Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.

PURPOSE: eHealth literacy, or the ability to seek, find, understand, and appraise health information from electronic sources, has become increasingly relevant in the era of COVID-19, when so many aspects of patient care became dependent on technology. We aimed to understand eHealth literacy among a diverse sample of patients with cancer and discuss ways for health systems and cancer centers to ensure that all patients have access to high-quality care. METHODS: A cross-sectional survey of patients with cancer and caregivers was conducted at an NCI-designated cancer center to assess access to the Internet, smartphone ownership, use of mobile apps, willingness to engage remotely with the health care team, and use of the patient portal. Descriptive statistics and bivariate analyses were used to assess frequencies and significant differences between variables. RESULTS: Of 363 participants, 55% (n = 201) were female, 71% (n = 241) identified as non-Hispanic White, and 29% (n = 85) reported that their highest level of education was a high school diploma. Most (90%, n = 323) reported having access to the Internet and most (82%, n = 283) reported owning a smartphone. Younger patients or those with a college degree were significantly more likely to own a smartphone, access health information online, know how to download an app on their own, have an interest in communicating with their health care team remotely, or have an account on the electronic patient portal. CONCLUSION: As cancer centers increasingly engage patients through electronic and mobile applications, patients with low or limited digital literacy may be excluded, exacerbating current cancer health disparities. Patient-, provider- and system-level technology barriers must be understood and mitigated.

PURPOSE: Germline testing (GT) for prostate cancer (PCA) is now central to treatment and hereditary cancer assessment. With rising demand for and shortage of genetic counseling (GC), tools to deliver pretest informed consent across practice settings are needed to improve access to GT and precision care. Here, we report on Evaluation and Management for Prostate Oncology, Wellness, and Risk (EMPOWER), a patient-choice study for pretest video-based genetic education (VBGE) versus GC to inform urgent practice needs. PATIENTS AND METHODS: Men with PCA or at risk for PCA (family history of PCA) were eligible and could choose pretest VBGE or GC. Outcomes included decisional conflict for GT, change in genetics knowledge, satisfaction, and intention to share results with family and/or providers. Descriptive statistics summarized results with counts and percentages for categorical variables and mean ± standard deviation for continuous variables. Data were compared with Fisher's exact, chi-squared, or Wilcoxon two-sample tests. Mean change in genetics knowledge was compared with t tests. The significance level was set a priori at .05. RESULTS: Data on the first 127 participants were analyzed. Characteristics were White (85.8%), bachelor's degree (66.9%), and PCA diagnosis (90.6%). The majority chose VBGE (71%) versus GC (29%; P < .001). No differences were observed in decisional conflict for GT or satisfaction. Cancer genetics knowledge improved in both groups without significant difference (+0.9 VBGE, +1.8 GC, P = .056). Men who chose VBGE had higher intention to share GT results (96.4% VBGE v 86.4% GC, P = .02). Both groups had high rates of GT uptake (VBGE 94.4%, GC 92%). CONCLUSION: A substantial proportion of men opted for pretest VBGE, with comparable patient-reported outcomes and uptake of GT. The results support the use of pretest video to address the critical GC shortage in the precision era.

Purpose. There are no standardized approaches for communicating with patients discharged from the emergency department with diagnostic uncertainty. This trial tested efficacy of the Uncertainty Communication Education Module, a simulation-based mastery learning curriculum designed to establish competency in communicating diagnostic uncertainty. Method. Resident physicians at 2 sites participated in a 2-arm waitlist randomized controlled trial from September 2019-June 2020. After baseline (T1) assessment of all participants via a standardized patient encounter using the Uncertainty Communication Checklist (UCC), immediate access physicians received training in the Uncertainty Communication Education Module, which included immediate feedback, online educational modules, a smartphone-based application, and telehealth deliberate practice with standardized patients. All physicians were retested 16-19 weeks later (T2) via in-person standardized patient encounters; delayed access physicians then received the intervention. A final test of all physicians occurred 11-15 weeks after T2 (T3). The primary outcome measured the percentage of physicians in the immediate versus delayed access groups meeting or exceeding the UCC minimum passing standard at T2. Results. Overall, 109 physicians were randomized, with mean age 29 years (range 25-46). The majority were male (n = 69, 63%), non-Hispanic/Latino (n = 99, 91%), and White (n = 78, 72%). At T2, when only the immediate access group had received the curriculum, immediate access physicians demonstrated significantly increased mastery (n = 29, 52.7%) compared to delayed access physicians (n = 2, 3.7%, P < .001; estimated adjusted odds ratio of mastery for the immediate access group, 31.1 [95% CI, 6.8–143.1]). There were no significant differences when adjusting for training site or stage of training. Conclusions. The Uncertainty Communication Education Module significantly increased mastery in communicating diagnostic uncertainty at the time of first post-intervention test among emergency physicians in standardized patient encounters. Further work should assess the impact of clinical implementation of these communication skills.

