Oropharyngeal Squamous Cell Carcinoma Patients Research Articles

Mutation patterns in recurrent and/or metastatic oropharyngeal squamous cell carcinomas in relation to human papillomavirus status.

Patients with HPV‐driven (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) have a significantly improved overall survival compared to patients with HPV‐negative (HPV−) OPSCC. Nevertheless, 13%–25% of patients with HPV+OPSCC develop local/distant recurrence (LDR) and have a course of disease similar to HPV−OPSCC. We hypothesize that HPV+OPSCCs of patients with LDR have a mutation frequency and pattern similar to HPV−OPSCCs, which is associated with severe outcome. We performed targeted next‐generation sequencing using a customized gene panel and compared data from 56 matched HPV+and HPV−OPSCC of patients with/without LDR regarding protein‐altering variants. Despite improved overall survival of patients with HPV+OPSCC, those who develop LDR show a strongly reduced survival rate that is similar or even worse compared to HPV−OPSCC patients. Overall, the number of mutations was similar in OPSCC of patients with and without LDR. In total and with respect to TP53, HPV−OPSCC had significantly more protein‐altering mutations than HPV+OPSCC. The number of mutations was similar in HPV−OPSCC of patients with and without LDR with the exception of FAT1, which was mutated more frequently in patients without LDR. In HPV+OPSCC, HRAS, PIK3R1, STK11 and TP63 were more frequently mutated in patients with LDR compared to patients without. HPV+OPSCC of patients with LDR have a similar mutation pattern as HPV−OPSCC, except TP53, which was mutated to a significantly lower extent. In conclusion, HPV−and HPV+OPSCC with LDR have similar mutation counts in the analyzed genes. We suspect that the number of mutations is not causal for disease progression, rather specific mutations could be important.

Decreasing treatment burden in HPV-related OPSCC: A systematic review of clinical trials.

Favorable outcomes are observed after treatment with standard chemoradiotherapy (CRT) for Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) patients. The consistent growing interest on treatment-related toxicity burden, potentially jeopardizing survivors' quality of life, led clinicians to investigate possible de-escalation strategies. A comprehensive systematic literature search of clinical trials was performed through the EMBASE database to provide an overview of the de-escalation strategies spectrum. Additionally, hand searching and clinicaltrials.gov were also used. Herein, we report and discuss different approaches to de-escalation of therapy, with respect to both local and systemic strategies. Several promising de-escalation experiences have been published. However, while further evidence is awaited, no changes in the management nor deviation from the standard of care should be made outside of clinical trials.

Correlation of HPV16 Gene Status and Gene Expression With Antibody Seropositivity and TIL Status in OPSCC.

IntroductionHuman papillomavirus 16 (HPV16) is the main cause of oropharyngeal squamous cell carcinoma (OPSCC). To date, the links between HPV16 gene expression and adaptive immune responses have not been investigated. We evaluated the correlation of HPV16 DNA, RNA transcripts and features of adaptive immune response by evaluating antibody isotypes against E2, E7 antigens and density of tumor-infiltrating lymphocytes (TIL).Material and MethodsFFPE-tissue from 27/77 p16-positive OPSCC patients was available. DNA and RNA were extracted and quantified using qPCR for all HPV16 genes. The TIL status was assessed. Immune responses against E2 and E7 were quantified by ELISA (IgG, IgA, and IgM; 77 serum samples pre-treatment, 36 matched post-treatment).ResultsAmounts of HPV16 genes were highly correlated at DNA and RNA levels. RNA co-expression of all genes was detected in 37% (7/19). E7 qPCR results were correlated with higher anti-E7 antibody (IgG, IgA) level in the blood. Patients with high anti-E2 IgG antibody (>median) had better overall survival (p=0.0311); anti-E2 and anti-E7 IgA levels had no detectable effect. During the first 6 months after treatment, IgA but not IgG increased significantly, and >6 months both antibody classes declined over time. Patients with immune cell-rich tumors had higher levels of circulating antibodies against HPV antigens.ConclusionWe describe an HPV16 qPCR assay to quantify genomic and transcriptomic expression and correlate this with serum antibody levels against HPV16 oncoproteins. Understanding DNA/RNA expression, relationship to the antibody response in patients regarding treatment and outcome offers an attractive tool to improve patient care.

Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma

BackgroundDespite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC).MethodsThe present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC.ResultsThe UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression.ConclusionsThese results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.

