Citations

Anticipating and understanding cancers’ need for specific gene activities is key for novel therapeutic development. Here we utilized DepMap, a cancer gene dependency screen, to demonstrate that machine learning combined with network biology can produce robust algorithms that both predict what genes a cancer is dependent on and what network features coordinate such gene dependencies. Using network topology and biological annotations, we constructed four groups of novel engineered machine learning features that produced high accuracies when predicting binary gene dependencies. We found that in all examined cancer types, F1 scores were greater than 0.90, and model accuracy remained robust under multiple hyperparameter tests. We then deconstructed these models to identify tumor type-specific coordinators of gene dependency and identified that in certain cancers, such as thyroid and kidney, tumors’ dependencies are highly predicted by gene connectivity. In contrast, other histologies relied on pathway-based features such as lung, where gene dependencies were highly predictive by associations with cell death pathway genes. In sum, we show that biologically informed network features can be a valuable and robust addition to predictive pharmacology models while simultaneously providing mechanistic insights.

Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) present a major health burden to society. Changes in brain structure and cognition are generally only observed at the late stage of the disease. Although advanced magnetic resonance imaging (MRI) techniques such as diffusion imaging may allow identification of biomarkers at earlier stages of neurodegeneration, early diagnosis is still challenging. Magnetic resonance elastography (MRE) is a noninvasive MRI technique for studying the mechanical properties of tissues by measuring the wave propagation induced in the tissues using a purpose‐built actuator. Here, we present a systematic review of preclinical and clinical studies in which MRE has been applied to study neurodegenerative diseases. Actuator systems for data acquisition, inversion algorithms for data analysis, and sample demographics are described and tissue stiffness measures obtained for the whole brain and internal structures are summarized. A total of six animal studies and eight human studies have been published. The animal studies refer to 123 experimental animals (68 AD and 55 PD) and 121 wild‐type animals, while the human studies refer to 142 patients with neurodegenerative disease (including 56 AD and 17 PD) and 166 controls. The animal studies are consistent in the reporting of decreased stiffness of the hippocampal region in AD mice. However, in terms of disease progression, although consistent decreases in either storage modulus or shear modulus magnitude are reported for whole brain, there is variation in the results reported for the hippocampal region. The clinical studies are consistent in reports of a significant decrease in either whole brain storage modulus or shear modulus magnitude, in both AD and PD and with different brain structures affected in different neurodegenerative diseases. MRE studies of neurodegenerative diseases are still in their infancy, and in future it will be interesting to investigate potential relationships between brain mechanical properties and clinical measures, which may help elucidate the mechanisms underlying onset and progression of neurodegenerative diseases.Evidence Level1.Technical EfficacyStage 2.

Abstract Objective To assess cardiovascular (CV) safety of erenumab in clinical trial patients associated with degree of CV risk. Background Hypertension has been considered a theoretical risk associated with the inhibition of the calcitonin gene‐related peptide pathway in migraine management, particularly in a patient population with pre‐existing CV risk factors. Methods Data pooled from four double‐blind, randomized trials were used to assess blood pressure (BP) changes and CV safety in patients grouped based on 10‐year risk of cardiac, cerebrovascular, and peripheral artery disease as no‐risk‐factors, low‐risk (>0% to ≤10%), moderate‐risk (>10% to ≤20%), and high‐risk (>20%) categories. CV safety was assessed as ischemic cardiovascular and cerebrovascular adverse events (ICCAE). Results There was no apparent difference between placebo‐ ( N = 1032) and erenumab‐treatment groups (70 mg, N = 885; 140 mg, N = 504) in clinical worsening of BP category from baseline to Months 1–3 (14% [143/1032] placebo vs. 13% [114/885] and 14% [71/504] for erenumab 70 and 140 mg, respectively) regardless of baseline BP category. The adverse event (AE) profile of erenumab was similar across CV risk categories throughout the long‐term analysis. Erenumab‐treated patients with high and moderate 10‐year CV risk ( N = 107) did not experience any ICCAEs during the double‐blind treatment period; there was a single ICCAE (a cerebral dural venous sinus thrombosis) observed in the low‐risk erenumab group ( N = 273). There were no increases in AEs during the long‐term extensions of up to 5 years ( N = 2499; 3482 patient‐years of exposure to erenumab) with exposure‐adjusted incidence rates of cardio/cerebrovascular disorder AEs of 0.4, 0.5, 0.0, and 1.1 (per 100 patient‐years) for no risk factor ( N = 1805), low ( N = 492), moderate ( N = 121), and high ( N = 81) 10‐year CV risk groups, respectively. Conclusions Ischemic CV and cerebrovascular AEs were uncommon and the incidence rates were similar across the 10‐year CV risk categories. This analysis helps provide more detail on the CV safety of erenumab.