PURPOSE: Racial and ethnic disparities in genetic awareness (GA) can diminish the impact of personalized cancer treatment and risk assessment. We assessed factors predictive of GA in a diverse population–based sample to inform awareness strategies and reduce disparities in genetic testing. METHODS: A cross-sectional study was conducted from July 2019 to August 2019, with the survey e-mailed to 7,575 adult residents in southeastern Pennsylvania and New Jersey. Constructs from National Cancer Institute Health Information and National Trends Survey assessed cancer attitudes or beliefs, health literacy, and numeracy. Characteristics were summarized with mean ± standard deviation for numeric variables and frequency counts and percentages for categorical variables. Comparison of factors by race or ethnicity (non-Hispanic White and non-Hispanic Black) and sex was conducted by t-tests, chi-square, or Fisher's exact tests. Multivariate logistic regression models were conducted to identify factors independently predictive of GA. RESULTS: Of 1,557 respondents, data from 940 respondents (the mean age was 45 ± 16.2 years, 35.5% males, and 23% non-Hispanic Blacks) were analyzed. Factors associated with higher GA included female gender ( P < .001), non-Hispanic White ( P < .001), college education ( P < .001), middle-higher income ( P < .001), stronger belief in genetic basis of cancer ( P < .001), lower cancer fatalism ( P = .004), motivation for cancer information ( P < .001), and higher numeracy ( P = .002). On multivariate analysis, college education (odds ratio [OR] 1.79; 95% CI, 1.22 to 2.63), higher motivation for cancer information (OR 1.56; 95% CI, 1.17 to 2.09), stronger belief in genetics of cancer (OR 2.21; 95% CI, 1.48 to 3.30), and higher medical literacy (OR 2.21; 95% CI, 1.34 to 3.65) predicted greater GA. CONCLUSION: This population-based study conducted in the precision medicine era identified novel modifiable factors, importantly perceptions of cancer genetics and medical literacy, as predictive of GA, which informs strategies to promote equitable engagement in genetically based cancer care.

Uveal melanoma is the most common primary ocular malignancy in adults, characterized by gene mutations in G protein subunit alpha q (GNAQ) and G protein subunit alpha 11 (GNA11). Although they are considered to be driver mutations, their role in MUM remains elusive. We investigated key somatic mutations of MUM and their impact on patients’ survival after development of systemic metastasis (Met-to-Death). Metastatic lesions from 87 MUM patients were analyzed by next generation sequencing (NGS). GNA11 (41/87) and GNAQ (39/87) mutations were most predominantly seen in MUM. Most GNA11 mutations were Q209L (36/41), whereas GNAQ mutations comprised Q209L (14/39) and Q209P (21/39). Epigenetic pathway mutations BAP1 (42/66), SF3B1 (11/66), FBXW7 (2/87), PBRM1 (1/66), and SETD2 (1/66) were found. No specimen had the EIF1AX mutation. Interestingly, Met-to-Death was longer in patients with GNAQ Q209P compared to GNAQ/GNA11 Q209L mutations, suggesting the difference in mutation type in GNAQ/GNA11 might determine the prognosis of MUM. Structural alterations of the GNAQ/GNA11 protein and their impact on survival of MUM patients should be further investigated.