Expression of p16INK4a in oropharyngeal squamous cell carcinoma from a tertiary cancer centre of South India: A preliminary study

Background & objectives:Human papillomavirus (HPV) and oropharyngeal squamous cell carcinoma (OPSCC) are found to be strongly associated with each other with an increase in incidence has been noted globally over the years. A literature search for data depicting the role of HPV in oropharyngeal carcinoma in South India, however, has resulted in little information, thus, the present study was aimed to assess a possible association between the two among OPSCC patients from a tertiary care cancer centre in South India.Methods:One hundred and fourty three OPSCC cases were included in the study and analyzed for age, gender, marital status, habits, clinical TNM staging, site, laterality, symptoms, histological type (keratinizing and non-keratinizing), primary treatment and follow up period. All the cases were subjected to p16INK4a immunostaining. Statistical analysis was done using SPSS software.Results:Of the 143 cases 12 were found to be p16 positive with no significant difference between the study variables among p16 positive and negative cases. Base of the tongue was the most commonly involved site for the p16 positive cases. The p16 positive cases presented at an elderly age, early stage and were mainly the keratinizing type.Interpretation & conclusions:The p16 positive OPSCC cases constituted a small proportion in the present study and behaved similar to p16 negative cases. Usage of tobacco and alcohol appear to be the susceptible factors even in p16 positive cases. More studies from other States would be helpful to determine if HPV-related SCC in the Indian subcontinent behave differently or similarly to cases from Western countries.

Abstract PO-232: Univariate and multivariate prognostic factors for overall survival among oropharyngeal cancer patients with known HPV/p16 status

Abstract Purpose: To assess the prognostic significance of tumor HPV/p16 status among oropharyngeal squamous-cell carcinoma (SCC) patients. Methods: A retrospective analysis of 80 patients diagnosed with oropharyngeal SCC between 2008 and 2018 at an academic medical center with known HPV/p16 status was performed. Pearson’s Chi-squared test was used to compare the proportional differences between the known tumor HPV status among positive and negative p16 staining groups. Kaplan- Meier analysis was used to estimate overall survival [OS] and local control [LC] between the HPV groups stratified by risk and compared using the log-rank test. Uni and multi-variable Cox hazard regression analyses were used to compare the risk of death among patients with HPV- positive and HPV- negative cancer. The SPSS v.24.0 was used for all statistical analyses. Results: Our patient cohort included 37.5% HPV- positive and 62.5% HPV-negative (median age, 61 y; range 45-86 y) patients. Patient groups were classified on the basis of risk factors: HPV/p16 status, pack-years [py] of tobacco smoking, and tumor stage into low (p16+, ≤ 10 py), intermediate (p16+, > 10 py/p16-, < 10 py), and high risk (p16-, > 10 py/ any T4), accounting for 36.7%, 36.7% and 26.7% of HPV-positive and 0%, 20% and 40% of HPV-negative patients, respectively (p=0.000). The median follow-up duration for this cohort was 34 months (range 0 to 154 months). The low risk HPV-positive group had better 5-year OS rates (87.5%, vs. 59.5% and 27.2%) compared to intermediate and high risk groups (p=0.003 by the log-rank test). After adjustment for gender, age, race, income level, distance travelled, tobacco exposure, alcohol history, tumor stage, and treatment modality, this group had a 63% reduction in the risk of death (hazard ratio, 0.37; 95% CI, 0.18-0.77; p= 0.008). Insurance and BMI was associated with a 71% reduction (hazard ratio, 0.29; 95% CI, 0.97-0.89; p=0.032), and a 49% reduction in the risk of death (hazard ratio, 0.51; 95% CI, 0.37-0.71; p=0.000), respectively. In terms of LC, the low risk HPV-positive patients had better 3-year rates 70.1%, vs. 55.7% and 39.9% compared to the intermediate and, high risk groups (p=0.379). Conclusion: Tumor HPV/p16 status may be an independent prognostic factor along with insurance status and BMI for overall survival among oropharyngeal SCC patients. Citation Format: Mary R. Nittala, Eswar K. Mundra, Ashley Albert, William C. Woods, Maria L. Smith, Robert D. Hamilton, Lana Jackson, Gina Jefferson, Satyaseelan Packianathan, Eldrin Bhanat, Varsha Manucha, Srinivasan Vijayakumar. Univariate and multivariate prognostic factors for overall survival among oropharyngeal cancer patients with known HPV/p16 status [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-232.

