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Summary of the mutational state of the expressed genes in each control SCC-PDX, and the acquired mutations in GefR and GefT SCC-PDXs, as compared to their respective control PDXs

Supplementary Figures and legend figures Supplementary Methods

Purpose:Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy.Experimental Design:We generated primary cell cultures and patient cSCC–derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance.Results:cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors.Conclusions:EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.

Cisplatin is the standard of treatment for squamous cell carcinoma of the head and neck (SCCHN) that has demonstrated efficacy, either in locally advanced disease when combined with radiotherapy at high doses, or in metastatic/recurrent disease when combined with other agents. However, the usual toxicities related to cisplatin, such as neurotoxicity, nephrotoxicity, ototoxicity, and hematologic toxicities, especially when high doses have been administered, have important implications in the patients’ quality of life. The decision to administer cisplatin depends on several patient factors, such as age, performance status, weight loss, comorbidities, previous toxicities, chronic viral infection, or even the current SARS-CoV-2 pandemic. In order to establish recommendations for the management of patients with SCCHN, a group of experts in medical and radiation oncology from Spain and Latin-American discussed how to identify patients who are not candidates for cisplatin to offer them the most suitable therapeutic alternative.

Background: Computed tomography images acquired during routine cancer care provide an opportunity to determine body composition with accuracy and precision. Quantification of skeletal muscle is of interest owing to its association with clinical outcomes. However, the standards of precision testing considered mandatory in other areas of radiology are lacking from the literature in this area. We aim to describe the change in skeletal muscle over time at different anatomical levels using the precision error. Methods: Thirty-eight male patients with squamous cell carcinoma of the head and neck were evaluated at two time points encompassing their treatment plan. Precision testing consisted of analyzing the crosssectional area (CSA) of the skeletal muscle and total adipose tissue of 76 CT studies (38 images at baseline repeated twice and 38 follow-up images repeated twice) measured by a skilled observer. The % coeffi-cient of variation (%CV), the root-mean-square standard deviation (RMS SD) and the corresponding 95% least significant change (LSC) were calculated for four anatomical levels: upper arm, thigh, chest and abdomen. Results: The median time between scans was 223.6 (SD 31.2) days. Precision error (% CV) for total skeletal muscle cross sectional area was 0.86% for upper arm, 0.26% for thigh, 0.39% for chest and 0.63% for abdomen. The corresponding LSC values in upper arm, thigh, chest and abdomen were 2.4%, 0.7%, 1.1% and 1.8%, respectively. Based on the LSC for RMS SD, patients were classified in two categories according to muscle crosssectional area: stable (i.e within LSC value) or gained and loss. To compare the four anatomical levels, the proportion of patients with muscle loss exceeding the LSC value was 74.3% for arm, 86.2% for thigh, 82.9% for chest and 76.3% for abdomen. For these same anatomic regions, the mean muscle loss for those patients classified below the LSC was 14.6% (SD 9.3), 13.4% (SD 7.8), 11.9% (SD 6.5) and 11.6% (SD 5.5), respectively. Only the loss of muscle area was significantly higher in thigh (p = 0.023), using L3 as the reference level. Conclusions: We recommend the uniform use of a standard precision test when reporting muscle change over time. LSC values vary from 0.7 to 2.4% depending on anatomic site; with the lowest precision error to detect change in the thigh. Based on this analysis, muscle wasting appears to be systemic and while present in limbs and trunk is significantly higher in the thigh than in the chest, abdomen or upper arm. (C) 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) represent a distinct clinical entity compared with HPV-negative tumors with particular regard to treatment response and survival outcome. The aim of this study was to assess the AmpFire Multiplex HR-HPV tests, for the detection and genotyping of 15 high-risk (HR) HPV types in formalin-fixed, paraffin-embedded (FFPE) samples and identify HPV-driven OPSCC. DNA from 160 OPSCC FFPE specimens plus 23 samples from other head and neck primary sites was tested. Results were compared with those obtained using Linear Array HPV-DNA Genotyping Test. Linear Array and AmpFire Multiplex HR-HPV tests showed, for all samples and specifically for OPSCCs, an overall concordance agreement of 98.9% and 99.4% and a Cohen ¿ coefficient of 0.972 and 0.984, respectively. A concordance of 100% for HPV16 and HPV18 was observed. The overall agreement between p16INK4a overexpression and HPV detection by the AmpFire Multiplex HR-HPV assay in 145 OPSCC samples was 93.8%, with a Cohen ¿ coefficient of 0.848. The AmpFire HPV Tests are simple assays for detection and genotyping of HPV-DNA in OPSCC FFPE samples and can be easily implemented in the clinical practice setting for HPV-DNA detection.

