Citations

AbstractBackgroundMyelofibrosis (MF)‐associated constitutional symptoms can severely impact health‐related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24‐week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy.MethodsLongitudinal symptom change was evaluated using mixed‐effect model repeated measure (MMRM) methodology with individual item‐level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item‐level odds ratios using multiple predictive imputations for missing data.ResultsMomelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post‐baseline visit in SIMPLIFY‐1. In SIMPLIFY‐2, the improvement in TSS observed in momelotinib‐treated patients was consistent with that observed in SIMPLIFY‐1, whereas progressive TSS deterioration was observed with control. Item‐level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib‐treated patients were categorized as “improved” or “stable” compared with control in SIMPLIFY‐1 and SIMPLIFY‐2, respectively. Odds ratios for between‐group comparison ranged from 0.75 to 1.21 in SIMPLIFY‐1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY‐2, the likelihood of symptom improvement in each item was higher in the momelotinib arm.ConclusionsThese findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor‐naïve and JAK inhibitor‐exposed settings.

Abstract Patients with glioblastoma (GBM) face poor outcomes; the 5-year survival rate is 7% with standard of care treatments, which are frequently associated with systemic toxicity. Tumor Treating Fields (TTFields) are electric fields that disrupt critical cancer cell processes. The TTFields therapy device consists of a portable electric field generator and arrays placed on the patient’s scalp, thus delivery is locoregional and noninvasive. Currently, TTFields therapy is approved for recurrent and newly diagnosed GBM, based on the phase 3 EF-11 (TTFields 200 kHz) and EF-14 studies (TTFields therapy 200 kHz + temozolomide), respectively. These studies confirmed that TTFields therapy had a tolerable safety profile with mild-to-moderate localized skin adverse events (AEs) being the most common related AEs. Here, we present an updated analysis of the largest global real-world evidence dataset of patients with brain tumors receiving TTFields therapy over an 11-year time period. Unsolicited safety data were obtained from routine post-marketing activities, including published literature and interactions with patients, caregivers, and healthcare professionals. Safety data were grouped according to age, diagnosis, and sex. AEs were categorized using MedDRA version 25. Data from 25,898 patients were included in this analysis; median age was 59 years (range: 3-103) for patients with known age. Diagnoses were ndGBM (67.7%), rGBM (26.1%), anaplastic astrocytoma/oligodendroglioma (4.2%) and other (2.1%). Most (n=17,817, 68.8%) patients were 18-65 years of age; n=93 (0.4%) were pediatric/adolescent patients (&lt;18 years), and n=7,808 (30.2%) were elderly patients (&gt;65 years). For 130 patients (0.5%) age was not known. Two-thirds of patients were male, which reflects the preponderance of CNS tumors in males. Most patients were based in North America (72.1%), followed by Europe, the Middle East and Africa (23.3%), and Japan (4.6%). Overall, 72.4% of patients experienced at least one AE, with 55.9% being related to TTFields therapy. The most common AEs (overall and related to TTFields therapy) were skin reactions (42.0%), electric (tingling) sensations (13.5%), and heat (warmth) sensations (11.8%). The percentage of patients experiencing ≥1 AE in the pediatric/adolescent, 18-65, and elderly groups was 63.4%, 74.6%, and 68.4%, respectively. The percentage of females and males experiencing ≥1 AE was 75.2% and 70.9%, respectively. These long-term, real-world data from the largest global dataset of patients with brain tumors using TTFields therapy to date demonstrate a tolerable safety profile consistent with pivotal clinical studies. There were no new safety signals, and most AEs were manageable localized mild-moderate skin events that can be resolved. The distribution of AEs between age and sex was similar, with broad applicability among different patient groups. Citation Format: Maciej M. Mrugala, Wenyin Shi, Fabio Iwamoto, Rimas V. Lukas, Joshua D. Palmer, John H. Suh, Martin Glas. Patients with glioblastoma (GBM) treated with tumor treating fields (TTFields) therapy: post-marketing safety data over the last decade [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 3221.