Abstract PO-104: Impact of race on outcomes in oropharyngeal squamous-cell carcinoma patients with known HPV/p16 status

Abstract Purpose: To evaluate the impact of race (African-American [AA] vs. Caucasians [C]) on the survival outcome in patients with oropharyngeal squamous-cell carcinoma (SCC) known HPV/p16 status. Methods: Between 2008 and 2018, eighty patients with known HPV/p16 status were diagnosed with oropharyngeal SCC in our academic state institution. Chi-square test, Kaplan-Meier method, and Cox regression models were used to assess for racial influence; p-values less than 0.05 were considered statistically significant. The SPSS v.24.0 was used for all statistical analyses. Results: The median follow-up duration was 34 months (range 0 to 154 months). Our patient cohort included 48.8% AA and 51.2% C (median age, 61 y; range 45-86 y) patients. Patient risk groups were stratified based on HPV/p16 status, pack-years [py] of tobacco smoking, and tumor stage into low (p16+, ≤10 py), intermediate (p16+, >10 py/p16-, <10 py), and high risk (p16-, >10 py/ any T4), accounting for 2.6%, 25.6% and 71.8% of AA vs. 24.4%, 26.8% and 48.8% of C patients, respectively (p=0.013). The C patients had better 5-year overall survival [OS] rates (88.9%, 62.2% and 37.5% vs. na, 48.0% and 25.6% compared to AA patients stratified by risk (p=0.009). The OS of low risk AA patients was not assessable because of a low number (1) of patients in that group. In the bivariate Cox regression analysis, the covariates stratified by race, type of insurance, BMI level, HPV/p16 status, risk groups, and 8th AJCC staging were statistically significant with p-value less than 0.05. In the multivariate analysis, the covariates of insurance-private was associated with 87% reduction (hazard ratio, 0.13; 95% CI, 0.03-0.61; p=0.010), insurance-Medicare was associated with 71% reduction (hazard ratio, 0.29; 95% CI, 0.11-0.74; p=0.010), and AJCC TNM stages III, IV and IVB (98%, 97% and 93%) with reduction in the risk of death (hazard ratio, 0.02; 95% CI, 0.00-0.38; p=0.009), (hazard ratio, 0.03; 95 CI, 0.00-0.55; p=0.017), (hazard ratio, 0.07; 95% CI, 0.00-0.92), respectively. In terms of local control [LC], the C patients also had better 3-year rates 66.4%, vs. 32.8% compared to AA patients (p=0.049). Conclusion: In our patient population, race appears to be an independent prognostic factor for OS and LC in oropharyngeal SCC patients with known HPV/p16 status. Citation Format: Mary R. Nittala, Eswar K. Mundra, Maurice L. King, Ashley Albert, Williams C. Woods, Maria L. Smith, Robert D. Hamilton, Lana Jackson, Gina Jefferson, Satyaseelan Packianathan, Varsha Manucha, Srinivasan Vijayakumar. Impact of race on outcomes in oropharyngeal squamous-cell carcinoma patients with known HPV/p16 status [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-104.

Human Papillomavirus DNA Detection by Droplet Digital PCR in Formalin-Fixed Paraffin-Embedded Tumor Tissue from Oropharyngeal Squamous Cell Carcinoma Patients.

High-risk human papillomavirus infection impacts staging and prognosis of oropharyngeal squamous cell carcinomas (OPSCCs). Determination of HPV status in tumor tissue by p16-immunohistochemistry (p16-IHC) can be challenging; therefore, complementary methodologies could be useful in a clinical setting. To test for accuracy and clinical relevance of HPV-DNA detection in formalin-fixed and paraffin-embedded (FFPE) tumor samples by droplet digital PCR (ddPCR). Fifty OPSCCs were tested for p16-IHC status followed by HPV-16/18 DNA detection/quantification in FFPE-recovered DNA using ddPCR. Accuracy for HPV status determination and association with patient information were also evaluated. 32.0% (16/50) of the cases were p16-IHC positive (p16 +), 42.0% (21/50) had detectable levels of HPV-16 DNA, and none were positive for HPV-18 DNA. A higher median viral load of HPV-16 DNA was observed in p16 + cases (p <0.0001). Concordance between p16-IHC and HPV-16 DNA ranged from 78.0 to 86.0% and accuracy rates were between 78.0 and 86.0%. P16-IHC and HPV-16 DNA detection was associated with gender, smoking status, and tumor subsite, while only HPV-16 DNA was associated with cT stage. The combination of HPV positivity by p16-IHC and ddPCR showed higher overall survival rates in comparison with p16 + /HPV-DNA- and p16 - /HPV-DNA- results. Type-specific HPV-DNA detection by ddPCR is highly specific but moderately sensitive for the determination of HPV status and showed clinical relevance, mainly when associated with p16-IHC status. Results highlight the importance of performing HPV-DNA testing in combination with p16-IHC for proper identification of HPV-associated OPSCC and to improve clinical management of OPSCC patients.