New key estimates of oral human papillomavirus (HPV) infection and insights on the relationship between oral infection and HPV-associated oropharyngeal cancer are presented. Observed differences in HPV-attributable fractions in oropharyngeal cancer cannot be explained by difference in the prevalence of oral HPV infection across healthy populations., Background Differences in oral human papillomavirus (HPV) prevalence and contrasts in HPV-attributable fractions (AFs) in oropharyngeal cancer (OPC) have not been evaluated in depth. Methods A systematic review was performed to identify studies in which at least 50 healthy individuals were tested for oral HPV infection. Information on sex, age, tobacco/alcohol consumption, sex practices, specimen collection, HPV detection, and population type was extracted. Prevalences were pooled using random-effects models for meta-analyses of binomial data. Correlations were assessed by the Spearman test. Results Forty-eight reports comprising 28 544 individuals fulfilled inclusion criteria. Global oral HPV prevalence was 4.9%. Estimates were highest in Europe, although regional differences were not statistically significant. HPV16 prevalence was 1.0% globally, and regional differences became statistically significant. A lifetime history of >6 sex partners showed a higher risk of oral HPV infection. The age-specific HPV distribution revealed a prevalence of ≥5% over 40 years of age and a lower prevalence at younger ages. There was no association between oral HPV prevalence and HPV-AFs or age-standardized rates (ASRs) of OPC, genital HPV in healthy women, or tobacco use. Conclusions Differences in HPV-AFs or ASRs of OPC cannot be explained by differences in the prevalence of oral HPV infection across healthy populations. Consistent research on determinants of oral HPV prevalence, acquisition, clearance, and persistence is warranted.

Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m2 in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease. Supplementary Information The online version contains supplementary material available at 10.1007/s12094-020-02533-1.

Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m

Purpose: Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy. Experimental Design: We generated primary cell cultures and patient cSCC–derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance. Results: cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors. Conclusions: EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.

The incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing in some regions. Nevertheless, the epidemiology of this disease has not been extensively investigated in southern Europe. We conducted a retrospective cohort study of patients diagnosed with primary oropharyngeal cancer from 1991 to 2016. Cancer tissues underwent histopathological evaluation, DNA quality control, HPV-DNA detection and p16INK4a immunohistochemistry. Data were collected from medical records. Factors associated with HPV positivity and time trends were evaluated with multivariable Bayesian models. The adjusted prevalence of HPV-related cases in 864 patients with a valid HPV-DNA result was 9.7%, with HPV-DNA/p16INK4a double positivity being considered. HPV-related oropharyngeal cancer was likely to occur in non-smokers and non-drinkers, to be located in the tonsil or diagnosed at advanced stages. Time-trend analysis showed an increasing risk of HPV-related oropharyngeal cancer in the most recent periods (5-year period increase of 30%). This increase was highest and with a clear increasing trend only in the most recent years (2012–2016). The prevalence of HPV-related oropharyngeal cancer started to sharply increase in the most recent years in our setting, as occurred two decades ago in areas where most oropharyngeal cancer cases are currently HPV-related. Our results provide a comprehensive assessment of the epidemiological landscape of HPV-related oropharyngeal cancer in a region of southern Europe.

