Citations

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Background: Physical inactivity and poor adherence to healthy eating guidelines impact cardiovascular health (CVH) outcomes in African American (AAs). Our randomized controlled trial (RCT) testing the FAITH! App, an mHealth lifestyle intervention, showed efficacy in promoting ideal CVH, particularly diet and physical activity (PA) among AAs, warranting exploration of underlying factors. Psychosocial factors (e.g., self-regulation, self-efficacy, social support) are key to healthy behavior adoption. Hypothesis: The intervention group would have greater improvements in diet and PA-related psychosocial factors than the control group after using the FAITH! App. Methods: A 2-arm cluster RCT was conducted among AAs from 16 churches in Minnesota comparing the FAITH! App intervention to a delayed intervention control group. The FAITH! App included culturally relevant, CVH-focused education modules, diet/PA self-monitoring and a sharing board. The outcomes were change in diet and PA self-regulation and self-efficacy (primary) and social support and barriers (secondary) at 6 months post-intervention. The intervention effect was assessed using linear regression. Results: Sixty-eight participants were included (71% female; mean age [SD]: 54.7 [12.6] years) ( Table 1 ). The intervention group showed a significantly greater increase in diet self-regulation [planning/tracking nutrition] (+0.66, p<.03) and PA self-regulation [step count strategies] (+0.47, p=.003) than the control group. Within groups, the intervention group demonstrated significant improvements across diet and PA self-regulation measures, while the control group showed an improvement only in fruit/vegetable and grain intake. No effect was observed in self-efficacy, social support, or barriers. Conclusions: Our culturally tailored mHealth lifestyle intervention was associated with notable increases in diet and PA self-regulation, suggesting a potential mechanism by which the FAITH! App improves healthy eating and PA among AAs.

Introduction/Objectives: Despite U.S. Preventive Services Task Force and American Cancer Society endorsement of primary HPV screening, limited published data shows low uptake. Primary Aim: Assess cervical cancer screening rates over time, particularly primary HPV test uptake, among patients in a midwestern practice. Secondary Aim: Evaluate associations between sociodemographics and screening adherence. Methods: Cross-sectional study. Qualifying subjects and type of screening test used were identified by applying ICD-9, ICD-10, lab test, and CPT codes to the Unified Data Platform. Sociodemographics were found through the electronic health record. Results: Primary HPV uptake represented <1% of annual screening from 1/2017 to 1/2022. On 1/1/2022, only 55% of 21 to 29 year old and 63% of 30 to 65 year old were up to date with screening among the studied population. For 21 to 29 year old, compared with White women, Black women were 28% less likely to be screened [RR = 0.72 (0.66-0.79)]. Compared with never-smokers, current smokers were 9% less likely to be screened [RR = 0.91 (0.87-0.96)], past smokers were 14% more likely [RR = 1.14 (1.09-1.2)]. Among 30 to 65 year old, compared with White women, Black women were 14% less likely to be screened [RR = 0.86 (0.81-0.9)]. Compared with never-smokers, current smokers were 21% less likely to be screened [RR = 0.79 (0.77-0.81)], past smokers were 6% less likely [RR = 0.94 (0.92-0.95)]. Jointly considering race, ethnicity, smoking status, Charlson score, and rurality, findings were similar for 21 to 29 year old; Black women were screened less than White women [RR = 0.73 (0.67-0.79)]; current smokers [RR = 0.9 (0.85-0.94)] and past smokers [RR = 1.12 (1.06-1.17)] were screened less than never smokers. For 30 to 65 year old, Black women were screened less than White women [RR = 0.83 (0.79-0.88)]; current smokers [RR = 0.8 (0.78-0.81)] and past smokers [RR = 0.95 (0.93-0.96)] were screened less than never smokers. Conclusions: Screening rates remained below the Healthy People 2030 goal of 79.2% over time, particularly for younger Black women and current smokers, with minimal use of primary HPV screening.

Abstract Deep learning may detect biologically important signals embedded in tumor morphologic features that confer distinct prognoses. Tumor morphologic features were quantified to enhance patient risk stratification within DNA mismatch repair (MMR) groups using deep learning. Using a quantitative segmentation algorithm (QuantCRC) that identifies 15 distinct morphologic features, we analyzed 402 resected stage III colon carcinomas [191 deficient (d)-MMR; 189 proficient (p)-MMR] from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy. Results were validated in an independent cohort (176 d-MMR; 1,094 p-MMR). Association of morphologic features with clinicopathologic variables, MMR, KRAS, BRAFV600E, and time-to-recurrence (TTR) was determined. Multivariable Cox proportional hazards models were developed to predict TTR. Tumor morphologic features differed significantly by MMR status. Cancers with p-MMR had more immature desmoplastic stroma. Tumors with d-MMR had increased inflammatory stroma, epithelial tumor-infiltrating lymphocytes (TIL), high-grade histology, mucin, and signet ring cells. Stromal subtype did not differ by BRAFV600E or KRAS status. In p-MMR tumors, multivariable analysis identified tumor-stroma ratio (TSR) as the strongest feature associated with TTR [HRadj 2.02; 95% confidence interval (CI), 1.14–3.57; P = 0.018; 3-year recurrence: 40.2% vs. 20.4%; Q1 vs. Q2–4]. Among d-MMR tumors, extent of inflammatory stroma (continuous HRadj 0.98; 95% CI, 0.96–0.99; P = 0.028; 3-year recurrence: 13.3% vs. 33.4%, Q4 vs. Q1) and N stage were the most robust prognostically. Association of TSR with TTR was independently validated. In conclusion, QuantCRC can quantify morphologic differences within MMR groups in routine tumor sections to determine their relative contributions to patient prognosis, and may elucidate relevant pathophysiologic mechanisms driving prognosis. Significance: A deep learning algorithm can quantify tumor morphologic features that may reflect underlying mechanisms driving prognosis within MMR groups. TSR was the most robust morphologic feature associated with TTR in p-MMR colon cancers. Extent of inflammatory stroma and N stage were the strongest prognostic features in d-MMR tumors. TIL density was not independently prognostic in either MMR group.