Prognostic Implication of SOX2 Expression Associated with p16 in Oropharyngeal Cancer: A Study of Consecutive Tissue Microarrays and TCGA

Simple SummaryThe role of human papillomavirus (HPV) in oropharyngeal cancer (OPSCC) as a cause agent has been reported in much of the literature. As a surrogate marker, p16 immunohistochemical staining is used as the standard for classifying OPSCC, and the prognosis of p16+ OPSCC has been reported to be better than p16− OPSCC. However, it was necessary to study what is the next biomarker that could predict the prognosis after classification by p16. We assumed that SOX2 may be a potential biomarker. For each p16+ and p16− OPSCC, SOX2 was used to analyze whether the degree of expression level differed in survival and recurrence rates. The results showed that both immunohistochemical staining and mRNA expression level of SOX2 significantly affected the survival and recurrence rates of p16+ OPSCC patients in two different datasets which were constructed in differently ways. Our study presented the clinical applicability of SOX2 as a biomarker.For oropharyngeal squamous cell carcinoma (OPSCC), there are not enough additional robust biomarkers for subgrouping after the distinct classification using p16. As SOX2 is an emerging biomarker for cancer treatment, its clinical implication in OPSCC was evaluated using a consecutive tissue microarray (TMA) cohort consisting of 111 patients who underwent surgery as an initial treatment from May 2002 to December 2016 and 79 patients in The Cancer Genome Atlas (TCGA) dataset. In both datasets, p16+/SOX2High (HPV+/SOX2High in TCGA) showed the best prognosis among the four groups classified by SOX2 and p16 for 5-year overall survival (OS) and recurrence (all p < 0.05), but SOX2 did not make a significant difference in the prognosis of the p16− group. In the TMA cohort, SOX2High was significantly correlated with response to radiotherapy and lower pathologic T classification in the p16+ group (p = 0.001). In TCGA, correlations between SOX2 and tumor stage classification or radiotherapy were not observed; however, HPV+/SOX2High had a significantly low tumor mutation burden among the four groups (all p < 0.05). In summary, SOX2 was proven to be a potential marker to predict overall survival and recurrence in p16+ OPSCC. However, the role of SOX2 has not yet been confirmed in p16− OPSCC patients.

The Relationship Between Human Papillomavirus, OFD1 and Primary Ciliogenesis in the Progression of Oropharyngeal Cancer: A Retrospective Cohort Study.

PurposeInfection with human papillomavirus (HPV) has been indicated to be a important risk factor for oropharyngeal squamous cell carcinoma (OPSCC). Primary ciliogenesis defects contribute to tumorigenesis, and OFD1 at centriolar satellites is a crucial suppressor of primary ciliogenesis. To identify novel markers associated with HPV-induced carcinogenesis, the interactions between HPV infection and primary ciliogenesis in the tumorigenesis and progression of OPSCC were investigated in this study.Patients and MethodsThe 1530 OPSCC patients recruited in this research were treated from 2000 to 2017. Immunohistochemistry and RT-PCR were performed on tissue samples to compare the expression of p16, TSLP, TGFβ1, IFNγ, OFD1, and their relationship with clinical characteristics of patients.ResultsWe speculate that the positive expression of p16 is related to early primary OPSCC, and the survival rate of p16 positive patients after radiotherapy and surgery is higher. Expression of TSLP on dendritic cells in HPV-positive OPSCC correlated with the expression of OFD1. HPV-positive OPSCC showed increased expression of OFD1 combined with reduced ciliogenesis. Hence, TSLP induced by HPV infection may reduce the invasive potential of OPSCC cells by promoting OFD1 expression, thereby inhibiting primary ciliogenesis.ConclusionOur study demonstrated that HPV may be related to the progression of OPSCC by regulating OFD1 expression and primary ciliogenesis, making this protein a potential therapeutic target.

Synchronous primary neoplasia in patients with oropharyngeal cancer: Impact of tumor HPV status. A GETTEC multicentric study.

Patients with oropharyngeal squamous cell carcinoma (OPSCC) display a significant risk of synchronous primary neoplasia (SPN) which could impact their management. The aims of this study were to evaluate the risk and distribution of SPN in OPSCC patients according to their HPV (p16) status, the predictive factors of SPN and the impact of SPN on therapeutic strategy and oncologic outcomes. All OPSCC patients treated from 2009 to 2014 were included in this multicentric retrospective study. Univariate analyses were conducted using Chi-2 and Fisher exact tests. For multivariate analyses, all variables associated with a p≤0.10 in univariate analysis were included in logistic regression models. Among the 1291 patients included in this study, 75 (5.8%) displayed a SPN which was preferentially located in the upper aerodigestive tract, lung and esophagus. Comorbidity level (p=0.03), alcohol (p=0.005) and tobacco (p=0.01) consumptions, and p16 tumor status (p<0.0001) were significant predictors of SPN. In multivariate analysis, p16+status was significantly associated with a lower risk of SPN (OR=0.251, IC95% [0.133;0.474]). Patients with a SPN were more frequently referred for non-curative treatment (p=0.02). In patients treated with curative intent, there was no impact of SPN on the therapeutic strategy (surgical vs. non-surgical treatment). We observed no overall survival differences between patients with or without SPN. P16 tumor status is the main predictive factor of SPN in OPSCC patients. This study provides crucial results which should help adapt the initial work-up and the global management of OPSCC patients.

