Citations

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

Abstract Several reports of concurrent MYC, BCL2, BCL6, and CCND1 rearrangements in high-grade B-cell lymphoma (HGBL) have been recently described. Herein, we aimed to delineate the scope of this entity through a review of HGBL with a “quadruple-hit” genetic profile identified at our institution. We performed a retrospective review (2015-2023) at our institution of B-cell lymphoma (BCL) cases that were evaluated with concurrent MYC, BCL2, and BCL6 break-apart and IGH::MYC and IGH::CCND1 dual-color dual-fusion fluorescence in situ hybridization studies. Of 203 cases meeting inclusion criteria, 2 (1%) with a quadruple-hit genetic profile were identified. Case 1 represented a 59-year-old female with widespread lymphadenopathy and a diagnosis of HGBL who exhibited primary refractoriness to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) chemotherapy. Case 2 represented a 58-year-old male with mediastinal and abdominal lymphadenopathy and a diagnosis of large BCL who died from disease after 1 cycle of DA-EPOCH-R chemotherapy. Similarly, a literature review of 7 previously reported cases of HGBL with a quadruple-hit profile also demonstrated aggressive disease behavior. Our study adds 2 new cases to the rarely encountered quadruple-hit HGBL, and a brief meta-analysis of the 9 available cases indicates aggressive disease behavior conferred by this constellation of genetic events.

Abstract Background: Benefit from single-agent immune checkpoint inhibitor has been observed in 5-10% of the patients with microsatellite stable (MSS) gastrointestinal (GI) cancers. However, a reliable predictive marker to immune checkpoint inhibitor has not been discovered in this patient population. We sought to assess the incidence of mismatch repair (MMR) gene alterations and their association with tumor mutational burden (TMB) in MSS GI cancers. Methods: This is a retrospective cohort study of patients with advanced GI cancer who had molecular profiling of the tumor using either Guardant360 blood-based or Tempus tissue next generation sequencing (NGS) platforms between 2020 and 2023. We assessed four MMR genes including MLH1, MSH2, MSH6 and PMS2 for alterations. Continuous variables were summarized as median and interquartile range (IQR) and compared using Mann-Whitney test. Categorical variables were summarized as counts and proportions and compared using Fisher’s exact test. Results: A total of 2920 patients with Guardant360 were included with a median age of 65 (IQR: 56-73) years. 870 (30%) patients had pancreas cancer; 846 (29%) patients had colorectal cancer; 688 (24%) patients had biliary tract cancers; and the rest had other GI cancers. Among patients evaluable for microsatellite instability (MSI) status, 58 patients (2%) had MSI-high GI cancers, 31 (53%) of whom had MMR gene alterations. 2445 (98%) patients had MSS GI cancers, 130 (5.3%) of whom had MMR gene alterations. Patients with MSS GI cancers bearing MMR gene alterations had a median age of 70 (IQR: 62-75) years, significantly older than those without MMR gene alterations (p<0.001). In addition, patients with MMR gene alterations had significantly higher median blood TMB of 11 (IQR: 7.4-16) mut/Mb compared to 7.7 (IQR: 4.8-11) mut/Mb in patients without MMR gene alterations. In MSS GI cancers, MMR gene alterations are more commonly associated with the presence of alterations in APC (p=0.03), TP53 (p=0.01), CTNNB1 (p<0.001) and SMAD4 (p=0.01). 1453 patients with GI cancer and Tempus tissue NGS data were included as a validation cohort. They had comparable demographics with the Guardant360 cohort. 14 (1.6%) of 896 patients with MSS GI cancers had MMR gene alterations, significantly fewer (p<0.001) than those found in the Guardant360 cohort. Patients with MMR gene alterations and wild type POLE had significantly higher (p=0.001) median TMB of 9.8 (IQR: 4.8-14) mut/Mb compared to 4.7 (IQR: 3.2-6.3) mut/Mb in patients without MMR gene alterations. Conclusions: MMR gene alterations can be identified by clinical NGS platforms in a small proportion of patients with MSS GI cancers. They are associated with elevated TMB, which may suggest a hypermutated profile serving as a basis for potential role of immune checkpoint inhibitor in MSS GI cancers. Citation Format: Conor D. O'Donnell, Mojun Zhu, Hao Xie. The association of mismatch repair gene alterations with elevated tumor mutational burden in microsatellite stable gastrointestinal cancers [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 6469.