Purpose of review Iron overload disorders such as hemochromatosis involve unregulated absorption of dietary iron, leading to excessive iron accumulation in multiple organs. Phlebotomy is the standard of care for removal of excess iron, but dietary modification is not standardized in practice. The purpose of this article is to help standardize hemochromatosis diet counseling based on commonly asked patient questions. Recent findings The clinical benefit regarding dietary modification in iron overload patients is limited due to lack of large clinical trials, but preliminary results are promising. Recent studies suggest diet modification could reduce iron burden in hemochromatosis patients resulting in less annual phlebotomy as supported through small patient studies, concepts of physiology, and animal studies. Summary This article is a guide for physicians to counsel hemochromatosis patients based on commonly asked questions such as foods to avoid, foods to consume, use of alcohol, and use of supplements. The goal of this guide is to help standardize hemochromatosis diet counseling to reduce phlebotomy amount in patients. Standardization of diet counseling could help facilitate future patient studies to analyze the clinical significance.

BACKGROUND: There are limited data regarding outcomes for patients with gastrointestinal (GI) primaries and brain metastases treated with stereotactic radiosurgery (SRS). OBJECTIVE: To examine clinical outcomes after SRS for patients with brain metastases from GI primaries and evaluate potential prognostic factors. METHODS: The International Radiosurgery Research Foundation centers were queried for patients with brain metastases from GI primaries managed with SRS. Primary outcomes were local control (LC) and overall survival (OS). Kaplan-Meier analysis was used for univariate analysis (UVA) of prognostic factors. Factors significant on UVA were evaluated with a Cox multivariate analysis proportional hazards model. Logistic regressions were used to examine correlations with RN. RESULTS: We identified 263 eligible patients with 543 brain metastases. Common primary sites were rectal (31.2%), colon (31.2%), and esophagus (25.5%) with a median age of 61.6 years (range: 37-91.4 years) and a median Karnofsky performance status (KPS) of 90% (range: 40%-100%). One-year and 2-year LC rates were 83.5% (95% CI: 78.9%-87.1%) and 73.0% (95% CI: 66.4%-78.5%), respectively. On UVA, age >65 years ( P = .001), dose <20 Gy ( P = .006) for single-fraction plans, KPS <90% ( P < .001), and planning target volume ≥2cc ( P = .007) were associated with inferior LC. All factors other than dose were significant on multivariate analysis ( P ≤ .002). One-year and 2-year OS rates were 68.0% (95% CI: 61.5%-73.6%) and 31.2% (95% CI: 24.6%-37.9%), respectively. Age > 65 years ( P = .006), KPS <90% ( P = .005), and extracranial metastases ( P = .05) were associated with inferior OS. CONCLUSION: SRS resulted in comparable LC with common primaries. Age and KPS were associated with both LC and OS with planning target volume and extracranial metastases correlating with LC and OS, respectively. These factors should be considered in GI cancer patient selection for SRS.

Abstract Background Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07–0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37–0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

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.

Background and Aims: Colonoscopies are routinely obtained before liver transplantation, although their utility is a highly debated topic in the literature. We aimed to determine the risk factors in patients with decompensated cirrhosis (DC) for post-colonoscopy complications (PCC). Materials and Methods: We performed a single-center retrospective study of patients with DC undergoing colonoscopy as part of their pre–liver-transplant evaluation. The primary composite outcome was defined as a complication occurring within 30 days of the colonoscopy. Complications included acute renal failure, new or worsening ascites or hepatic encephalopathy, gastrointestinal bleeding, or any cardiopulmonary or infectious complication. Logistic regression analysis was utilized to derive a risk score in predicting the primary composite outcome. Results: The strongest predictors of post-colonoscopy complication were MELD-Na ≥21 [aOR 4.0026 (P=0.0050)] and history of any infection in the 30 days before colonoscopy [aOR 8.4345 (P=0.0093)]. The area under the receiver operating characteristic curve of the final model was 0.78. The predicted risk of any complication at the lowest quartile was 16.2% to 39.4%, and the observed risk was 30.6% (95% CI: 15.5-45.6%), while the predicted risk at the highest quartile was 71.9% to 97.1%, and the observed risk was 81.3% (95% CI: 67.7-95%). Conclusion: In this cohort of patients with DC undergoing colonoscopy for pre–liver-transplant evaluation, a history of ascites, spontaneous bacterial peritonitis, and MELD-Na were found to be predictive of PCC. This risk score may help to predict PCC in patients with DC undergoing a pre-transplant colonoscopy. External validation is recommended.

