Citations

Abstract BACKGROUND: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. Data from preclinical models strongly support epidermal growth factor receptor (EGFR) as a target for chemoprevention of HCC. Erlotinib is a small-molecular EGFR tyrosine kinase inhibitor that is FDA-approved for cancer treatment. The side effects of erlotinib observed in patients receiving the oncology dose (150 mg/day) render it unacceptable as a chemoprevention agent at this dose. OBJECTIVE: The objective of this clinical trial was determination of a safe and minimum effective dose of erlortinib for which a ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed. RESULTS: 46 participants were pre-registered and 25 participants were registered in this multicenter trial. In a dose de-escalation trial design, cohorts of participants received a 7 day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. A favorable modulation of the Prognostic Liver Signature was observed in participants that received the higher erlotinib doses (50 and 75 mg/day). CONCLUSION: These data support the selection a dose of 25 mg/day of erlotinib for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug. Citation Format: Kenneth K. Tanabe, David Zahrieh, Carrie A. Strand, Yujin Hoshida, Thomas J. Flotte, Gary Della’Zanna, Asad Umar, Paul Limburg. Pilot study of EGFR inhibition with erlotinib in liver fibrosis for hepatocellular carcinoma prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3031.

Background: Risk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods: The 3793 cases and 7834 controls (11.6% of cases were individuals of African, Hispanic/Latino, or Asian ancestry) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results: Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only PROC (odds ratio, 6.2 for carriers of rare variants; P =7.4×10 −14 ) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at PROC (odds ratio, 3.8; P =1.6×10 −14 ), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: PROS1 became significant (minimum P =1.8×10 −6 with the secondary filter), while SERPINC1 did not (minimum P =4.4×10 −5 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, MS4A1 , became significant ( P =4.4×10 −7 using all missense variants with minor allele frequency <0.0005). Conclusions: Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel MS4A1 locus and to identify additional rare variation associated with venous thromboembolism.

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.

SummaryThe Children's Oncology Group AHOD0831 study used a positron emission tomography (PET) response‐adapted approach in high‐risk Hodgkin lymphoma, whereby slow early responders (SERs) received more intensive therapy than rapid early responders (RERs). We explored if baseline PET‐based characteristics would improve risk stratification. Of 166 patients enrolled in the COG AHOD0831 study, 94 (57%) had baseline PET scans evaluable for quantitative analysis. For these patients, total body metabolic tumour volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax) and peak SUV (SUVpeak) were obtained. MTV/TLG thresholds were an SUV of 2.5 (MTV2.5/TLG2.5) and 40% of the tumour SUVmax (MTV40%/TLG40%). TLG2.5 was associated with event‐free survival (EFS) in the complete cohort (p = 0.04) and in RERs (p = 0.01), but not in SERs (p = 0.8). The Youden index cut‐off for TLG2.5 was 1841. Four‐year EFS was 92% for RER/TLG2.5 up to 1841, 60% for RER/TLG2.5 greater than 1841, 74% for SER/TLG2.5 up to 1841 and 79% for SER/TLG2.5 greater than 1841. Second EFS for RER/TLG2.5 up to 1841 was 100%. Thus, RERs with a low baseline TLG2.5 experienced excellent EFS with less intensive therapy, whereas RERs with a high baseline TLG2.5 experienced poor EFS. These findings suggest that patients with a high upfront tumour burden may benefit from intensified therapy, even if they achieve a RER.

Background: Racial/ethnic (R/E) minorities with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes compared to White patients. While disparities in patient outcomes for R/E minorities have been well documented, the specific drivers of the inferior outcomes remain poorly understood. Patients and Methods: This was a population-based retrospective cohort study that analyzed HNSCC patients using the National Cancer Database (NCDB) from 2000–2016. Patient outcomes were stratified by R/E groups including White, Black, Hispanic, Native American/Other, and Asian. The main outcome in this study was overall survival (OS). Univariate time-to-event survival analyses were performed using the Kaplan–Meier product limit estimates and the log-rank test to evaluate the differences between strata. Results: There were 304,138 patients with HNSCC identified in this study, of which 262,762 (86.3%) were White, 32,528 (10.6%) were Black, 6191 were Asian (2.0%), and 2657 were Native American/Other (0.9%). Black R/E minorities were more likely to be uninsured (9% vs. 5%, p < 0.0001), have Medicaid insurance (22% vs. 8%, p < 0.0001), be in a lower income quartile (<30,000, 42% vs. 13%, p < 0.0001), have metastatic disease (5% vs. 2%, p < 0.001), and have a total treatment time 6 days longer than White patients (median 107 vs. 101 days, p < 0.001). The 5-year OS for White, Black, Native American/Other, and Asian patients was 50.8%, 38.6%, 51.1%, and 55.8%, respectively. Among the oropharynx HNSCC patients, the 5-year OS rates in p16+ White, Black, and Asian patients were 65.7%, 39.4%%, and 55%, respectively. After a multivariate analysis, Black race was still associated with an inferior OS (HR:1.09, 95% CI: 1.03–1.15, p = 0.002). Conclusions: This large cohort study of HNSCC patients demonstrates that Black race is independently associated with worse OS, in part due to socioeconomic, clinical, and treatment-related factors.