Role of Radiomics and advanced MR imaging (Diffusion MRI) in prediction of molecular phenotypes (P16, EGFR, P53) and Clinical prognostication among Oropharyngeal squamous cell carcinoma (OPSCC)

Human papillomavirus (HPV) and smoking are independent factors affecting survival in OPSCC. Radiomics has emerged as a promising tool for imaging biomarker discovery in era of precision medicine. We investigate the ability of Radiomics to predict molecular phenotype from a study population of OPSCC. Further we explored potential of Radiomics alone and in combination with diffusion imaging derived quantitative parameter apparent diffusion co-efficient (ADC), clinical parameters (addiction- smoking) using supervised classification algorithms in predicting outcomes. Retrospective evaluation of the imaging was conducted for a study cohort of 40 patients in whom p16, EGFR and p53 molecular phenotype was done using immunohistochemistry (IHC). One radiologist having 6 years of experience manually drew the region of interest on the tumor for purposes of segmentation and textural analysis. ADC values were calculated from conventional from the darkest part of the tumor, both before and post treatment with chemo radiation. The segmented tumor was validated independently by two radiologists having 30 years of experience each. A total of 851 Radiomics features were extracted from the available imaging using slicer 3D software and Pyradiomics. Feature selection (48 for molecular phenotype and 32 for clinical determinants) was done by taking the union of the features which had Pearson correlation >0.3 with p16 and EGFR status, > 0.4 for p53, > 0.3 with Grade of tumor and > 0.6 with T Stage. Models were trained to predict the biomarkers using leave one out cross-validation and different algorithms for biomarker prediction and prognostic outcomes (T stage, Grade of tumor and Recurrence). Using Radiomics features alone and different machine learning models in prediction of molecular phenotypes we were able to achieve an accuracy of 89% for p16 and 80% for EGFR. The Kappa score (0.51) and the area under the curve (AUC) was 0.79 for EGFR expression. Using the Monotype multilayer perceptron neural network to determine grade of tumor best results (accuracy 89%, kappa 0.61 and AUC 0.82) were achieved when Radiomics was used alone. The combination of Radiomics with addiction provided better AUC of 0.86 and accuracy of 88%. Accuracy for T staging was 60 % with AUC 0.81, while for recurrence combination of Radiomics, baseline ADC values and clinical addiction gave us best model with accuracy of 81%, AUC 0.76 and kappa of 0.45. (Details in table) The study is an effort to bridge the unmet need of translational predictive biomarkers in stratification of HPV positive OPSCC patients based on prognosis value. Radiomics features on imaging could be vital in deciphering molecular phenotypes, serve as tools for prognostication and predict recurrence.

Radiation Treatment Breaks: Are They Detrimental to Outcomes for Oropharyngeal Carcinoma Treated with Definitive Chemoradiation?

Varying practices exist to account for radiation treatment breaks (rTBs) resulting from institutional holidays during treatment of oropharyngeal squamous cell carcinoma (OPSCC) cancer patients undergoing concurrent chemoradiation (CRT). Studies in radiation biology suggest that local therapy delays may result in accelerated repopulation of residual tumor cells, however the clinical effects of this model in the setting of concurrent systemic therapy are unclear. We, therefore, evaluated the effect of rTBs in patients who received CRT on disease-free survival (DFS) in a consecutive cohort of patients with OPSCC. Patients with recurrent OPSCC, M1 disease, less than 6 months follow-up, or those treated with surgery or RT alone were excluded. Data collected included age, sex, KPS, smoking status, T stage, N stage, p16 IHC or HPV ISH status, RT dose and fractions, systemic therapy, total treatment duration, number of total and cumulative rTBs, overall survival/local/regional/distant failure (calculated from start of RT). rTBs were defined as any breaks taken during RT. Cumulative rTBs were defined as largest number of consecutive rTBs, not including weekends. The Kaplan-Meier method was used to estimate time-to-event outcomes on univariate analysis (UVA) and the Cox proportional hazards model was used to determine the effects of covariates on multivariate analysis (MVA). 462 OPSCC patients meeting inclusion criteria treated between 1/1/2010 and 12/31/2015. Median follow up was 5 years (6 months -10 yrs). Median total treatment duration was 48 days (41-64 days). 457 (99%) patients received 70 Gy of RT, 1 patient received a 400 cGy boost, and 4 patients received 66-68 Gy. 54 (12%) patients received induction chemotherapy. 369 (80%) patients received a cisplatin-based regimen and 93 (20%) received a non-cisplatin regimen. 345 (75%) were HPV or p16 positive, 45 (10%) were negative, and 72 (15%) were unknown. Table 1 describes the rTBs experienced by our cohort and results of our analysis. On UVA, only cumulative rTBs of 3 days were found to be significant (p = 0.04). On MVA, however, treatment duration, total rTBs, and cumulative rTBs were not significantly associated with DFS. We did not find a significant decrease in DFS for patients who had rTBs of 3 days in the setting of CRT for OPSCC. However, extended consecutive breaks (>3 days) may be associated with poorer outcomes, warranting further investigation.Abstract 3986; TableResults of UVA and MVA for DFSn (%)UVAMVATotal Breaks (days) 0140 (30) 1166 (36)p = 0.21p = 0.63HR 1.68 [0.21-13.65] 279 (17)p = 0.72p = 0.71HR 1.48 [0.19-11.44] 329 (6)p = 0.95p = 0.96HR 0.93 [0.10-9.32] 417 (4)p = 0.41p = 0.51HR 0.42 [0.03-5.70] 5+*31 (7)p = 0.10p = 0.81HR 1.34 [0.12-15.24]Cumulative Breaks (days) 0147 (32) 1256 (55)p = 0.34p = 0.96HR 0.92 [0.12-7.03] 225 (5)p = 0.53p = 0.71HR 1.55 [0.16-14.59] 314 (3)p = 0.04p = 1.00HR 1.00 [0.10-10.03] 410 (2)p = 0.52p = 0.83HR 0.73 [0.04-13.08] 510 (2)p = 0.38p = 65HR 1.83 [0.14-24.79]*Range 5-14 days. Open table in a new tab

