Citations

5606 Background: The National Comprehensive Cancer Network (NCCN) recommends that patients with endometrial cancer under age 50 undergo germline genetic testing. Despite this recommendation, completion rates are suboptimal for patients with gynecologic malignancies. The reasons for failure to complete testing are unknown, but oncology providers may not refer patients to genetic counselors, who frequently order this testing. Best practice advisories (BPAs) in electronic medical records can alert providers of patients who meet guideline-based treatments and testing criteria. It is unknown how oncology providers interact with a BPA indicating patients with endometrial cancer meet NCCN germline testing criteria. The objective of this study is to evaluate genetic counseling referral patterns after implementing a BPA. Methods: Our team developed a BPA to prompt oncology providers to order genetic counseling referrals for patients diagnosed with endometrial or uterine cancer under age 50. We reviewed all provider-BPA interactions between go-live (January 2022) and January 2023. Patient demographic, histopathologic, and cancer treatment data were collected. Provider actions, including BPA cancellation and order placement, were collected. The Chi-Square goodness of fit test was used to identify differences in referral rates by patient or disease characteristics. Results: The BPA displayed 1121 times for 103 patients. Attending physicians received 535 alerts, fellow physicians – 269, and advanced practice providers (APPs) – 317. The median number of alerts per patient was 7 (range 1-87). Of the 103 patients, 23 were excluded from analysis due to no diagnosis of endometrial cancer, patient declined referral, previously completed, or a lack of provider visits within the study period. Of the 80 eligible patients, 36 (45%) received referrals; 18 were placed by attending physicians, 17 by fellows, and one by an APP. Patients under age 40 versus age 40-49 were more likely to be referred (65% vs. 35%; p = 0.011). Patients with active disease were more likely to be referred than those in surveillance (65% vs. 18%; p < 0.001). There were no differences in referral rates by primary language, race, body mass index ≥40, fertility-sparing versus definitive treatment, stage I versus stage II-IV disease, or grade 1-2 versus three tumors. Conclusions: Despite implementing a BPA, only 45% of eligible patients received indicated referrals. Attending and fellow physicians frequently manage patients with active disease and often order referrals; however, APPs frequently manage patients in surveillance and infrequently place referrals, highlighting an opportunity for education. In addition, patients aged 40-49 are less likely to be referred, suggesting a need for new strategies to improve referral rates. Further research is indicated to identify referral barriers for patients undergoing active treatment.

4146 Background: Currently, ICI therapy is recommended for patients with metastatic PDAC whose tumors exhibit dMMR, MSI-H, or high TMB (≥10 mutations/Mb). However, due to the low prevalence of high TMB in PDAC (~1%), few studies have evaluated the role of ICI therapy in this subpopulation. This study aimed to compare GA between PDAC patients with high TMB and low TMB ( < 10 mutations/Mb) and to evaluate the effectiveness of ICIs in real-world PDAC patients by TMB status. Methods: This study included PDAC patients who underwent genomic testing using Foundation Medicine tissue comprehensive genomic profiling (CGP) assays. GA were compared between tissue specimens with high and low TMB by chi-squared, adjusted for multiple comparisons. Patient clinical data was obtained by the US-wide de-identified Flatiron Health and Foundation Medicine real-world clinicogenomic pancreatic database (CGDB), originated from ~280 US cancer clinics between 01/2011 and 09/2022. Real-world overall survival (OS) and time to treatment discontinuation (TTD) were compared between patients receiving an ICI (high TMB versus low TMB) and between patients with high TMB (ICI versus other therapies) by Cox models. Results: We included 21,932 patients with PDAC with tissue CGP data available; 98.7% with low TMB and 1.3% with high TMB. Among actionable alterations, patients with high TMB had higher prevalence of mutations in BRCA2 (p < 0.0001), BRAF (p < 0.0001), PALB2 (p < 0.0001), and genes of the mismatch repair pathway ( MSH2, MSH6, MLH1, and PMS2, p < 0.0001), but lower prevalence of KRAS mutations (p < 0.0001). The most common KRAS mutation in both groups of patients was G12D. In CGDB, 51 patients received an ICI (10 with high TMB and 41 with low TMB) and 17 patients with high TMB received other therapies. Among patients receiving an ICI, those with high TMB had more favorable median OS compared to those with low TMB (25.7 versus 5.2 months, hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.09 - 0.76, p = 0.01) and median TTD (20.7 versus 3.0 months, HR 0.33, 95% CI 0.13 - 0.82, p = 0.02). Among patients with high TMB, those receiving an ICI had more favorable OS compared to those receiving other therapies (25.7 versus 6.6 months, HR 0.31, 95% CI 0.10-0.96, p = 0.043), nominally favoring ICI use in this small cohort (n = 10 versus 17). Conclusions: There is no randomized clinical trial evaluating ICI versus other therapies in PDAC. To our knowledge, this is the largest cohort to date comparing ICI effectiveness in PDAC. We observed more favorable OS among PDAC patients with high TMB receiving ICI versus those with low TMB who received an ICI and more favorable to those with high TMB receiving other therapies. This study supports the FDA-approved use of ICIs in patients with PDAC and high TMB and demonstrates the importance of TMB assessment for patients with PDAC.