BACKGROUND Clinical natural language processing (cNLP) systems are of crucial importance due to their increasing capability in extracting clinically important information from free text contained in electronic health records (EHRs). The conversion of a nonstructured representation of a patient’s clinical history into a structured format enables medical doctors to generate clinical knowledge at a level that was not possible before. Finally, the interpretation of the insights gained provided by cNLP systems has a great potential in driving decisions about clinical practice. However, carrying out robust evaluations of those cNLP systems is a complex task that is hindered by a lack of standard guidance on how to systematically approach them. OBJECTIVE Our objective was to offer natural language processing (NLP) experts a methodology for the evaluation of cNLP systems to assist them in carrying out this task. By following the proposed phases, the robustness and representativeness of the performance metrics of their own cNLP systems can be assured. METHODS The proposed evaluation methodology comprised five phases: (1) the definition of the target population, (2) the statistical document collection, (3) the design of the annotation guidelines and annotation project, (4) the external annotations, and (5) the cNLP system performance evaluation. We presented the application of all phases to evaluate the performance of a cNLP system called “EHRead Technology” (developed by Savana, an international medical company), applied in a study on patients with asthma. As part of the evaluation methodology, we introduced the Sample Size Calculator for Evaluations (SLiCE), a software tool that calculates the number of documents needed to achieve a statistically useful and resourceful gold standard. RESULTS The application of the proposed evaluation methodology on a real use-case study of patients with asthma revealed the benefit of the different phases for cNLP system evaluations. By using SLiCE to adjust the number of documents needed, a meaningful and resourceful gold standard was created. In the presented use-case, using as little as 519 EHRs, it was possible to evaluate the performance of the cNLP system and obtain performance metrics for the primary variable within the expected CIs. CONCLUSIONS We showed that our evaluation methodology can offer guidance to NLP experts on how to approach the evaluation of their cNLP systems. By following the five phases, NLP experts can assure the robustness of their evaluation and avoid unnecessary investment of human and financial resources. Besides the theoretical guidance, we offer SLiCE as an easy-to-use, open-source Python library. CLINICALTRIAL

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p, This research was funded by the health research program of the “Instituto de Salud Carlos III” (PI14/00071) co financed with FEDER founds and for the Health Regional Management of the Junta de Castilla y León (GRS1385/A/16). J. Fernández-Mateos was partially supported by a predoctoral research grant from the Consejería de Educación—Junta de Castilla y León and the European Social Fund to CC-B (EDU/1084/2012).

High-risk human papillomavirus (HPV) is now recognised as the principal cause of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in some parts of the world. The primary risk factor for developing HPV-related OPSCC is oral HPV-infection and the majority of oral HPV-infections are acquired by oral sex. Progression into an OPSCC includes persistent infection with evasion of immune response in the microenvironment, the activation of viral early genes (E6, E7) in basal epithelial cells, the deregulation of cell cycle and the accumulation of chromosomal instability. Patients affected by HPV-related OPSCC tend to be younger and have better outcomes. This observation has lead current research to evaluate treatment de-escalation options to reduce long-term associated morbidity. Moreover, a different molecular profile for HPV-related OPSCC has been described, opening new options for targeted therapy and immunotherapy approaches. This paper comprehensively reviews our accumulated knowledge regarding the role of HPV in OPSCC spanning from infection to cancer development, including its clinical diagnosis, management and preventive strategies.

BACKGROUND Sexual behavior and oral human papillomavirus (HPV) infection are risk factors for oral squamous cell carcinoma (OSCC). The effects of OSCC diagnosis and treatment on subsequent relationship stress and sexual behavior are unknown. METHODS Incident cases of HPV-positive or HPV-negative OSCC in patients who had a partnered relationship and partners of patients with oropharyngeal cancer were eligible for a study in which surveys were administered at diagnosis and at the 6-month follow-up time point to assess relationship distress, HPV transmission and concerns about health consequences, and sexual behavior. The frequency distributions of responses, stratified by tumor HPV status, were compared at baseline and follow-up. RESULTS In total, 262 patients with OSCC and 81 partners were enrolled. Among the patients, 142 (54.2%) had HPV-positive OSCC, and 120 (45.8%) had HPV-negative OSCC. Relationship distress was infrequently reported, and 69% of patients felt that their relationship had strengthened since the cancer diagnosis. Both HPV-positive patients (25%) and their partners (14%) reported feelings of guilt or responsibility for the diagnosis of an HPV-caused cancer. Concern over sexual, but not nonsexual, HPV transmission to partners was reported by 50%. Significant declines in the frequency of vaginal and oral sexual behaviors were reported at follow-up, regardless of tumor HPV status. From baseline to 6 months, significant increases in abstinence from vaginal sex (from 10% to 34%; P