Decreased overall survival in black patients with HPV-associated oropharyngeal cancer.

Racial disparities for overall survival (OS) in head and neck cancer have been well described. However, the extent to which these disparities exist for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), and the contribution of demographic, clinical, and socioeconomic status (SES) variables, is unknown. Patients were identified from the Carolina Head and Neck Cancer Epidemiology Study (CHANCE), a population-based study in North Carolina. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for OS in black versus white patients with sequential adjustment sets. A total of 157 HPV-associated OPSCC patients were identified. Of these, 93% were white and 7% were black. Black patients with HPV-associated OPSCC were more likely to be younger, have an income <$20,000, live farther away from clinic where biopsy was performed, and have advanced T stage at diagnosis. Black patients had worse OS in the unadjusted analysis (HR 4.9, 95% CI 2.2-11.1, p<0.0001). The racial disparity in OS slightly decreased when sequentially adjusting for demographic, clinical, and SES variables. However, HR for black race remained statistically elevated in the final adjustment set which controlled for age, sex, stage, smoking, alcohol use, and individual-level household income, insurance, and education level (HR 3.4, 95% CI 1.1-10.1, p=0.028). This is the first population-based study that confirms persistence of racial disparities in HPV-associated OPSCC after controlling for demographic, clinical, and individual-level socioeconomic factors.

CT and FDG-PET radiologic biomarkers in p16+ oropharyngeal squamous cell carcinoma patients treated with definitive chemoradiotherapy

PurposeTo assess associations between imaging biomarkers from standard of care pre-treatment CT and FDG-PET scans and locoregional (LR) and distant metastatic (DM) recurrences in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiotherapy (CRT). MethodsAn institutional database from a single NCI-designated cancer center identified 266 patients with p16+ OPSCC treated with definitive CRT in our department from 2005 to 2016 with evaluable pre-treatment FDG-PET scans. Quantitative SUV metrics and qualitative imaging metrics were determined from FDG-PET and CT scans, while clinical characteristics were abstracted from the medical record. Associations between clinical/imaging features and time to LR (TTLRF) or DM (TTDMF) failure and overall survival (OS) were assessed using univariable Cox regression and penalized stepwise regression for multivariable analyses (MVA). ResultsThere were 27 LR and 32 DM recurrences as incident failures. Imaging biomarkers were significantly associated with TTLRF, TTDMF and OS. FDG-PET metrics outperformed CT and clinical metrics for TTLRF, with metabolic tumor volume being the only significant feature selected on MVA: C-index = 0.68 (p = 0.01). Radiographic extranodal extension (rENE), positive retropharyngeal nodes (RPN+), and clinical stage were significant on MVA for TTDMF: C-index = 0.84 (p < 0.001). rENE, group stage, and RPN+ were significant on MVA for OS: C-index = 0.77 (p < 0.001). ConclusionsIn the largest study to date of uniformly treated patients with CRT to evaluate both pretreatment CT and FDG-PET, radiographic biomarkers were significantly associated with TTLRF, TTDMF and OS among patients with p16+ OPSCC treated with CRT. CT metrics performed best to predict TTDMF, while FDG-PET metrics showed improved prediction for LRRFS. These metrics may help identify candidates for treatment intensification or de-escalation of therapy. Statement of translational relevancePre-treatment imaging features from standard-of-care PET/CT imaging show promise for predicting long-term outcomes following HPV-associated oropharynx cancer (HPV-OPC) therapy. This study comprehensively characterizes qualitative and quantitative pre-treatment imaging metrics associated with time to pattern-specific failure in a cohort of 266 patients treated uniformly with definitive chemoradiation. Multivariate analysis (MVA) for time to locoregional failure (TTLRF), time to distant metastatic failure (TTDMF), and overall survival (OS) was performed. FDG-PET metrics outperformed CT and clinical metrics for TTLRF. CT radiographic extranodal extension, positive retropharyngeal nodes, and stage strongly predicted TTDMF (combined C-index = 0.84, log rank p < 0.001). Number of smoking pack-years complemented clinical and imaging features only in patients without radiographic extranodal extension or positive retropharyngeal nodes. Time to pattern-specific failure is important for guiding treatment de-escalation strategies, which intend to reduce treatment-related toxicity in patients with relatively long expected survival times. This study suggests that PET/CT features should play a crucial role in future de-escalation trials and management of HPV-OPC patients.

