Citations

PURPOSE Identification of those at risk of hereditary cancer syndromes using electronic health record (EHR) data sources is important for clinical care, quality improvement, and research. We describe diagnostic processes, previously seldom reported, for a common hereditary cancer syndrome, Lynch syndrome (LS), using EHR data within a community-based, multicenter, demographically diverse health system. METHODS Within a retrospective cohort enrolled between 2015 and 2020 at Kaiser Permanente Northern California, we assessed electronic diagnostic domains for LS including (1) family history of LS-associated cancer; (2) personal history of LS-associated cancer; (3) LS screening via mismatch repair deficiency (MMRD) testing of newly diagnosed malignancy; (4) germline genetic test results; and (5) clinician-entered diagnostic codes for LS. We calculated proportions and overlap for each diagnostic domain descriptively. RESULTS Among 5.8 million individuals, (1) 28,492 (0.49%) had a family history of LS-associated cancer of whom 3,635 (13%) underwent genetic testing; (2) 100,046 (1.7%) had a personal history of a LS-associated cancer; and (3) 8,711 (0.1%) were diagnosed with colorectal cancer of whom 7,533 (86%) underwent MMRD screening and of the positive screens (486), 130 (27%) underwent germline testing. One thousand seven hundred and fifty-seven (0.03%) were diagnosed with endometrial cancer of whom 1,613 (92%) underwent MMRD screening and of the 195 who screened positive, 55 (28%) underwent genetic testing. (4) 30,790 (0.05%) had LS germline genetic testing with 707 (0.01%) testing positive; and (5) 1,273 (0.02%) had a clinician-entered diagnosis of LS. CONCLUSION It is feasible to electronically characterize the diagnostic processes of LS. No single data source comprehensively identifies all LS carriers. There is underutilization of LS genetic testing for those eligible and underdiagnosis of LS. Our work informs similar efforts in other settings for hereditary cancer syndromes.

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.

Abstract Background Cholangiocarcinoma (CCA) is a heterogeneous malignancy. Platinum-based chemotherapy (Gemcitabine and Cisplatin) has been the standard treatment for over a decade and is the base for the current immunotherapy combinations. Response rates are typically between 20-30%. Herein, we present outcomes of preclinical efficacy trials on CCA PDX models in correlation with baseline multiomics profiling of CCA patient-derived xenograft (PDX) models to identify molecular features associated with response. Methods Tumor samples from twenty-eight CCA PDX were used to isolate RNA and protein to be included in multiomics analysis (Phosphoproteomics, Proteomics, and Transcriptomics). A subset of PDX models were treated with various doses of Gemcitabine and Cisplatin. The Median Efficacy Index (MEI) was calculated as the ratio of the difference in median of delta in tumor volume at the last day of the study between the treatment and the control arms divided by the median of delta in tumor volume of the control at the last day of the treatment (positive= growth, negative=inhibition, and 0=no efficacy). A Hierarchical All-Against-All algorithm was utilized to compare multiomics features to the MEI and pathway analysis completed for identified molecular features. Results After conducting preclinical efficacy trials, the five tested CCA PDX models were classified into sensitive, moderately sensitive, and resistant models based on the MEI on each treatment arm. The top up-regulated genes were identified for Gemcitabine response (SRPK2, GLK2, and RIOK2) and Cisplatin response (NTRK1, PRPF4B, and SRPK2). The top up-regulated genes related to Gemcitabine resistance were NTRK1, PIP5K1C, and CSNK2A2, while those related to Cisplatin resistance were SRPK1, PRPF4B, and CSNK2A1. Conclusion Cholangiocarcinoma multiomics signatures can predict therapeutic response to standard-of-care chemotherapy in preclinical models. Novel mechanisms of Gemcitabine and Cisplatin resistance were identified related to NTRK1, SRPK1 and SRPK2. Resistant signatures will be challenged with the appropriate targeted therapies on the resistant CCA PDX models. Citation Format: Amro M. Abdelrahman, Danielle M. Carlson, Erik Jessen, Dong-Gi Mun, Isaac Lynch, Alessandro Fogliati, Stella Konadu Adjei Antwi, Aushinie Abeynayake, Akhilesh Pandey, Mark J. Truty, Gregory J. Gores, Rory L. Smoot. Pretreatment multiomics in conjunction with preclinical trials on patient-derived xenograft models of cholangiocarcinoma can identify chemotherapy response signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6912.

