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Systematic efforts to sequence the cancer genome have identified large numbers of relevant mutations and copy number alterations in human cancers; however, elucidating their functional consequences, and their interactions to drive or maintain oncogenic states, is still a significant challenge. Here we introduce REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene-dependency of oncogenic pathways or the sensitivity to a drug treatment. We use REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes.

Aim: The response rates to immune checkpoint inhibitors (ICI) remain low (13%-20%) in metastatic head and neck cancer patients, indicating an urgent need to better understand factors predictive of response to these agents. This study explored the impact of smoking status, marijuana use, and alcohol consumption on treatment outcomes in recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients treated with ICI., Methods: A retrospective analysis was performed on 201 R/M HNSCC patients treated with ICI between January 15th 2016 and April 9th 2020 at a single institution., Results: Gender: 154 male (77%), 47 female (23%). Median age 61 (IQR: 55-68). ICI drug: pembrolizumab 100 (50%), nivolumab 91 (45%), nivolumab + ipilimumab 10 (5%). Line of therapy: first: 98 (49%), second and beyond: 103 (51%). Tumor site: oropharynx 84 (42%), oral cavity 45 (22%), larynx 26 (13%), other sites 46 (23%). p16 tumor status: negative 132 (66%), positive 69 (34%). Smoking status: former 111 (55%), never 54 (27%), current 36 (18%), median pack-year 18 (IQR: 0-37). Alcohol use: yes 110 (55%), no 91 (54%). Marijuana use: yes 47 (23%), no 154 (77%). Overall response rate: 36 (18%). Median OS: 12 months (95% CI: 9.4-14.8). Tobacco: former (HR: 0.75, 95% CI: 0.50, 1.11), current (HR: 0.58, 95% CI: 0.33, 1.02). Marijuana: yes (HR: 0.93, 95% CI: 0.58, 1.49). Alcohol: yes (HR: 1.04, 95% CI: 0.72, 1.49)., Conclusion: In our cohort, smoking status, marijuana use, and alcohol consumption did not have a statistically significant impact on OS in patients with R/M HNSCC treated with ICI., (© 2024 John Wiley & Sons Australia, Ltd.)

Importance: National Comprehensive Cancer Network guidelines recommend weekly cisplatin as an alternative concurrent systemic therapy for definitive chemoradiation in patients with head and neck cancer. However, the impact of different levels of adherence to weekly cisplatin on outcomes stratified by human papillomavirus p16 status remains unclear., Objective: To evaluate the association between the number of weekly cisplatin cycles and outcomes., Design, Setting, and Participants: This retrospective, observational, single-institution cohort study at The Ohio State Comprehensive Cancer Center included patients with a diagnosis of nonmetastatic head and neck cancer between December 1, 2011, and March 30, 2020, who received chemoradiation. Data analysis was performed between March and May 2024., Exposure: A total of 5, 6, or 7 to 8 weekly cisplatin cycles., Main Outcomes and Measures: The primary outcomes were overall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF). Cox multivariable analysis was performed for variables associated with OS and PFS, and Fine-Gray multivariable analysis was performed for variables associated with LRF and DF., Results: A total of 142 patients met the criteria (119 men [83.8%]; median [IQR] age, 59 [54-63] years). Median (IQR) follow-up was 46.8 (40.8-55.6) months. Among 92 patients with reasons for cisplatin interruption reported, the most common reason was low blood counts (42 patients [45.7%]). Those who missed weekly cisplatin cycles had worse OS (adjusted hazard ratio [aHR], 2.22; 95% CI, 1.19-4.17; P = .01) and PFS (aHR, 1.83; 95% CI, 1.06-3.15; P = .03) than those who received 7 to 8 cycles. Cancer control outcomes were comparable between these groups (LRF aHR, 0.53; 95% CI, 0.15-1.93; P = .34; DF aHR, 1.51; 95% CI, 0.60-3.82; P = .38). Patients with p16-negative tumors who missed weekly cisplatin cycles had worse OS (for every missing cisplatin cycle, aHR, 11.34, 1.51-84.94; P = .02) than those treated with 7 to 8 cycles. However, for those with p16-positive tumors, there were no statistically significant differences in OS between those who missed weekly cisplatin cycles vs others who received 7 to 8 cycles (aHR, 1.21; 95% CI, 0.47-3.14; P = .69)., Conclusions and Relevance: In this cohort study of patients with head and neck cancer who received definitive chemoradiation, those with p16-negative tumors who missed weekly cisplatin cycles had lower OS than those who received 7 to 8 cycles, although OS was comparable between these groups for p16-positive tumors. Cytopenia represented the most common reason for cisplatin interruption.