A MicroRNA Expression Signature as Prognostic Marker for Oropharyngeal Squamous Cell Carcinoma.

Improved prognostication of oropharyngeal squamous cell carcinoma (OPSCC) may facilitate individualized patient management. The goal of this study was to develop and validate a prognostic signature based on microRNA sequencing (miRNA-seq) analysis. We collected tumor specimens for miRNA-seq analysis from OPSCC patients treated at Washington University in St Louis (n = 324) and Vanderbilt University (n = 130). OPSCC patients (n = 79) from The Cancer Genome Atlas Program were also included for independent validation. Univariate and multivariable Cox regression analyses were performed to identify miRNAs associated with disease outcomes. All statistical tests were 2-sided. By miRNA-seq profiling analysis, we identified a 26-miRNA signature. Based on computed risk scores of the signature, we classified the patients into low- and high-risk groups. In the training cohort, the high-risk group had much shorter overall survival compared with the low-risk group (hazard ratio [HR] = 3.80, 95% confidence interval [CI] = 2.37 to 6.10, P < .001). Subgroup analysis further revealed that the signature was prognostic for HPV-positive OPSCCs (HR = 3.07, 95% CI = 1.65 to 5.71, P < .001). Multivariable analysis indicated that the signature was independent of common clinicopathologic factors for OPSCCs. Importantly, the miRNA signature was a statistically significant predictor of overall survival in independent validation cohorts (The Cancer Genome Atlas Program cohort: HR = 6.05, 95% CI = 2.10 to 17.37, P < .001; Vanderbilt cohort: HR = 7.98, 95% CI = 3.99 to 15.97, P < .001; Vanderbilt HPV-positive cohort: HR = 8.71, 95% CI = 2.70 to 28.14, P < .001). The miRNA signature is a robust and independent prognostic tool for risk stratification of OPSCCs including HPV-positive OPSCCs.

A prognostic gene expression signature for oropharyngeal squamous cell carcinoma.

BackgroundRobust prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is important for developing individualized treatment plans. This study was conducted to develop and validate a clinically feasible prognostic classifier based on transcriptome-wide gene expression profiles.MethodsTumor tissues were collected from 208 OPSCC patients treated at Washington University in St. Louis and 130 OPSCC patients treated at Vanderbilt University, used for model training and validation, respectively. OPSCC patients (n = 70) from the TCGA cohort were also included for independent validation. Based on RNA-seq profiling data, Cox proportional hazards regression analysis was performed to identify genes associated with disease outcomes. Then, Lasso-penalized multivariate survival models were constructed to identify biomarker genes for developing a prognostic gene signature.FindingsA 60-gene signature was identified by RNA-seq profiling analysis. Computed risk score of the gene signature was significantly predictive of 5-year overall survival of the training cohort (Hazard ratio (HR) 28·32, P = 4·3E-41). Subgroup analysis stratified by HPV status revealed that the signature was prognostic in HPV-positive OPSCC patients (HR 30·55, P = 7·0E-37) and was independent of clinical features. Importantly, the gene signature was validated in two independent patient cohorts, including the TCGA cohort (HR 3·94, P = 0·0018) and the Vanderbilt cohort (HR 8·50, P = 5·7E-09) for overall survival.InterpretationThe prognostic gene signature is a robust tool for risk stratification of OPSCC patients. The signature remains prognostic among HPV-positive OPSCC patients.FundingNational Institutes of Health.

Clinical variables and magnetic resonance imaging-based radiomics predict human papillomavirus status of oropharyngeal cancer.