BACKGROUND: Predictive performance of polygenic risk scores (PRS) varies across populations. To facilitate equitable clinical use, we developed PRS for coronary heart disease (CHD; PRS CHD ) for 5 genetic ancestry groups. METHODS: We derived ancestry-specific and multi-ancestry PRS CHD based on pruning and thresholding (PRS PT ) and ancestry-based continuous shrinkage priors (PRS CSx ) applied to summary statistics from the largest multi-ancestry genome-wide association study meta-analysis for CHD to date, including 1.1 million participants from 5 major genetic ancestry groups. Following training and optimization in the Million Veteran Program, we evaluated the best-performing PRS CHD in 176,988 individuals across 9 diverse cohorts. RESULTS: Multi-ancestry PRS PT and PRS CSx outperformed ancestry-specific PRS PT and PRS CSx across a range of tuning values. Two best-performing multi-ancestry PRS CHD (ie, PRS PTmult and PRS CSxmult ) and 1 ancestry-specific (PRS CSxEUR ) were taken forward for validation. PRS PTmult demonstrated the strongest association with CHD in individuals of South Asian ancestry and European ancestry (odds ratio per 1 SD [95% CI, 2.75 [2.41–3.14], 1.65 [1.59–1.72]), followed by East Asian ancestry (1.56 [1.50–1.61]), Hispanic/Latino ancestry (1.38 [1.24–1.54]), and African ancestry (1.16 [1.11–1.21]). PRS CSxmult showed the strongest associations in South Asian ancestry (2.67 [2.38–3.00]) and European ancestry (1.65 [1.59–1.71]), lower in East Asian ancestry (1.59 [1.54–1.64]), Hispanic/Latino ancestry (1.51 [1.35–1.69]), and the lowest in African ancestry (1.20 [1.15–1.26]). CONCLUSIONS: The use of summary statistics from a large multi-ancestry genome-wide meta-analysis improved the performance of PRS CHD in most ancestry groups compared with single-ancestry methods. Despite the use of one of the largest and most diverse sets of training and validation cohorts to date, improvement of predictive performance was limited in African ancestry. This highlights the need for larger genome-wide association study datasets of underrepresented populations to enhance the performance of PRS CHD .

Abstract Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took β blockers (BBs) with hydrochlorothiazide (HCTZ), (−5.05 mmHg; 95% confidence interval [CI], 10.0 to −0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (−5.47 mmHg; 95% CI, 10.9 to −0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

175 Background: Alterations to mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2, can lead to microsatellite instability-high (MSI-H) tumors. MMR mutations can be inherited in Lynch syndrome (LS) but can also be a result of de novo alterations resulting in MSI-H malignancies. Treatment with immune checkpoint inhibitors (ICIs) have been shown to improve survival in such patients (pts) compared to systemic chemotherapy. However, there is a paucity of information in the literature with respect to outcomes of pts with germline vs somatic MMR mutations in MSI-H colorectal cancer (CRC). Furthermore, the presence of underlying BRAF mutation confers resistance to chemotherapy in pts with CRC, however data regarding outcomes with immunotherapy in such pts with MSI-H CRC is lacking. Methods: Pt records from the Mayo Clinic (AZ, MN, FL) between 2008-2023 denoted as MSI-H CRC, were included for retrospective review. Pt demographics, treatment courses, and genomic profiles were collected. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Outcome differences between sub-groups were accessed with the log rank test and univariate analyses were assessed with Cox-regression. Results: A total of 81 pt records were identified (n = 18 LS, n = 63 non-LS). Stage IV disease was found in 28% of LS pts vs 59% of non-LS pts at diagnosis. Pembrolizumab was the most common ICI selected for metastatic CRC pts for both LS and non-LS pts (65% vs 94%) with median treatment duration for each group 11.7 vs 8.8 months. There were no differences in OS or PFS for any stage between LS vs non-LS. Median OS for all patients was 82 months. For all stage IV patients, median OS was 44 months, and median PFS was 19 months. Interestingly, for stage IV pts treated with immunotherapy, tumors that harbored BRAF V600E mutation (n = 21) vs BRAF wild type (n = 20) had a significantly lower median OS 19 vs 113 months (HR = 2.69, p = 0.043) as well as median PFS 12 vs 95 months (HR = 2.48, p = 0.041). Conclusions: In this study, we found that patient treated with ICIs have similar outcomes in the presence of germline vs. somatic MMR mutations in MSI-H CRC. The presence of an associated BRAF V600E mutation, which occurs in non-LS MSI-H CRC conferred worse outcomes.

Abstract Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors’ association with colorectal cancer risk and survival differs by SBS88. Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer–specific survival using Cox proportional hazards regression (N = 3,465 cases). Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66–0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer–specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47–7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78–1.21, Pheterogeneity = 0.066). Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer–specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.