Circulating tumor tissue modified (TTMV)-HPV DNA has emerged as a promising biomarker in human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV-OPSCC). The objective of this study was to assess ctHPVDNA TTMV clearance kinetics during RT and its relationship with progression in HPV-OPSCC. We identified 80 non-metastatic HPV-OPSCC patients with 366 TTMV samples who underwent prospective plasma TTMV testing before, during and after curative intent RT or CRT between June 2021 and February 2023. Patients with rapid favorable clearance (>95% decline from pre-treatment value) of TTMV were compared to those with suboptimal clearance (<95%). The primary objective was to evaluate the relationship between TTMV clearance during CRT and its impact on progression free survival (PFS). The median follow-up was 14.7 months. Clinical nodal stage was associated with higher TTMV-HPV DNA scores at baseline, with a median score of 128, 778, and 1219 for N0/N1, N2a/b, and N2c/3 patients, respectively. Patients who had persistent TTMV at the end of RT had an inferior PFS compared to those who cleared their TTMV at 2 years (91.7% vs. 71.7%) (log rank, p = .042). Among patients who had complete clearance of their TTMV at 3 months, those who had a negative, equivocal, and incomplete PET response had a 2-year PFS of 94.3%, 77.8%, and 59.3%, respectively (log-rank, p = .029). Our study indicates that persistent TTMV-HPV DNA is associated with worse PFS and may portend unfavorable outcomes. Thus, monitoring TTMV clearance kinetics could be a valuable biomarker for guiding treatment decisions in patients with HPV-OPSCC., (© 2024 UICC.)

HPV viral E6 and E7 onco-proteins play a well-known role in carcinogenesis. Host genomic alterations also play a key role in the development of HPV-related oropharyngeal cancer and have been under-recognized. We describe a case series of 6 metastatic/locoregionally recurrent HPVOPSCC patients with FGFR alterations. HPVOPSCC presents with distinct pattern of spread both temporally and sites of recurrence compared to  non-HPV-related oropharyngeal cancer. Identification and reporting of genomic alterations in HPV are crucial to the understanding of disease biology and could aid in development of novel therapeutics for these patients. In addition, use of circulating tumor DNA may lead to early detection and supplement imaging in the follow up of these patients. Loco-regional treatments may also play a key role in the management of metastatic HPV OPSCC depending on the pattern of presentation. Our case series highlights all these novelties that could lead to better treatment outcomes., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Radiation-associated sarcomas (RASs) are rare tumors with limited contemporary data to inform prognostication and management. We sought to identify the clinical presentation, patterns of care, and prognostic factors of RASs. RAS patients treated at a single institution from 2015 to 2021 were retrospectively reviewed for clinicopathologic variables, treatment strategies, and outcomes. Thirty-eight patients were identified with a median follow-up of 30.5 months. The median age at RAS diagnosis was 68.4 years (27.9-85.4), with a median latency from index radiotherapy (RT) of 9.1 years (3.7-46.3). RAS histologies included angiosarcoma (26%), undifferentiated pleomorphic sarcoma (21%), and osteosarcoma (18%). Most were high-grade (76%). Genomic profiling revealed low tumor mutational burden, frequent inactivating TP53 mutations (44%), CDKN2A deletions (26%), and MYC amplifications (22%), particularly in breast angiosarcomas. Of 38 patients, 33 presented with localized disease, 26 of whom were treated with curative intent. Overall, the median progression-free survival (PFS) was 9.5 months (1.4-34.7), and the overall survival (OS) was 11.1 months (0.6-31.6). Patients with localized vs. metastatic RASs had a longer PFS (HR, 3.0 [1.1-8.5]; p = 0.03) and OS (HR, 3.0 [1.04-8.68]; p = 0.03). Among localized RAS patients, high grade was associated with shorter OS (HR, 4.6 [1.04-20.30]; p = 0.03) and resection with longer OS (mean 58.8 vs. 6.1 months, HR, 0.1 [0.03-0.28]; p < 0.001). Among patients undergoing resection, negative margins were associated with improved OS (mean 71.0 vs. 15.5 months, HR, 5.1 [1.4-18.2]; p = 0.006). Patients with localized disease, particularly those undergoing R0 resection, demonstrated significantly better outcomes. Novel strategies are urgently needed to improve treatment outcomes in this challenging group of diseases.