Background Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. Methods We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy. Available data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, approved CGRP-R and CGRP monoclonal antibodies and of atogepant were examined for prevention outcomes based on patient sex. Preventive outcomes were analyzed separately for patients with episodic migraine and chronic migraine. Results In women, the three approved gepants produced statistically significant drug effects regardless of dose tested on the FDA mandated co-primary endpoints, the proportion of patients achieving two-hour pain-freedom and the proportion of patients free of their most bothersome symptom at two hours post-dose. In women, the average placebo-subtracted two-hour pain-freedom proportion was 9.5% (CI: 7.4 to 11.6) and the average numbers needed to treat was 11. The free from most bothersome symptom at two hours outcomes were also significant in women. The gepant drugs did not reach statistically significant effects on the two-hour pain-freedom endpoint in the men, with an average drug effect of 2.8% (CI: −2.5 to 8.2) and an average number needed to treat of 36. For freedom from most bothersome symptom at two hours post-dose endpoint, differences were not significant in male patients. The treatment effect in each of the gepant studies was always numerically greater in women than in men. In evaluation of prevention outcomes with the antibodies or atogepant using the change from the specified primary endpoint (e.g., monthly migraine days), the observed treatment effect for episodic migraine patients almost always favored drug over placebo in both women and men. For chronic migraine patients the treatment effects of antibodies were similar in men and women and always favored the drug treated group. Conclusion/Interpretation: Small molecule CGRP-R antagonists are effective in acute migraine therapy in women but available data do not demonstrate effectiveness in men. CGRP-targeting therapies are effective for migraine prevention in both male and female episodic migraine patients but possible sex differences remain uncertain. In male and female chronic migraine patients, CGRP/CGRP-R antibodies were similarly effective. The data highlight possible differential effects of CGRP targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women.

Abstract Grouping gene expression into gene set activity scores (GSAS) provides better biological insights than studying individual genes. However, existing gene set projection methods cannot return representative, robust, and interpretable GSAS. We developed NetActivity, a machine learning framework that generates GSAS based on a sparsely-connected autoencoder, where each neuron in the inner layer represents a gene set. We proposed a three-tier training that yielded representative, robust, and interpretable GSAS. NetActivity model was trained with 1518 GO biological processes terms and KEGG pathways and all GTEx samples. NetActivity generates GSAS robust to the initialization parameters and representative of the original transcriptome, and assigned higher importance to more biologically relevant genes. Moreover, NetActivity returns GSAS with a more consistent definition and higher interpretability than GSVA and hipathia, state-of-the-art gene set projection methods. Finally, NetActivity enables combining bulk RNA-seq and microarray datasets in a meta-analysis of prostate cancer progression, highlighting gene sets related to cell division, key for disease progression. When applied to metastatic prostate cancer, gene sets associated with cancer progression were also altered due to drug resistance, while a classical enrichment analysis identified gene sets irrelevant to the phenotype. NetActivity is publicly available in Bioconductor and GitHub.

PURPOSE The phase III Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial found no difference in overall survival (OS) in patients with metastatic colorectal cancer receiving first-line chemotherapy in combination with either bevacizumab or cetuximab. We investigated the potential prognostic and predictive value of HER2 amplification and gene expression using next-generation sequencing (NGS) and NanoString data. PATIENTS AND METHODS Primary tumor DNA from 559 patients was profiled for HER2 amplification by NGS (FoundationOne CDx). Tumor tissue from 925 patients was tested for NanoString gene expression using an 800-gene panel. OS and progression-free survival (PFS) were the time-to-event end points. RESULTS High HER2 expression (dichotomized at median) was associated with longer PFS (11.6 v 10 months, P = .012) and OS (32 v 25.3 months, P = .033), independent of treatment. An OS benefit for cetuximab versus bevacizumab was observed in the high HER2 expression group ( P = .02), whereas a worse PFS for cetuximab was seen in the low-expression group ( P = .019). When modeled as a continuous variable, increased HER2 expression was associated with longer OS (hazard ratio [HR], 0.83 [95% CI, 0.75 to 0.93]; adjusted P = .0007) and PFS (HR, 0.82 [95% CI, 0.74 to 0.91]; adjusted P = .0002), reaching a plateau effect after the median. In patients with HER2 expression lower than median, treatment with cetuximab was associated with worse PFS (HR, 1.38 [95% CI, 1.12 to 1.71]; adjusted P = .0027) and OS (HR, 1.28 [95% CI, 1.02 to 1.59]; adjusted P = .03) compared with that with bevacizumab. A significant interaction between HER2 expression and the treatment arm was observed for OS ( P intx = .017), PFS ( P intx = .048), and objective response rate ( P intx = .001). CONCLUSION HER2 gene expression was prognostic and predictive in CALGB/SWOG 80405. HER2 tumor expression may inform treatment selection for patients with low HER2 favoring bevacizumab- versus cetuximab-based therapies.

