Clinical implication of genetic intratumor heterogeneity for targeted therapy in head and neck cancer.

BACKGROUND: Genomic profiling is increasingly used both in therapeutic decision-making and as inclusion criteria for trials testing targeted therapies. However, the mutational landscape may vary across different areas of a tumor and intratumor heterogeneity will challenge treatments or clinical decisions based on single tumor biopsies. The purpose of this study was to assess the clinical relevance of genetic intratumor heterogeneity in head and neck squamous cell carcinomas (HNSCC) using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). MATERIALS AND METHODS: This prospective study included 33 whole tumor specimens from 28 patients with primary or recurrent HNSCC referred for surgery. Three tumor blocks were selected from central, semi-peripheral, and peripheral positions, mimicking biopsies in three different locations. Genetic analysis of somatic copy number alterations (SCNAs) was performed on the three biopsies using Oncoscan, focusing on 45 preselected HNSCC genes of interest. Clinical relevance was assessed using the ESCAT score to investigate whether and how treatment decisions would change based on the three biopsies from the same tumor. RESULTS: The SCNAs identified among 45 preselected genes within the three tumor biopsies derived from the same tumor revealed distinct variations. The detected discrepancies could potentially influence treatment approaches or clinical decisions in 36% of the patients if only one tumor biopsy was used. Recurrent tumors exhibited significantly higher variation in SCNAs than primary tumors (p = .024). No significant correlation between tumor size and heterogeneity (p = .7) was observed. CONCLUSION: In 36% of patients diagnosed with HNSCC, clinically significant intratumor heterogeneity was observed which may have implications for patient management. This finding substantiates the need for future studies that specifically investigate the clinical implications associated with intratumor heterogeneity.

3D Ultrasound and MRI in Assessing Resection Margins during Tongue Cancer Surgery: A Research Protocol for a Clinical Diagnostic Accuracy Study.

Surgery is the primary treatment for tongue cancer. The goal is a complete resection of the tumor with an adequate margin of healthy tissue around the tumor.Inadequate margins lead to a high risk of local cancer recurrence and the need for adjuvant therapies. Ex vivo imaging of the resected surgical specimen has been suggested for margin assessment and improved surgical results. Therefore, we have developed a novel three-dimensional (3D) ultrasound imaging technique to improve the assessment of resection margins during surgery. In this research protocol, we describe a study comparing the accuracy of 3D ultrasound, magnetic resonance imaging (MRI), and clinical examination of the surgical specimen to assess the resection margins during cancer surgery. Tumor segmentation and margin measurement will be performed using 3D ultrasound and MRI of the ex vivo specimen. We will determine the accuracy of each method by comparing the margin measurements and the proportion of correctly classified margins (positive, close, and free) obtained by each technique with respect to the gold standard histopathology.

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis.

BACKGROUND: p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. METHODS: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. FINDINGS: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0·744, p=0·0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5-82·7) for p16+/HPV+, 40·4% (38·6-42·4) for p16-/HPV-, 53·2% (46·6-60·8) for p16-/HPV+, and 54·7% (49·2-60·9) for p16+/HPV-. 5-year disease-free survival was 84·3% (95% CI 82·9-85·7) for p16+/HPV+, 60·8% (58·8-62·9) for p16-/HPV-; 71·1% (64·7-78·2) for p16-/HPV+, and 67·9% (62·5-73·7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. INTERPRETATION: Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. FUNDING: European Regional Development Fund, Generalitat de Catalunya, National Institute for Health Research (NIHR) UK, Cancer Research UK, Medical Research Council UK, and The Swedish Cancer Foundation and the Stockholm Cancer Society.

Impact of time to treatment initiation for patients with oral cavity squamous cell carcinoma: a population-based, retrospective study.

