluate test performance for cancer signal detection (specificity, overall sensitivity, and sensitivity by clinical stage) among racial/ethnic groups. Plasma cfDNA from evaluable samples was analyzed using a targeted methylation bisulfite sequencing assay and a machine learning approach. Overall, 4077 participants comprised the independent validation set with confirmed status (cancer: n = 2823; non-cancer: n = 1254). The groups stratified by race/ethnicity were White Non-Hispanic, Black Non-Hispanic, Other Non-Hispanic (including but not limited to Asian, Native Hawaiian, Pacific Islander, American Indian, Alaska Native), Hispanic (all races), and Other/unknown. The study was not powered to detect statistical differences between groups. Results: Cancer and non-cancer groups were predominantly White (2316/2823, 82.0% and 996/1254, 79.4%, respectively). Across racial/ethnic groups, specificity for cancer signal detection was 99.6% (White Non-Hispanic: 992/996, 95% confidence interval [99.0-99.8%]), 100.0% (Black Non-Hispanic: 85/85 [95.7-100.0%]), 100.0% (Other Non-Hispanic: 33/33 [89.6-100.0%]), 98.1% (Hispanic: 101/103 [93.2-99.5%]), and 100% (Other/unknown: 37/37 [90.6-100.0%]). Despite slight differences in cancer type and staging across racial/ethnic groups, overall sensitivity for cancer signal detection among groups ranged from 43.9% to 63.0% (White Non-Hispanic: 50.5%, 1169/2316 [48.4-52.5%], Black Non-Hispanic: 53.9%, 104/193 [46.8-60.8%], Other Non-Hispanic: 43.9%, 25/57 [31.8-56.7%], Hispanic: 63.0%, 121/192 [56.0-69.5%], and Other/unknown: 52.3%, 34/65 [40.4-64.0%]). For all racial/ethnic groups, sensitivity generally increased with clinical stage (with limited exceptions at Stage IV in some groups with small sample sizes). Conclusions: The MCED test demonstrated consistent specificity and sensitivity across racial/ethnic groups, though results are limited by sample size for some groups. These findings indicate broad applicability and support clinical implementation of this MCED test on a population scale. 1. Zavela et al. Brit J Cancer 2021. Clinical trial information: NCT02889978.

Aromatase inhibitors (AIs) are the treatment of choice for hormone receptor–positive early breast cancer in postmenopausal women. None of the third‐generation AIs are superior to the others in terms of efficacy. We attempted to identify genetic factors that could differentiate between the effectiveness of adjuvant anastrozole and exemestane by examining single‐nucleotide polymorphism (SNP)‐treatment interaction in 4,465 patients. A group of SNPs were found to be differentially associated between anastrozole and exemestane regarding outcomes. However, they showed no association with outcome in the combined analysis. We followed up common SNPs near LY75 and GPR160 that could differentiate anastrozole from exemestane efficacy. LY75 and GPR160 participate in epithelial‐to‐mesenchymal transition and growth pathways, in both cases with SNP‐dependent variation in regulation. Collectively, these studies identified SNPs that differentiate the efficacy of anastrozole and exemestane and they suggest additional genetic biomarkers for possible use in selecting an AI for a given patient.

Abstract Background We studied the efficacy and safety of ustekinumab (UST) vs adalimumab (ADA) through 1 year in biologic-naïve patients (pts) with moderate-to-severe Crohn’s disease. Methods SEAVUE was a multicenter, randomized, blinded, parallel-group, active-controlled study in adults with CD Activity Index (CDAI) scores ≥220/≤450. Biologic-naïve pts failing/intolerant to conventional therapy with any size ulcer on baseline (BL) ileocolonoscopy were eligible. Pts were randomized 1:1 to UST (⁓6mg/kg IV at BL then 90mg SC every 8 weeks [Ws]) or ADA (160/80mg SC at BL/W2, then 40mg SC every 2 Ws) per US-approved regimens (no dose modifications). Primary endpoint was clinical remission at W52 (CDAI <150). Major secondary endpoints were corticosteroid-free remission, clinical response (≥100-point CDAI decrease from BL), remission in pt-reported CDAI components (PRO-2 symptom remission: abdominal pain mean daily score ≤1 and stool frequency mean daily score ≤3), and endoscopic remission (SES-CD score ≤3/0 for pts with BL score=3) at W52 and clinical remission at W16. Results 386 pts were randomized to UST or ADA. BL demographics and disease characteristics were balanced between groups and indicative of pts with early, moderate-to-severe CD (median CD duration, 2.58 years; CDAI, 289.5; SES-CD, 8.0). At W52, 65% of UST-treated and 61% of ADA-treated pts achieved clinical remission (Δ=4.0%; 95% CI, -5.5%, 13.5%; p=0.417). Major secondary endpoints, including endoscopic remission, were similar between groups (Table 1), as were remission rates at assessment points through W52. Some other secondary endpoints showed numerical (not statistical) differences between UST and ADA (Table 1). Key safety events are summarized in Table 2. Among UST-treated and ADA-treated pts, 34.0% and 40.5% had infections, 2.6% and 7.2% had serious adverse events (AEs) of worsening CD, and 6.3% and 11.3% had AEs that led to discontinuation (DC) of study drug, respectively. One ADA-treated pt had active pulmonary TB. Injection-site reactions associated with active treatment occurred in 1.0% of UST-treated and 10.3% of ADA-treated pts. Overall, 15.2% of UST-treated and 23.6% of ADA-treated pts DC before W52. Reasons for DC were primarily lack of efficacy (UST, 2.1% vs ADA, 5.1%), AEs (UST, 5.7% vs ADA, 10.7%), and withdrawal of consent (UST, 5.8% vs ADA, 5.1%). Time to treatment DC was longer with UST vs ADA (post hoc analysis). Conclusion Both UST and ADA were highly effective in this population of biologic-naïve pts. Rates of clinical remission at W52 were not statistically significantly different between treatment groups. DC rates were numerically lower for UST. Safety results were consistent with prior experience for both treatments.