e15131 Background: Elimusertib is a highly selective oral inhibitor of the Ataxia telangiectasia and Rad3 related (ATR) kinase, which is required for efficient end-joining repair of double-stranded breaks, particularly during DNA replication. Many pediatric cancers involve potential ATR susceptibilities such as increased replication stress due to oncogenic fusions, specific DNA damage repair (DDR) deficiencies, oncogenic activation of DNA damage and nucleases such as PGBD5, as well as alternative lengthening of telomeres. We report the initial phase 1 results of PEPN2112 (NCT05071209), an ongoing pediatric phase 1/2 clinical trial of elimusertib monotherapy. Methods: Eligible patients (pts) included children, adolescents, and young adults with relapsed or refractory tumors with: (1) Ewing sarcoma or related EWSR1 fusion positive tumors (EWS), (2) alveolar rhabdomyosarcoma, PAX3-FOXO1 fusion positive (aRMS), or (3) non-CNS primary tumors exhibiting specific DDR pathway defects anticipated to sensitize to ATR inhibition. For pts < 18 years (yrs), a rolling-six design was used to evaluate elimusertib administered BID x3 days/week of a 28-day cycle starting at the adult equivalent recommended phase 2 dose (RP2D) of 24 mg/m2/dose (max 40 mg) with a potential de-escalation to 18 mg/m2/dose (max 30 mg). The pediatric RP2D determination was based upon dose limiting toxicity (DLT) criteria (CTCAEv5) during cycle 1. Pharmacokinetic (PK) studies were performed. Pts > 18 yrs could enroll onto the phase 2 cohorts at the adult RP2D simultaneously with the pediatric phase 1. Once the pediatric RP2D was defined, pts < 18 yrs accrued to the phase 2 cohorts and a PK expansion for pts < 12 yrs was opened. Results: 8 eligible pts were enrolled (4 males) on the phase 1 part of the study. 2 pts were inevaluable for DLT as they received < 75% of protocol therapy. Median (range) age was 13 (10-17) yrs. Diagnoses included: EWS (n = 4) and 1 pt each with aRMS, adrenocortical carcinoma, clear cell sarcoma, and osteosarcoma. At 24 mg/m2/dose, no DLTs were observed. Toxicities were hematologic, with grade 3 toxicities including anemia (n = 3), neutropenia (n = 4), and decreased white blood cells (n = 1). One pt experienced grade 4 lymphopenia. There were no grade 3/4 non-hematologic toxicities. Day 1 mean ± SD values of Tmax, Cmax, AUC0-8h and t1/2 were 1.6 ± 0.5 h, 1532 ± 385 ng/mL, 5863 ± 1841 h*ng/mL and 3.6 ± 0.9 h, respectively. Conclusions: Elimusertib-related toxicities were primarily hematologic. The RP2D for elimusertib monotherapy in pediatric pts is 24 mg/m2/dose (max 40 mg) orally BID x3 days/week continuously, analogous to dosing in adults with similar PK. Phase 2 and PK expansion cohorts as well as pharmacodynamic studies are ongoing. Clinical trial information: NCT05071209 .