Purpose: Significant heterogeneity exists in clinical quality assurance (QA) practices within radiation oncology departments, with most chart rounds lacking prospective peer-reviewed contour evaluation. This has the potential to significantly affect patient outcomes, particularly for head and neck cancers (HNC) given the large variance in target volume delineation. With this understanding, we incorporated a prospective systematic peer contour-review process into our workflow for all patients with HNC. This study aims to assess the effectiveness of implementing prospective peer review into practice for our National Cancer Institute Designated Cancer Center and to report factors associated with contour modifications., Methods and Materials: Starting in November 2020, our department adopted a systematic QA process with real-time metrics, in which contours for all patients with HNC treated with radiation therapy were prospectively peer reviewed and graded. Contours were graded with green (unnecessary), yellow (minor), or red (major) colors based on the degree of peer-recommended modifications. Contours from November 2020 through September 2021 were included for analysis., Results: Three hundred sixty contours were included. Contour grades were made up of 89.7% green, 8.9% yellow, and 1.4% red grades. Physicians with >12 months of clinical experience were less likely to have contour changes requested than those with <12 months (8.3% vs 40.9%; P < .001). Contour grades were significantly associated with physician case load, with physicians presenting more than the median number of 50 cases having significantly less modifications requested than those presenting <50 (6.7% vs 13.3%; P = .013). Physicians working with a resident or fellow were less likely to have contour changes requested than those without a trainee (5.2% vs 12.6%; P = .039). Frequency of major modification requests significantly decreased over time after adoption of prospective peer contour review, with no red grades occurring >6 months after adoption., Conclusions: This study highlights the importance of prospective peer contour-review implementation into systematic clinical QA processes for HNC. Physician experience proved to be the highest predictor of approved contours. A growth curve was demonstrated, with major modifications declining after prospective contour review implementation. Even within a high-volume academic practice with subspecialist attendings, >10% of patients had contour changes made as a direct result of prospective peer review., Competing Interests: Disclosures None., (Published by Elsevier Inc.)

The incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing among elderly (≥70 years) patients and the optimal treatment approach is not known. In this study, we aimed to determine disease and toxicity outcomes in an elderly HPV-OPSCC population primarily treated with a chemoradiation (CRT) approach. We identified 70 elderly HPV-OPSCC patients who were treated with either surgery, radiotherapy, or CRT between 2011 and 2021. Time-to-event analysis for overall survival (OS), progression-free survival (PFS), and local control (LC) were conducted using the Kaplan-Meier method. Univariate and multivariable cox regression models were used to estimate the hazard ratio associated with covariates. The median follow-up for our cohort was 43.9 months. Of the 70 elderly patients, 55 (78.6%) receive CRT and 15 (22.4%) received RT alone. Two patients underwent TORS resection. Of the 55 patients treated with CRT, the most common systemic agents were weekly carboplatin/taxol (n = 18), cetuximab (n = 17), and weekly cisplatin (n = 11). The 5-year OS, PFS, and LC were 57%, 52%, and 91%, respectively. On univariate analysis, Eastern Cooperative Oncology Group performance status and Charlson Comorbidity Index (CCI) were significant predictors of OS, while on multivariate analysis only CCI was a significant predictor of OS (p = 0.006). The rate of late peg tube dependency, osteoradionecrosis, and aspiration was 10%, 4%, and 4%, respectively. Definitive local therapy in elderly HPV-OPSCC patients is associated with excellent LC and a low rate of late toxicities. Prospective studies are needed to further stratify subgroups of elderly patients who may benefit from aggressive definitive local therapy., (© 2023 Wiley Periodicals LLC.)