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.

Introduction: Hypothalamic amenorrhea (HA) is a neuroendocrine disorder characterized by ovulatory dysfunction, anovulation, and infertility, which can be prolonged for months to years. Menstrual cycle irregularity and amenorrhea identify individuals with higher CVD risk, but existing evidence has not examined HA separately from polycystic ovary syndrome (PCOS). It remains unknown whether HA is associated with CVD events across the lifecourse. Hypothesis: We hypothesized that the HA phenotype (oligo/amenorrhea without PCOS traits) would identify individuals at increased risk for CVD. Methods: Nurses’ Health Study II participants with available information on menstrual cycle characteristics who were premenopausal and free of CVD at baseline comprised the analytic sample (n=83,281). Menstrual cycle regularity was retrospectively reported for ages 18-22y on the baseline questionnaire in 1989 while the 1993 biennial questionnaire captured current menstrual cycle regularity (at ages 29-49y); PCOS traits (severe acne, hirsutism) were additionally ascertained in 1993. Participants were followed for confirmed incident CVD (MI, stroke, and fatal CHD) from 1993 through 2017. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the relationship between HA and CVD, adjusted for age, race/ethnicity, parental education, parental history of CVD <60y, and behavioral risk factors (smoking, physical activity, diet, alcohol intake, body mass index). Results: Thirteen percent of participants (n=11,071) ever had HA: 8.5% of participants (n=7,081) had HA at ages 18-22y while 6.5% (n=5,428) had HA at ages 29-46y. Persistent HA (HA at both 18-22y and 29-46 y) was identified in 1.7% of participants (n=1,438). CVD events occurred in 253 individuals who ever had HA (HA at either 18-22y or 29-46y) and 1,228 individuals without the HA phenotype. Individuals who ever had HA had a 20% higher rate of CVD (CI: 1.05-1.38). HA phenotype at ages 18-22y was not associated with CVD risk (HR=1.14; CI: 0.96-1.35) while HA phenotype at ages 29-46y was associated with a 30% higher rate of CVD (CI: 1.10-1.54) compared to individuals without HA phenotype. Individuals with persistent HA across both age ranges had a 69% higher rate of CVD (CI: 1.24-2.28). Underlying associations were strongest between ever HA and stroke (HR=1.25; CI: 1.03-1.51) and between persistent HA and CHD (HR=1.90; CI: 1.27-2.86), although case counts were small. Conclusions: HA phenotype in mid-adulthood identified individuals at increased risk of CVD compared to those without HA. As there are multiple HA subtypes, defined by varying combinations of psychosocial stress, anxiety, physical activity and weight loss, future studies should examine which HA subtypes are associated with CVD risk.

AbstractBackgroundVEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic) syndrome is an autoinflammatory disease with frequent cutaneous manifestations.MethodsWe conducted a retrospective study of all patients with genetically confirmed VEXAS syndrome seen at our institution. Available clinical photographs and skin biopsy slides were reviewed.ResultsCutaneous manifestations developed in 22/25 (88%) patients with VEXAS syndrome. From this group, 10/22 (45%) developed skin involvement before or at the time of other clinical features of VEXAS. Twenty distinct dermatologic presentations of VEXAS from 14 patients were reviewed, and histopathologic patterns were classified as follows: neutrophilic urticarial dermatosis (n = 5, 25%), leukocytoclastic/urticarial vasculitis (n = 4, 20%), urticarial tissue reaction (n = 4, 20%), neutrophilic dermatosis (n = 3, 15%), neutrophilic panniculitis (n = 2, 10%), and nonspecific chronic septal panniculitis (n = 2, 10%). Common systemic findings included macrocytic anemia (96%), fever (88%), thrombocytopenia (76%), weight loss (76%), ocular inflammation (64%), pulmonary infiltrates (56%), deep venous thrombosis or pulmonary embolism (52%), and inflammatory arthritis (52%).ConclusionsCutaneous involvement is a common feature of VEXAS syndrome, and histopathologic findings exist on a spectrum of neutrophilic inflammatory dermatoses.