Abstract Background The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. Methods We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. Results We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. Conclusions Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

TPS283 Background: There is no clear standard of care for biochemically recurrent prostate cancer (PCa) with positron emission tomography (PET)-detected oligometastases and normal conventional imaging (CIM). Phase II trials show that stereotactic ablative body radiotherapy (SABR) to oligometastases may delay cancer progression and initiation of androgen deprivation therapy (ADT) and its untoward effects. ADT with radiation prolongs survival in locally advanced PCa and in CIM metastatic PCa. However, there is a knowledge gap about timing and benefit vs toxicity of ADT with SABR in early oligometastatic PCa. NRG GU011 (PROMETHEAN) is a randomized phase II trial of SABR with or without relugolix for early PET-detected recurrent oligometastatic PCa. This study aims to evaluate the impact of relugolix, a novel oral gonadotropin-releasing hormone receptor antagonist, when combined with SABR to oligometastases. Relugolix allows for rapid testosterone recovery and is associated with fewer cardiovascular events when compared to leuprolide and is hypothesized to have low late ADT toxicity. GU011 will provide patients and their physicians data on the relative risks and benefits of early or delayed ADT in this setting. Methods: NRG-GU011 NCT# 05053152 is a randomized phase II double-blinded, placebo-controlled trial with randomization to SABR + 6 months placebo vs SABR + 6 months relugolix. Eligible patients have biochemical recurrence after prior curative intent radiation or surgery for localized PCa, PSA < 10 ng/mL, negative CIM and 1-5 PET-evident metastases (≥1 extrapelvic). SABR is delivered in 1-5 fractions to BED >100 Gy1.5, followed by placebo or relugolix 120mg daily for 6 months. Patients will then be followed with imaging at time of biochemical recurrence. The planned sample size of 260 patients (130 per arm) will provide 85% power to detect a hazard ratio of 0.65 for radiographic progression-free survival (rPFS), based on a one-sided test at alpha 0.10. Planned enrollment is predicted at 8 patients per month with an estimated study completion date of late 2026. The primary endpoint is CIM rPFS. Secondary endpoints include PET-based rPFS, sexual and hormonal quality of life (QoL) assessed by EPIC-26, other QoL measures from EQ5D-5L, EORTC QLQ-30 and PROMIS Fatigue, and between-group comparisons of time to salvage therapy, castration-resistance, local progression (SABR-targeted lesion), biochemical progression, distant metastases, prostate cancer-specific mortality, metastasis-free survival, and overall survival. We also aim to determine adverse event rates for both treatment arms and evaluate genomic and blood markers of treatment response. This study opened in December 2021. Clinical trial information: NCT05053152 .

199 Background: Contained within the spectrum of metastatic cancer is an oligometastatic state where metastases are limited in number. Recent prospective data have shown that metastasis directed therapy (MDT) can alter the natural history of oligometastatic disease. In hormone-sensitive prostate cancer (HSPC), the positive clinical effect of MDT has been observed by the phase II STOMP and ORIOLE trials. Circulating tumor cells (CTCs) are a likely origin of the formation of macroscopic metastases. CTCs thus may provide an approach for identifying subgroups of patients with oligometastatic HSPC (oligoHSPC) that would benefit most from MDT. Our main goal was to evaluate the association between presence of CTCs at baseline or day 180 with clinical outcomes in the ORIOLE trial. Methods: ORIOLE was a phase II trial randomizing men with recurrent oligoHSPC with 1-3 metastases to observation (Obs) versus stereotactic ablative radiotherapy (SABR) MDT. Blood samples were prospectively collected at baseline and day 180. Progression-free survival (PFS) was a composite endpoint including any of the following: a PSA rise of at least 2 ng/dL and 25% above nadir; radiologic progression by CT, MRI or bone scan (RECIST v1.1); symptomatic progression of disease; initiation of ADT; or death. Patient blood samples were shipped for analysis on Epic Sciences liquid biopsy platform (Epic Sciences, San Diego, CA). Machine learning algorithms identified CTCs and characterized androgen receptor (AR) expression. Comparisons of patient and tumor characteristics between the groups were performed by two-sample t-tests. Survival curves were generated using the Kaplan-Meier method and p-values were calculated using log-rank test. Analysis was performed using SPSS version 28. Results: A total of 82 samples were collected: 70 from the SABR arm (35 baseline and 35 on day 180) and 12 Obs (7 baseline and 5 on day 180). CTCs were detected in 30/42 samples at baseline (71%, AR+= 7) and in 26/40 samples on day 180 (65%, AR+= 9). In the SABR group there was no difference between CTC+ versus CTC- and AR + versus AR- groups for PSA evaluated at baseline, day 90 or day 180 or Gleason score. With a median follow-up of 41.7 months, PFS was significantly lower in the patients with AR+ versus AR- CTCs at baseline in the SABR arm (p = 0.011, mean PFS: AR+ = 9.3 months, AR- = 27.1 months). The mean biochemical failure-free survival was AR+= 12.9 versus AR-= 29.2 months (p = 0.058). Conclusions: Our preliminary results demonstrate an association between AR+ CTCs at baseline and Day 180 with clinical outcomes following SABR MDT in oligoHSPC. This is the first report examining baseline and dynamic presence of CTCs in oligoHSPC treated from a prospective randomized trial of SABR. Longer follow-up, further analysis and a greater number of patients are needed for a more comprehensive conclusion.