2616 Background: Non-small cell lung cancer (NSCLC) tissue is a valuable resource for diagnosis, treatment planning, and drug development. Current 2D histopathological techniques introduce under-sampling error (i.e., a single 5 µm section represents 0.5% of a 1 mm thick biopsy), interobserver variability, and failure to capture the biology contained within the entire tissue sample. We have developed a suite of technologies to stain, chemically clarify, image, visualize, and analyze entire, intact lung tissue samples. Herein, we present analysis methods for comprehensive 3D assessment of intact NSCLC tissue. Methods: Human NSCLC tissue, stored frozen in optimal cutting temperature (OCT) compound, was fixed in 4% paraformaldehyde, stained with nuclear (TOPRO-3) and general protein (Eosin) fluorescent dyes, and optically cleared using a modified iDISCO protocol with ethyl cinnamate as the refractive index matching solution. Twenty tissue samples measuring 1-5 mm3 in volume were imaged at 2 µm/pixel resolution with a hybrid open-top light-sheet microscope. Smaller regions of interest (ROIs) with interesting pathologic features were re-imaged at higher resolution, 0.17 µm/pixel. Visualization and analysis was performed using Aivia software, custom spatial analysis software and python scripts. Results: All NSCLC tissue samples were successfully imaged in 3D at both low and high resolution. Computational approaches, such as machine learning, were used to segment and classify tumor cells and lymphocytes within the high resolution ROIs. In one example we quantified a 0.0045 mm3 ROI containing 1x109 voxels. We segmented 1,474 unique objects, and classified 683 (46%) of the objects as lymphocytes and 309 (20%) of the cells as tumor cells. We found that on average the lymphocytes were within 12 µm of the nearest tumor cell. Additionally the tissue was broken into separate lymphocyte dense (58% of volume) and tumor dense regions (42% of volume). Further analysis is in progress to quantify more features, such as tertiary lymphoid structures, stromal cells, and fibrosis over the full 20 sample dataset. Conclusions: We successfully implemented 3D machine learning analysis pipelines using images from intact NSCLC tissue samples measuring up to 5 mm3. The imaging was performed using our custom hybrid open-top light-sheet microscope. This novel method enables us to identify and quantify key histological features such as tumor cells and lymphocytes within the tumor microenvironment. In addition, machine learning driven algorithms clustered cells into distinct tissue regions in 3D which enables a more precise assessment of disease state and heterogeneity. Further investigation is ongoing to link these results to patient outcomes.

TPS623 Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (<11, 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER &/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% vs 91.6% for the omission of RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1% per yr. Some of the T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. Current accrual (02-08-2023) is 370 screened and 323 randomized (~87% of predicted accrual). Clinical trial information: NCT04852887 .

Abstract Aims Left ventricular hypertrophy (LVH) is an established, independent predictor of cardiovascular disease. Indices derived from the electrocardiogram (ECG) have been used to infer the presence of LVH with limited sensitivity. This study aimed to classify LVH defined by cardiovascular magnetic resonance (CMR) imaging using the 12-lead ECG for cost-effective patient stratification. Methods and results We extracted ECG biomarkers with a known physiological association with LVH from the 12-lead ECG of 37 534 participants in the UK Biobank imaging study. Classification models integrating ECG biomarkers and clinical variables were built using logistic regression, support vector machine (SVM) and random forest (RF). The dataset was split into 80% training and 20% test sets for performance evaluation. Ten-fold cross validation was applied with further validation testing performed by separating data based on UK Biobank imaging centres. QRS amplitude and blood pressure (P &lt; 0.001) were the features most strongly associated with LVH. Classification with logistic regression had an accuracy of 81% [sensitivity 70%, specificity 81%, Area under the receiver operator curve (AUC) 0.86], SVM 81% accuracy (sensitivity 72%, specificity 81%, AUC 0.85) and RF 72% accuracy (sensitivity 74%, specificity 72%, AUC 0.83). ECG biomarkers enhanced model performance of all classifiers, compared to using clinical variables alone. Validation testing by UK Biobank imaging centres demonstrated robustness of our models. Conclusion A combination of ECG biomarkers and clinical variables were able to predict LVH defined by CMR. Our findings provide support for the ECG as an inexpensive screening tool to risk stratify patients with LVH as a prelude to advanced imaging.