Abstract Introduction: Identifying dysregulated gene expression in ovarian cancers has been limited by a deficit of available normal tissues. Here, we generated the largest set of high-grade serous ovarian cancer (HGSOC) tumors with normal precursor tissues for transcriptome analyses to identify lncRNA expression patterns, provide insight into their cellular contexts and functions, and assess their relevance to HGSOC pathogenesis and genetic susceptibility. Methods: We performed RNA sequencing on 220 primary HGSOCs and 116 benign epithelia (micro-dissected fallopian tube, ovarian surface, and inclusion cyst epithelia), and combined samples with 428 HGSOCs from TCGA, 60 HGSOCs from a prior study, and 180 bulk ovary tissues from GTEx. Reads were processed with a uniform bioinformatic and quality control pipeline, combined and batch corrected. Normalized TPM expression values were compared using the Wilcoxon rank sum test with >2-fold change and FDR <1% considered statistically significant. We computed weighted gene co-expression networks for each tissue type and tested for enrichment of differentially expressed genes (DEGs) and gene ontologies within co-expression modules. Results: Transcriptomes included 27,700 expressed genes (8,202 lncRNAs) across 706 HGSOCs, 180 bulk ovary, and 88 ovarian epithelia tissues. Most genes were expressed in all tissues, though 5% each showed HGSOC- or normal tissue-specific expression which comprised ≥50% lncRNA. Comparing HGSOCs to normal tissues identified 11,804 DEGs with 4,522 lncRNAs (DElncRNA) of which ~50% were tissue-specific. DEGs included MUC16 and multiple GWAS/TWAS implicated susceptibility genes including RAD51, BRIP1, BNC2, TIPARP-AS1, PRC1, KANSL1, ANKLE1, CHMP4C, ESRP2, and CCNE1. The most highly expressed DElncRNA in HGSOC were upregulated RMRP (P=1.4 × 10−39), SNHG1 (P=3.0 × 10−27), and HAGLR (P=2.0 × 10−24) at the HOXD risk locus. Lower proportions of lncRNA were seen in the HGSOC co-expression modules compared to those in normal tissues and less (3% vs. 15%) HGSOC modules were considered strongly lncRNA regulated (>50% lncRNA in module). Tissue-specific DElncRNA tended toward upregulation in HGSOC compared to ovarian epithelia with enriched modules associated with cell cycle regulation (P=1.5 × 10−38); and toward downregulation in HGSOC compared to bulk ovary with enriched modules associated with chemokine signaling/response (P=1.7 × 10−113). Conclusions: The lower proportion of lncRNA involved in HGSOC co-expression networks indicates a marked loss of regulation by lncRNA. Preliminary interrogation of HGSOC-dysregulated lncRNA expression revealed tissue-specific differences that highlight unique biological pathways in precursor epithelia and the ovarian microenvironment that contribute to HGSOC pathogenesis. Our results provide additional support for previously nominated risk genes. eQTL analysis has recently been completed and integration with GWAS are underway to elucidate lncRNA and lncRNA-regulated susceptibility genes and will be presented at the conference. Citation Format: Brett M. Reid, Ann Chen, Zhihua Chen, Florian A. Karreth, Peter Kanetsky, Jennifer B. Permuth, Ozlen Saglam, Jamie K. Teer, Xiaoqing Yu, Simon Gayther, Ellen Goode, Paul Pharoah, Thomas A. Sellers, Kate Lawrenson, Jonathan Tyrer. Patterns of lncRNA-regulated gene expression in high-grade serous ovarian carcinomas [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A004.

Exposure to polycyclic aromatic hydrocarbons (PAHs), byproducts of incomplete combustion, and their effects on the development of cancer are still being evaluated. Recent studies have analyzed the relationship between PAHs and tobacco or dietary intake in the form of processed foods and smoked/well-done meats. This study aims to assess the association of a blood biomarker and metabolite of PAHs, r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), dietary intake, selected metabolism SNPs, and pancreatic cancer. Demographics, food-frequency data, SNPs, treatment history, and levels of PheT in plasma were determined from 400 participants (202 cases and 198 controls) and evaluated based on pancreatic adenocarcinoma diagnosis. Demographic and dietary variables were selected based on previously published literature indicating association with pancreatic cancer. A multiple regression model combined the significant demographic and food items with SNPs. Final multivariate logistic regression significant factors (p-value < 0.05) associated with pancreatic cancer included: Type 2 Diabetes [OR = 6.26 (95% CI = 2.83, 14.46)], PheT [1.03 (1.02, 1.05)], very well-done red meat [0.90 (0.83, 0.96)], fruit/vegetable servings [1.35 (1.06, 1.73)], recessive (rs12203582) [4.11 (1.77, 9.91)], recessive (rs56679) [0.2 (0.06, 0.85)], overdominant (rs3784605) [3.14 (1.69, 6.01)], and overdominant (rs721430) [0.39 (0.19, 0.76)]. Of note, by design, the level of smoking did not differ between our cases and controls. This study does not provide strong evidence that PheT is a biomarker of pancreatic cancer susceptibility independent of dietary intake and select metabolism SNPs among a nonsmoking population.