BackgroundHuman papillomavirus (HPV)‐positive oropharyngeal squamous cell carcinoma (OPSCC) have better prognosis and treatment response compared to HPV‐negative OPSCC. This study aims to noninvasively predict HPV status of OPSCC using clinical and/or radiological variables.MethodsSeventy‐seven magnetic resonance radiomic features were extracted from T1‐weighted postcontrast images of the primary tumor of 153 patients. Logistic regression models were created to predict HPV status, determined with immunohistochemistry, based on clinical variables, radiomic features, and its combination. Model performance was evaluated using area under the curve (AUC).ResultsModel performance showed AUCs of 0.794, 0.764, and 0.871 for the clinical, radiomic, and combined models, respectively. Smoking, higher T‐classification (T3 and T4), larger, less round, and heterogeneous tumors were associated with HPV‐negative tumors.ConclusionModels based on clinical variables and/or radiomic tumor features can predict HPV status in OPSCC patients with good performance and can be considered when HPV testing is not available.

Predictive value of suvmax changes between two sequential post-therapeutic FDG-pet in head and neck squamous cell carcinomas

18-flurodesoxyglucose position emission tomography (FDG-PET) with computed tomography (CT) or magnetic resonance imaging (MRI) is a broadly accepted tool for pretherapeutic staging and post-therapeutic assessment of response. The prognostic value of sequential post-therapeutic FDG-PETs and the impact of change in metabolic activity has been scarcely reported so far. We hypothesized that an increase in metabolic activity (as measured by maximum standardized uptake value, SUVmax) would be predictive for recurrence. We retrospectively assessed all oral, oropharyngeal, laryngeal, and hypopharyngeal squamous cell carcinoma patients treated at the Department of Otorhinolaryngology—Head and Neck Surgery, University Hospital Zurich between April 1st, 2010 and September 30th, 2018 (N = 337). After a negative post-treatment FDG-PET at 3 months, we measured the SUVmax of the local tumor area and the regional lymph nodes on follow-up FDG-PET at 9 months. We then correlated SUVmax difference between 9 and 3 months with tumor recurrence using Kaplan Meier analysis. During follow-up, 68 patients (20.2%) had local recurrence and 53 had regional recurrence (15.7%) at a median time of 9.0 (IQR 4.25–14) and 7.0 (IQR 5.25–23) months, respectively. An increase in local and/or regional SUVmax from the 3 months to the 9 months post-therapeutic FDG-PET resulted in a poorer recurrence-free survival (Log rank, P = 0.001, for both). An increase in local SUVmax between 3 and 9 months was associated with a hazard ratio of 4.17 for recurrence (95%CI 1.89–9.2, P = 0.0003). In conclusion, an increase in metabolic activity/SUVmax between two post-therapeutic FDG-PETs requires a histological examination as it is associated with tumor recurrence.

Prognostic significance of pre-treatment serum Cyfra21-1 as a tumor marker in patients with oropharyngeal squamous cell carcinoma treated with concurrent chemoradiotherapy.

BackgroundOropharyngeal squamous cell carcinoma (OPSCC) is a kind of squamous cell carcinoma of head and neck, and its incidence is on the rise in recent years. A variety of prognostic markers for OPSCC have been reported in many studies, but they are expensive or difficult to obtain. So, we retrospectively studied the prognostic significance of cytokeratin 19 soluble fragment (Cyfra21-1) in patients with OPSCC, in order to provide theoretical basis for accurate prognosis assessment.MethodsA retrospective analysis of the clinicopathological data of 85 OPSCC patients with concurrent radiotherapy and chemotherapy (CRT) admitted from January 2010 to June 2017. Serum Cyfra21-1 levels were measured before treatment. Analyze the relationship between Cyfra21-1 and clinical pathological characteristics of patients. The receiver operating characteristic (ROC) curve was used to calculate the cut-off value of Cyfra21-1. The Cox proportional hazard model was used to conduct univariate and multivariate analysis of related prognostic factors, and to determine the factors related to overall survival (OS) and progression-free survival (PFS).ResultsThe cutoff value for Cyfra21-1 was 2.93 ng/mL. The baseline data of patients in different Cyfra21-1 groups were balanced and comparable. In the univariate and multivariate analyses, it was found that Cyfra21-1 was associated with OS and PFS. A measurement of Cyfra21-1 ≥2.93 ng/mL indicated poor OS (P<0.001) and PFS (P=0.001). After adjusting for age and disease stage, Cyfra21-1 can independently affect the OS (HR =3.57, 95% CI: 1.60–7.99, P=0.002) and PFS (HR =2.89, 95% CI: 1.41–5.91, P=0.004) of patients with OPSCC treated with CRT.ConclusionsPre-treatment Cyfra21-1 can be used as a prognostic marker for patients with OPSCC treated with CRT, which has important clinical significance.