Renal diseases pose a significant socio‐economic burden on healthcare systems. The development of better diagnostics and prognostics is well‐recognized as a key strategy to resolve these challenges. Central to these developments are MRI biomarkers, due to their potential for monitoring of early pathophysiological changes, renal disease progression or treatment effects. The surge in renal MRI involves major cross‐domain initiatives, large clinical studies, and educational programs. In parallel with these translational efforts, the need for greater (patho)physiological specificity remains, to enable engagement with clinical nephrologists and increase the associated health impact. The ISMRM 2022 Member Initiated Symposium (MIS) on renal MRI spotlighted this issue with the goal of inspiring more solutions from the ISMRM community. This work is a summary of the MIS presentations devoted to: 1) educating imaging scientists and clinicians on renal (patho)physiology and demands from clinical nephrologists, 2) elucidating the connection of MRI parameters with renal physiology, 3) presenting the current state of leading MR surrogates in assessing renal structure and functions as well as their next generation of innovation, and 4) describing the potential of these imaging markers for providing clinically meaningful renal characterization to guide or supplement clinical decision making. We hope to continue momentum of recent years and introduce new entrants to the development process, connecting (patho)physiology with (bio)physics, and conceiving new clinical applications. We envision this process to benefit from cross‐disciplinary collaboration and analogous efforts in other body organs, but also to maximally leverage the unique opportunities of renal physiology.Level of Evidence1Technical Efficacy Stage2

AbstractCardiac physiologic pacing (CPP), encompassing cardiac resynchronization therapy (CRT) and conduction system pacing (CSP), has emerged as a pacing therapy strategy that may mitigate or prevent the development of heart failure (HF) in patients with ventricular dyssynchrony or pacing‐induced cardiomyopathy. This clinical practice guideline is intended to provide guidance on indications for CRT for HF therapy and CPP in patients with pacemaker indications or HF, patient selection, pre‐procedure evaluation and preparation, implant procedure management, follow‐up evaluation and optimization of CPP response, and use in pediatric populations. Gaps in knowledge, pointing to new directions for future research, are also identified.

Abstract Background and Aims The FDA-approved multitarget stool-DNA [mt-sDNA] test is a successful colorectal cancer [CRC] screening tool in average-risk individuals but is not indicated for patients with inflammatory bowel disease [IBD]. We determined the performance of the mt-sDNA assay without the haemoglobin component [mt-sDNAHgb-] in patients with IBD, while measuring sensitivity for colorectal cancer and advanced colorectal neoplasia [ACRN]. Methods This was a multi-centre, proof-of-concept investigation in persons aged 18–84 years with a diagnosis of IBD, or primary sclerosing cholangitis [PSC] with IBD. Enrolment occurred between March 2013 and May 2016. Stool was tested with the mt-sDNA molecular markers only, minus the immunochemical haemoglobin component. Results The analysis set contained 355 samples. The median age was 52 [range 39–62] years, 45.6% were female and 93% were White. Two-thirds [63%] had ulcerative colitis [UC] and 10.1% had PSC/IBD. Colonoscopy revealed cancer in 8.5% [N = 30], advanced precancerous lesions [APLs] in 9.3% [N = 33] and non-advanced precancerous lesions in 7.6% [N = 27], and three-quarters [74.7%, N = 265] had negative findings. mt-sDNAHgb- sensitivity was 73.3% for any stage cancers, and 76.2% for ACRN. Sensitivity was highest for IBD-associated high-grade dysplasia at 100% and 84.6% for IBD-associated low-grade dysplasia ≥1 cm. The test showed higher sensitivity and lower specificity in UC than in Crohn’s disease. Increasing inflammation score was associated with a significant decrease in mt-sDNAHgb- test score [ = 0.028] amongst neoplasia-negative individuals, but not in patients with ACRN. Conclusions These data highlight the potential of multitarget stool-DNA marker testing as an important addition to colorectal cancer surveillance by complementing colonoscopic evaluations in IBD patients.