Abstract Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor, either at presentation or at recurrence. To date, most published cases lack molecular characterization. We describe the histologic and molecular features of 3 patients presenting with BRAF p. V600E-mutant GG (CNS WHO grade 1) with high-grade glial transformation at recurrence. The tumors occurred in pediatric patients (age 9–16 years) with time to recurrence from 20 months to 7 years. At presentation, each tumor was low-grade, with a BRAFV600E-positive ganglion cell component and a glial component resembling pleomorphic xanthoastrocytoma (PXA) or fibrillary astrocytoma. At recurrence, tumors resembled anaplastic PXA or high-grade astrocytomas without neuronal differentiation. CDKN2A homozygous deletion (HD) was absent in all primary tumors. At recurrence, 2 cases acquired CDKN2A HD; the third case showed loss of p16 and MTAP immunoexpression, but no CDKN2A/B HD or mutation was identified. By DNA methylation profiling, all primary and recurrent tumors either grouped or definitely matched to different methylation classes. Our findings indicate that malignant progression of the glial component can occur in GG and suggest that CDKN2A/B inactivation plays a significant role in this process.

Abstract Introduction: LAS is a selective estrogen receptor modulator (SERM)/tissue-selective estrogen agonist/antagonist studied in women with osteoporosis and vulvar-vaginal atrophy, and most recently, metastatic breast cancer (mBC) with ESR1 mutations. LAS data in healthy postmenopausal women and young men show linear PK and no differences by age or race (Gardner. J Clin Pharmacol 2006;46:52-58; Prakash. Drug Metab Dispos 2008;26:1218-26; Data on file). Also, no PK differences were found between Caucasian and Japanese patients (Jhee. AACR-JCA 2022, abstract A83; Fountaine. J Clin Pharmacol 2006;46:693-99). Here we report select PK data of LAS (5 mg/day) from women with mBC in the ELAINE 1 and ELAINE 2 oncology trials to indirectly investigate possible drug-drug interactions between LAS and Abema. Methods: Patients with mBC and ESR1 mutations who progressed on endocrine therapy and CDK4/6 inhibitors received LAS 5 mg/day as monotherapy (ELAINE 1) or combined with Abema (provided by Eli Lilly and Co) 150 mg BID (ELAINE 2). Blood was collected prior to daily dosing at weeks 2, 4, 8, and every 4 weeks up to the final visit in ELAINE 1, and visits during the first 8 weeks in ELAINE 2, to determine the plasma trough steady-state concentrations (Css) of LAS, Abema, and two active Abema metabolites (M2 and M20). LAS was assayed using validated high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS; detection 0.025 to 25.0 ng/mL); levels below the lower limit of quantification (LLOQ) were reported as 0 ng/mL. Abema and its M2 and M20 metabolites were measured by validated Turbo Ion Spray LC/MS/MS (detection 1.00 to 500 ng/mL); values below the LLOQ were reported as &lt; LLOQ ng/mL. Mean trough Css at each visit were calculated for LAS (ELAINE 1 and 2), and Abema and its M2 and M20 metabolites (ELAINE 2). LAS levels from ELAINE 1 and 2 were compared, while Abema, M2 and M20 plasma levels in ELAINE 2 were compared with previously reported levels. Such indirect comparisons may help determine if Abema altered the metabolism of LAS, or if LAS altered that of Abema, M2, or M20. The relationships of LAS and Abema levels with progression-free survival (PFS) were also explored. Results: Across all time points for subjects who had PK samples assessed, the LAS mean trough Css was 33.6 ng/mL (CV%, 39.8) in ELAINE 1 (n=40) and 30.9 ng/mL (CV 50.5%) in ELAINE 2 (n=29); in both studies, LAS concentrations were consistent across visits. LAS levels in ELAINE 2 were similar to those in ELAINE 1 with no evidence of accumulation. Mean (CV%) Abema plasma concentrations at weeks 2, 4, 6 and 8 were 199 (102%), 107 (130%), 82 (271%), and 94.3 (223%) ng/mL, respectively. Minimum and maximums of the mean trough Css for LAS, Abema, M2, and M20 are shown in Table 1. No relationships between LAS or Abema levels and antitumor activity measured by PFS were seen (data to be presented). Conclusion: The steady-state PK of 5 mg LAS in the ELAINE 1 and 2 studies suggest that the addition of abemaciclib to LAS did not result in an obvious or significant LAS-Abema, drug-drug interaction. Abema PK data from ELAINE 2 were consistent with published data (European Medicines Agency, Verzenio). These results support the continued development of LAS alone and combined with Abema for treating ER+/HER2-, ESR1-mutated mBC that progressed on endocrine therapy and CDK4/6 inhibitors. Table. Mean trough, steady-state concentrations of lasofoxifene and abemaciclib. XX- XX aData from patients who received oral LAS (5 mg/day) plus Abema (150 mg BID). Abema, abemaciclib; LAS, lasofoxifene; M2 and M20 are Abema metabolites. Citation Format: Senthil Damodaran, Paul V. Plourde, Simon Jenkins, Phil Mayer, David J Portman, Matthew Goetz. Pharmacokinetics (PK) of lasofoxifene (LAS) monotherapy and combined with abemaciclib (Abema) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-05.

AbstractSurvivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer ‐ metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population‐based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow‐up time of 12 years (incidence: 2.0 per 1000 person‐years). CRC cases with a synchronous CRC were 3.4‐fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89–5.98) than those without a synchronous tumour. CRC cases with MMR‐deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11–2.64) compared to those with MMR‐proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06–0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR‐deficient.

Background: Aortic Valve Calcification (AVC) is intrinsic to aortic stenosis (AS). While established concepts assume homogeneous calcification causing AS, wide variability in hemodynamic severity at any given AVC burden suggests other operative mechanisms. Multidetector computed tomography (MDCT) now accurately measures global AVC, but AVC spatial distribution remains elusive due to imaging orientation. Methods and Results: We developed ‘en-face’ imaging by re-registration of 4D-MDCT to quantify AVC spatial distribution and analyzed global AVC load and AVC distribution in 418 patients with AS (76±9 years; mean gradient 35±17 mmHg). 4D-volume-rendered MDCT datasets were re-oriented to en-face view of aortic valve for AVC spatial scoring with individual cusp calcification load, cusp-edge calcification and AVC asymmetry. Despite high total AVC load (450 [250-666] AU/cm 2 ), asymmetry was frequent (50%), with a difference between most- and least-calcified cusp of 112 [66-182] AU/cm 2 . Maximum AVC was in the non-coronary cusp in 61% (p<0.001). Cusp edge calcification was none-mild in 26%, moderate in 62% and severe in 12%. Adjusting for total AVC, severe AS (mean gradient >40 mmHg) was more likely with symmetrical AVC (odds ratio [OR] 2.36, p<0.001) and with edge calcification moderate (OR 4.16, p=0.001 vs none-mild) to severe (OR 10.7, p=0.001). Inclusion of AVC distribution improved models predicting AS severity over total AVC (p<0.001). Conclusions: Four-dimensional MDCT en-face re-registration and AVC quantitation provides new insight into AS pathophysiology. Contrary to classical concepts, AVC is frequently inhomogeneous and asymmetric. Hemodynamic AS severity is independently affected not only by global AVC but also by variations in AVC distribution and location within cusps, emphasizing the importance of 4D AVC assessment in AS. Impact of quantified AVC asymmetry and location on outcome of transcutaneous aortic valve replacement should be evaluated.

Introduction: Soluble ST2 (sST2) is a serum marker of cardiomyocyte stress associated with a large risk of death and heart failure after myocardial infarction (MI). The relationship between sST2 and cardiac structure and function after MI however remains incompletely defined, and greater characterization is required prior to clinical application. Methods: Olmsted County, Minnesota residents who experienced their first MI between 2007 and 2012 were prospectively recruited. MIs were validated using standardized criteria and patients underwent simultaneous comprehensive Doppler echocardiography and sST2 measurement. The association between cardiac morphology and hemodynamics and sST2 were examined. Published normal values were used as referent ranges for sST2 levels. Results: Among 316 patients (mean age 65 [SD 14] years, 67% men, 32% ST-elevation MI), sST2 was measured 2.5 [SD 1.6] days after MI and within 0.7 [SD 2.3] days of echocardiography. Soluble ST2 was elevated in 33% of patients and univariately associated with decreased LV ejection fraction (LVEF), increased LV mass, impaired LV diastolic function and increased pulmonary artery pressure (ePAP) (Table). After adjustment for age, sex, LVEF and key measures of LV filling pressures, elevated sST2 was independently associated with reduced LVEF (p=0.01) mitral valve deceleration time (p=0.03), greater left atrial volume (p=0.03) and mitral regurgitation (≥mild; p=0.09). LVEF and ePAP exhibited the strongest associations with elevated sST2 (both p<0.001). Conclusions: Soluble ST2 is frequently elevated following MI and is strongly associated with the morphologic and hemodynamic determinants of adverse LV remodeling that infer poor long-term outcome after MI.