Background: Ten-year all-cause death according to incomplete (IR) versus complete revascularization (CR) has not been fully investigated in patients with 3-vessel disease and left main coronary artery disease undergoing percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). Methods: The SYNTAX Extended Survival study (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES]) evaluated vital status up to 10 years in patients who were originally enrolled in the SYNTAX trial. In the present substudy, outcomes of the CABG CR group were compared with the CABG IR, PCI CR, and PCI IR groups. In addition, in the PCI cohort, the residual SYNTAX score (rSS) was used to quantify the extent of IR and to assess its association with fatal late outcome. The rSS of 0 suggests CR, whereas a rSS>0 identifies the degree of IR. Results: IR was more frequently observed in patients with PCI versus CABG (56.6% versus 36.8%) and more common in those with 3-vessel disease than left main coronary artery disease in both the PCI arm (58.5% versus 53.8%) and the CABG arm (42.8% versus 27.5%). Patients undergoing PCI with CR had no significant difference in 10-year all-cause death compared with those undergoing CABG (22.2% for PCI with CR versus 24.3% for CABG with IR versus 23.8% for CABG with CR). In contrast, those with PCI and IR had a significantly higher risk of all-cause death at 10 years compared with CABG and CR (33.5% versus 23.7%; adjusted hazard ratio, 1.48 [95% CI, 1.15–1.91]). When patients with PCI were stratified according to the rSS, those with a rSS≤8 had no significant difference in all-cause death at 10 years as the other terciles (22.2% for rSS=0 versus 23.9% for rSS>0–4 versus 28.9% for rSS>4–8), whereas a rSS>8 had a significantly higher risk of 10-year all-cause death than those undergoing PCI with CR (50.1% versus 22.2%; adjusted hazard ratio, 3.40 [95% CI, 2.13–5.43]). Conclusions: IR is common after PCI, and the degree of incompleteness was associated with 10-year mortality. If it is unlikely that complete (or nearly complete; rSS<8) revascularization can be achieved with PCI in patients with 3-vessel disease, CABG should be considered. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00114972. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03417050.

Objectives We previously discovered that the single nucleotide polymorphisms (SNP) rs9940645 in the ZNF423 gene regulate ZNF423 expression and serve as a potential biomarker for response to selective estrogen receptor modulators (SERMs). Here we explored pathways involved in ZNF423-mediated SERMs response and drugs that potentially sensitize SERMs. Methods RNA sequencing and label-free quantitative proteomics were performed to identify genes and pathways that are regulated by ZNF423 and the ZNF423 SNP. Both cultured cells and mouse xenograft models with different ZNF423 SNP genotypes were used to study the cellular responses to metformin. Results We identified ribosome and AMP-activated protein kinase (AMPK) signaling as potential pathways regulated by ZNF423 or ZNF423 rs9940645 SNP. Moreover, using clustered regularly interspaced short palindromic repeats/Cas9-engineered ZR75-1 breast cancer cells with different ZNF423 SNP genotypes, striking differences in cellular responses to metformin, either alone or in the combination of tamoxifen, were observed in both cell culture and the mouse xenograft model. Conclusions We found that AMPK signaling is modulated by the ZNF423 rs9940645 SNP in estrogen and SERM-dependent fashion. The ZNF423 rs9940645 SNP affects metformin response in breast cancer and could be a potential biomarker for tailoring the metformin treatment.