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p&lt; 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was &gt;20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was &lt; 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.

Objectives:Patients with inflammatory bowel disease (IBD) frequently have extraintestinal manifestations. The goal of this pilot study was to assess exocrine pancreatic function in cases with suspicion for or an established diagnosis of IBD.Methods:Direct stimulated endoscopic pancreatic function test (ePFT) was performed in 74 children with IBD, in both newly diagnosed and established cases. Demographic, clinical, and laboratory parameters were entered into a database and analyzed.Results:Among the 74 children, 49 were newly diagnosed and 25 had an established diagnosis of IBD. A majority had the diagnosis of Crohn disease (CD) (n = 48; 32 new and 16 established cases) with male predominance (64.6%). Altogether, 42 (56.7%) children had either generalized or partial exocrine pancreatic insufficiency (EPI). Twenty‐four of the 48 CD children (50%) had abnormal ePFT. In those with ulcerative colitis (UC), 18 of the 26 (62.9%) had abnormal ePFT. The highest abnormality rate was in lipase enzyme activity. Weight z scores were significantly lower in those with abnormal ePFT (Crohn cases: P = 0.008; UC cases: P = 0.046). Peak protein concentration in collected pancreatic fluid was significantly lower in children with CD who had abnormal ePFT (P = 0.013).Conclusions:This pilot study revealed a relatively high prevalence of EPI in children with IBD through use of ePFT. EPI can result in maldigestion, with decreased capacity to digest fat. Further prospective studies are needed to assess need and efficacy of pancreatic enzyme replacement therapy in children with IBD and abnormal ePFT.

559 Background: Cabozantinib, a multikanase inhibitor, is approved by the Food and Drug Administration (FDA) for treatment of advanced stage hepatocellular carcinoma (HCC) following progression on sorafenib. The CELESTIAL study which demonstrated benefit from cabozantinib following sorafenib included only patients with Child Pugh class A liver function. Recently, bevacizumab plus atezolizumab has replaced sorafenib as the first line treatment for HCC. It is unclear whether there is benefit from using Cabozantinib following progression on immunotherapy as CELESTIAL trial included very few patients who received prior immunotherapy. We describe the outcomes of individuals with advanced stage HCC treated with Cabozantinib following progression on immunotherapy. Methods: This was a multicenter, retrospective analysis of patients with advanced HCC diagnosed between 2010-2021 at Mayo Clinic Arizona, Florida, and Minnesota. Progression free survival (PFS) and median overall survival analysis were performed using Kaplan-Meier method. Results: We identified a total of 26 patients with advanced stage HCC who received cabozantinib following progression on immunotherapy. The median age of patients was 61 years (range, 39 – 81) and the majority were male (85%). Eighteen (72%) patients had Child Pugh A at initiation of cabozantinib therapy. Four (15%) patients received cabozantinib as second line therapy, the rest received it as third line or later. PFS on cabozantinib was 2.1 months (95% CI: 1.3 – 3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3 – 14.9). PFS was shorter with Child Pugh Class B, 1.3 months (95% CI: 0.9 – NE) compared to those with Child Pugh Class A, 2.1 months (95% CI: 1.5 – 4); although this difference was not significant (p=0.55). Common adverse events included fatigue (50%), anorexia (35%), aspartate aminotransferase (AST) elevation (35%), and diarrhea (31%); 7 (26%) patients experienced Grade 3 or greater adverse events including hypertension, diarrhea, anorexia, and bowel obstruction. Two patients discontinued cabozantinib due to side effects including one for uncontrolled blood pressure elevations and the other due to fatigue. Conclusions: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy is unknown. Treatment with cabozantinib may improve clinical outcomes following progression on immunotherapy with similar adverse event profile. This study included patients with Child Pugh class B liver disease (28%) and heavily pretreated population and demonstrated mPFS and mOS similar to other work examining outcomes of cabozantinib in real world setting after progression on sorafenib. Further studies to determine optimal treatment sequencing for this patient population are needed.