Background: The addition of radiation therapy to surgery for retroperitoneal sarcoma remains controversial. Improved patient selection may help identify optimal candidates for multimodality treatment. The aim of this analysis was to define prognostic factors among patients who receive radiation therapy and surgery to aid in patient selection for multimodal therapy., Methods: Patients who received radiation therapy and underwent curative-intent resection for retroperitoneal sarcoma between 2004 and 2016 were identified from a national cohort in the United States (National Cancer Database). A machine-based classification and regression tree model was used to generate similar groups of patients relative to overall survival based on preoperative factors., Results: A total of 1,443 patients received radiation therapy in addition to surgery. Median age was 61 years old and 55.0% were female. Most patients (66%) received care at an academic or integrated network cancer program. With a median follow-up of 84 months, receipt of radiation therapy was not associated with improved overall survival (P = .81). Classification and regression tree analysis revealed a significant association between overall survival and American Joint Committee on Cancer stage group, age, tumor histology, and Charlson comorbidity score. Application of these parameters via machine learning stratified patients into 5 cohorts with distinct survival outcomes. In the most favorable cohort (Cohort 1: American Joint Committee on Cancer stage group ≤II, age ≤61, histology including fibrosarcoma, well differentiated liposarcoma, myxoid liposarcoma, and leiomyosarcoma), the 5-year overall survival was 81.7% and median overall survival was not reached; in the least favorable cohort (Cohort 6: American Joint Committee on Cancer stage group >II, age >68) where the 5-year survival was 41.3% and median overall survival was 45.2 months (P < .001 versus Cohort 1)., Conclusion: In the absence of a defined survival benefit, patients with advanced American Joint Committee on Cancer stage group, older age, and medical comorbidities have relatively unfavorable overall survival after combined modality therapy and therefore stand the least to gain from the addition of radiation therapy to surgery. In contrast, younger patients with good performance status and retroperitoneal sarcoma histologies with a higher propensity for local recurrence may have the greatest opportunity to benefit from radiation therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Genome-wide association studies in cohorts of European descent have identified novel genomic regions as associated with lipids, but their relevance in African Americans remains unclear., Methods and Results: We genotyped 8 index single nucleotide polymorphisms (SNPs) and 488 tagging SNPs across 8 novel lipid loci in the Jackson Heart Study, a community-based cohort of 4605 African Americans. For each trait, we calculated residuals adjusted for age, sex, and global ancestry and performed multivariable linear regression to detect genotype-phenotype association with adjustment for local ancestry. To explore admixture effects, we conducted stratified analyses in individuals with a high probability of 2 African ancestral alleles or at least 1 European allele at each locus. We confirmed 2 index SNPs as associated with lipid traits in African Americans, with suggestive association for 3 more. However, the effect sizes for 4 of the 5 associated SNPs were larger in the European local ancestry subgroup compared with the African local ancestry subgroup, suggesting that the replication is driven by European ancestry segments. Through fine-mapping, we discovered 3 new SNPs with significant associations, 2 with consistent effect on triglyceride levels across ancestral groups: rs636523 near DOCK7/ANGPTL3 and rs780093 in GCKR. African linkage disequilibrium patterns did not assist in narrowing association signals., Conclusions: We confirm that 5 genetic regions associated with lipid traits in European-derived populations are relevant in African Americans. To further evaluate these loci, fine-mapping in larger African American cohorts and/or resequencing will be required.