ABSTRACT Introduction: The impact of albumin resuscitation on sepsis outcomes is debated, particularly in the initial phase of resuscitation. We aimed to investigate the association between albumin use in the initial 6 h of resuscitation and subsequent outcomes in adult septic patients. Methods: This single-center, retrospective, propensity score-matched cohort study included adult patients admitted to intensive care units (ICUs) with sepsis or septic shock from January 1, 2006, to May 4, 2018, at a tertiary referral hospital. We compared two groups based on albumin receipt within the initial six resuscitation hours (albumin group vs. non-albumin group). We performed a 1:2 propensity score matching to assess shock-free time in ICU as the primary outcome. Results: Of 2,732 patients with medical sepsis, 286 cases in the albumin group were matched with 549 individuals in the non-albumin group. Compared to the non-albumin group, the albumin group required more intravenous fluids and had higher net fluid balance, lower mean arterial pressure, and lower serum base excess level in the initial 6 and 24 h of resuscitation. Shock-free time, ICU and hospital length of stay, and 28-day mortality were not different between albumin and non-albumin groups (56 vs. 66 h, P = 0.18; 3.5 days vs. 3.7 days, P = 0.61; 9.1 days vs. 9.5 days, P = 0.27; 36% vs. 32%, P = 0.25, respectively). Conclusions: Using albumin during the initial 6 h of resuscitation was not associated with benefits in clinical outcomes of patients with medical sepsis.

Abstract Background Persistent organ failure (POF) is the strongest determinant of mortality in acute pancreatitis (AP). There is a paucity of data regarding the impact of different POF attributes on mortality and the role of different characteristics of systemic inflammatory response syndrome (SIRS) in the risk of developing POF. Objective We aimed to assess the association of POF dynamic features with mortality and SIRS characteristics with POF. Methods We studied 1544 AP subjects prospectively enrolled at 22 international centers (APPRENTICE consortium). First, we estimated the association of onset, duration, and maximal score of SIRS with POF. Then, we evaluated the risk of mortality based on POF onset, duration, number, type, and sequence of organs affected. Analyses were adjusted for potential confounders. Results 58% had SIRS, 11% developed POF, and 2.5% died. Early SIRS, persistent SIRS, and maximal SIRS score ≥ 3 were independently associated with higher risk of POF ( p < 0.05). Mortality risk in POF was higher with two (33%, odds ratio [OR] = 10.8, 3.3–34.9) and three (48%, OR = 20.2, 5.9–68.6) organs failing, in comparison to single POF (4%). In subjects with multiple POF, mortality was higher when the cardiovascular and respiratory systems failed first or concurrently as compared to when the renal system failed first or concurrently with other organ ( p < 0.05). In multivariate regression model, the number and sequence of organs affected in POF were associated with mortality ( p < 0.05). Onset and duration of POF had no impact mortality. Conclusion In AP patients with POF, the risk of mortality is influenced by the number, type, and sequence of organs affected. These results are useful for future revisions of AP severity classification systems.

Abstract Purpose To evaluate dosimetric properties of intensity‐modulated proton therapy (IMPT) for simulated treatment planning in patients with atrial fibrillation (AF) targeting left atrial‐pulmonary vein junction (LA‐PVJ), in comparison with volumetric‐modulated arc therapy (VMAT) and helical tomotherapy (TOMO). Methods Ten thoracic 4D‐CT scans with respiratory motion and one with cardiac motion were used for the study. Ten respiratory 4D‐CTs were planned with VMAT, TOMO, and IMPT for simulated AF. Targets at the LA‐PVJ were defined as wide‐area circumferential ablation line. A single fraction of 25 Gy was prescribed to all plans. The interplay effects from cardiac motion were evaluated based on the cardiac 4D‐CT scan. Dose‐volume histograms (DVHs) of the ITV and normal tissues were compared. Statistical analysis was evaluated via one‐way Repeated‐Measures ANOVA and Friedman’s test with Bonferroni’s multiple comparisons test. Results The median volume of ITV was 8.72cc. All plans had adequate target coverage (V 23.75Gy ≥ 99%). Compared with VMAT and TOMO, IMPT resulted in significantly lower dose of most normal tissues. For VMAT, TOMO, and IMPT plans, D mean of the whole heart was 5.52 ± 0.90 Gy, 5.89 ± 0.78 Gy, and 3.01 ± 0.57 Gy ( P < 0.001), mean dose of pericardium was 4.74 ± 0.76 Gy, 4.98 ± 0.62 Gy, and 2.59 ± 0.44 Gy ( P < 0.001), and D 0.03cc of left circumflex artery (LCX) was 13.96 ± 5.45 Gy, 14.34 ± 5.91 Gy, and 8.43 ± 7.24 Gy ( P < 0.001), respectively. However, no significant advantage for one technique over the others was observed when examining the D 0.03cc of esophagus and main bronchi. Conclusions IMPT targeting LA‐PVJ for patients with AF has high potential to reduce dose to surrounding tissues compared to VMAT or TOMO. Motion mitigation techniques are critical for a particle‐therapy approach.