Total kidney volume (TKV) is a valuable readout in preclinical studies for autosomal dominant and autosomal recessive polycystic kidney diseases (ADPKD and ARPKD). Since conventional TKV assessment by manual contouring of kidney areas in all images is time-consuming, we developed a template-based semiautomatic image segmentation method (SAM) and validated it in three commonly used ADPKD and ARPKD models. SAM-based TKV measurements were fast, highly reproducible, and accurate across mouse and rat ARPKD and ADPKD models.

Abstract Background Venous thromboembolism (VTE) in pregnancy is a major cause of maternal morbidity and death. The use of low-molecular-weight heparin (LMWH), despite being the standard of care to prevent VTE, comes with some challenges. Shared decision-making (SDM) interventions are recommended to support patients and clinicians in making preference-sensitive decisions. The quality of the SDM process has been widely assessed with the decisional conflict scale (DCS). Our aim is to report participants’ perspectives of each of the components of an SDM intervention (DASH-TOP) in relation to the different subscales of the DCS. Methods Design: A convergent, parallel, mixed-methods design. Participants: The sample consisted of 22 health care professionals, students of an Applied Clinical Research in Health Sciences (ICACS) master program. Intervention: We randomly divided the participants in three groups: Group 1 received one component (evidence -based information), Group 2 received two components (first component and value elicitation exercises), and Group 3 received all three components (the first two and a decision analysis recommendation) of the SDM intervention. Analysis: For the quantitative strand, we used a non-parametric test to analyze the differences in the DCS subscales between the three groups. For the qualitative strand, we conducted a content analysis using the decisional conflict domains to deductively categorize the responses. Results Groups that received more intervention components experienced less conflict and better decision-making quality, although the differences between groups were not statistically significant. The decision analysis recommendation improved the efficacy with the decision-making process, however there are some challenges when implementing it in clinical practice. The uncertainty subscale showed a high decisional conflict for all three groups; contributing factors included low certainty of the evidence-based information provided and a perceived small effect of the drug to reduce the risk of a VTE event. Conclusions The DASH-TOP intervention reduced decisional conflict in the decision -making process, with decision analysis being the most effective component to improve the quality of the decision. There is a need for more implementation research to improve the delivery of SDM interventions in the clinical encounter.

198 Background: HER2 overexpression/amplification (HER2+) occurs in 3%-5% of patients (pts) w/ metastatic colorectal cancer (mCRC). Rates of HER2+ can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. The MOUNTAINEER trial (NCT03043313) evaluated the efficacy and safety of the investigational combination of tucatinib with trastuzumab in pts with HER2+ and RAS wild-type mCRC. Established regional guidelines for mCRC recommend HER2 testing and HER2-directed treatment options; however, there is currently no established best practice for HER2 testing and interpretation in mCRC. Here, we present data from a concordance analysis comparing breast and gastric HER2 testing algorithms in the mCRC setting. Methods: The MOUNTAINEER trial enrolled pts w/ HER2+ mCRC identified using ≥1 method: tissue-based local immunohistochemistry (IHC), in situ hybridization (ISH), and/or next-generation sequencing (NGS) testing. Archival or fresh tumor tissue was submitted to a sponsor-designated central laboratory for confirmatory HER2 testing w/ IHC/FISH per the package insert of the FDA approved assay and scored by both the breast and gastric algorithms for HER2 IHC. A positive result per the breast scoring criteria for IHC requires circumferential membrane staining for HER2, while the gastric criteria allows for circumferential, basolateral, or lateral staining patterns. Results: A total of 114 pts were enrolled with HER2+ tumors per ≥1 local testing methods; 69 pts were HER2+ by NGS, 46 by IHC 3+, and 36 by ISH. Of 105 pts who had tissue available for central HER2 testing w/IHC/FISH, 98 had valid HER2 results; 82/98 (83.7%) of pts had tumors centrally confirmed as HER2+ using both the breast and gastric algorithms. Tissue samples from pts in the MOUNTAINEER trial had 100% concordance between breast and gastric algorithms in HER2 status and 99% concordance in HER2 IHC score. Conclusions: Central pathology testing using both the breast and gastric criteria showed high concordance between these two commonly used algorithms. A high central confirmation rate of local HER2+ results was also observed. These data support the use of either the breast or gastric algorithms to identify HER2+ mCRC tumors until an FDA-approved HER2 assay is available for mCRC. Clinical trial information: NCT03043313 . [Table: see text]