BACKGROUND: The increasing incidence of oral cavity squamous cell carcinoma (OSCC) is challenging the capacity to treat patients efficiently. The aim of this study was to evaluate the impact of time to treatment initiation (TTI) on overall survival (OS) and recurrence free survival (RFS) for patients with primary OSCC. MATERIAL AND METHODS: All patients with primary OSCC treated with curative intent at Rigshospitalet in the period 2000-2014 with known date of diagnosis and treatment initiation were included. Correlation analyses between TTI and Charlson comorbidity index (CCI), UICC stage, and year of diagnosis were performed in addition to uni- and multivariate Cox proportional hazard regression analyses. Further, interaction analysis of TTI and UICC stage were conducted. RESULTS: Eight hundred and sixty-two patients (64% men) with a median age at diagnosis of 62 years (range: 28-95 years) were included. The median TTI was 31 days (range: 2-137 days). Correlation analyses showed correlations between TTI and CCI, TTI and UICC stage, and TTI and year of diagnosis (rho = -0.10, p-value = <.01; rho = 0.16, p-value = <.001; rho = -0.47 p-value = <.001). Univariate analyses showed a statistically significant increase in hazard ratio for both OS and RFS with a five-day increase in TTI (HR = 1.05, 95%CI: 1.02-1.07 and HR = 1.04, 95%CI: 1.02-1.07). However, when adjusting for age, sex, smoking, UICC stage, tumor sublocation, CCI, and year of diagnosis in a multivariate analysis, the increase in HR with TTI was not statistically significant. There was no statistically significant interaction between TTI and UICC stage. CONCLUSION: Survival of OSCC patients decreased with increasing TTI, yet not statistically significant in multivariate analysis. There was no difference in the effect of TTI between patients diagnosed in low or advanced stages.

High nodal FDG uptake increases risk of distant metastasis in patients with oropharyngeal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to investigate if FDG uptake metrics in primary tumor and lymph node metastases in patients with oropharyngeal squamous cell carcinoma (OPSCC) has a prognostic value beyond UICC8 staging in a multiple endpoint model. METHODS: Patients with OPSCC treated with primary radiotherapy at Rigshospitalet in the period 2010-2017 were included. All patients had a pretreatment FDG PET/CT scan performed. Four cause-specific Cox regression models were built for the hazard ratios (HR) of recurrence in T-, N-, M-site, and death with no evidence of disease (NED), respectively. The following variables were included: T-, N-stage, p16 status, metabolic tumor volume, and FDG uptake in both primary tumor and lymph nodes. A competing risk analysis was performed and absolute risk estimates were estimated using the Aalen-Johansen method. RESULTS: Overall, 441 patients were included. Thirty-four patients had T-site recurrence, 31 N-site recurrence, 32 M-site recurrence, and 52 patients had death NED as event. Nodal FDG uptake had a significant impact on N- and M-site recurrence, with HRs of 2.13 (CI 1.20-3.77) and 2.18 (CI 1.16-4.10). The individual prognostication of absolute risk of the four events for any given patient can be assessed in the online tool (https://rasmussen.shinyapps.io/OPSCCmodelFDG_PET/). CONCLUSION: High nodal FDG uptake increases the risk of N- and M-site recurrence in patients with OPSCC in a competing risk scenario. The reported results are available in an easy applicable online tool and can help identify relevant candidates for future trials testing treatment approaches.

Risk of Thyroid Cancer in 1,504 Patients Referred for Thyroid Surgery with Assumed Benign Histology.

OBJECTIVES: The aims of this study were to report the risk of thyroid malignancy in cases of either benign fine-needle aspiration (FNA) or without FNA performed, and to investigate possible predictive factors for thyroid malignancy in a population with recent moderately low iodine intake. METHODS: All patients referred for thyroid surgery in a tertiary cancer centre between 2000 and 2016 were included (n = 3,703). After excluding cases indicating malignant histology, we included group 1: patients with benign FNA (n = 764), and group 2: patients without FNA (n = 740), leaving 1,504 eligible for further investigation. Information on age, gender, tracheal compression or dislocation, thyroid specimen weight, scintigraphy, ultrasound, medically treated thyrotoxicosis, serum stimulating thyroid hormone, indication for surgery, TNM classification, stage, and outcome were retrieved. RESULTS: The malignancy risk was 7.6% (58/764) in group 1 and 6.8% (50/740) in group 2. Patients with T2-4 tumours constituted 2.2% (33/1,504). In the combined groups, ultrasound verified that solitary solid tumour was predictive for malignancy (p = 0.01 by χ2, and OR = 1.69, p = 0.02 in multiple logistic regression). For group 1 patients, thyrotoxicosis (which in this case was medically treated) was a significant predictive factor for malignancy (p = 0.04). CONCLUSIONS: The risk of malignancy of 7.6% and 6.8% was high, considering that patients with malignant FNA, suspicious FNA, or clinical findings indicating malignancy were excluded, and 2.2% of these malignancies were stages T2-4. In cases with solitary solid tumour on ultrasound, the risk of malignancy should not be ignored, even with benign FNA.