ObjectivesTo examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab.Material and methodsMulticenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods.ResultsAcneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p

Anti-programmed cell death protein 1 (PD-1) agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and are currently being evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides Programmed death ligand-1 (PD-L1) expression, other biomarkers such as immune infiltration, tumor mutational burden or immune-gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review examines the available evidence on emerging immune predictive biomarkers of response to anti-PD-1/PD-L1 therapy in HNSCC, introducing the microbiota and its potential use as a predictive immune biomarker in this disease.

BackgroundHuman papillomavirus (HPV) is the cause of a fraction of head and neck squamous cell carcinoma. Although this relation is well-known, it is still not clear the role of HPV in premalignant oral lesions such as oral lichen planus (OLP) and dysplasia. We aimed to evaluate the HPV-DNA prevalence and type distribution in a set of oral biopsies obtained from patients diagnosed with OLP and dysplasia, as well as the role of HPV in these lesions.MethodsA retrospective cohort of all premalignant oral lesions consecutively diagnosed from March 30th 1995 to May 21st 2014 at Hospital of Bellvitge and Odontological University Hospital of Bellvitge was identified and classified in four groups: OLP (groups 1 and 2) and dysplasias (groups 3 and 4) that progressed or not to invasive cancer during follow-up. A random selection targeting 25 cases was aimed to be performed for each group. All selected cases were subjected to pathological evaluation, DNA quality control and HPV-DNA detection. HPV-DNA positive samples were further subject to p16INK4a analysis.ResultsA total of 83 cases yielded a valid HPV-DNA result. From those, 7 and 34 cases were OLP that progressed or not to invasive cancer during follow-up, whereas 24 and 18 cases were displasias that progressed or not to invasive cancer during follow-up, respectively. HPV-DNA was detected in 4 samples (3 dysplastic lesions and 1 OLP). Two samples were HPV16 positive (2%), 1 sample HPV18 positive (1%) and 1 sample (1%) was HPV indeterminate. Two out of four HPV-DNA positive cases had high p16INK4a expression and none of the HPV positive cases progressed to invasive cancer during long-term follow-up.ConclusionsWe found a low HPV-DNA attributable fraction in premalignant lesions of the oral cavity, suggesting that HPV is unlikely to play a significant role in oral carcinogenesis in our setting.

Background LIPI, based on derived NLR (neutrophils/(leucocytes-neutrophils)) and lactate dehydrogenase (LDH) level, has been correlated to ICI outcomes in advanced non small cell lung cancer. We evaluated if HN-LIPI could offer the same role in R/M SCCHN. Methods This is a multicentric (9 European centers) retrospective study including R/M SCCHN patients (pts) treated with ICI from September 2014 to May 2019 and a control cohort (N = 83) only treated with chemotherapy. Baseline biological and clinicaldata were collected from medical records. According to dNLR>3 and LDH > upper limit of normal, HN-LIPI defines 3 groups (Good: 0 factor; Intermediate: 1 factor; Poor: 2 factors).The primary endpoint was overall survival (OS), and secondary endpoints was progression free survival (PFS). Results We included 273 pts (84% male, 84% smokers and 87% with PS ≤ 1, median age 59 years). Primary tumor locations were: oropharynx (37%), oral cavity (23%) and hypopharynx (17%). p16by immunohistochemistry was positive in 33% oropharynx pts. ICI were administered in 53% of patients as monotherapy and in 47% in combination. The median number of prior lines was 2 (1-7) with 65% of pts receiving ≥2. Median follow up of 13.2 months (mo).The median (m) PFS and OS were 2.84 mo [2.53-3.52] and 11.8mo [9.4-15.8]. dNLR >3 was associated to poor OS(HR 1.6, 95%CI: 1.1-2.3) but not with PFS (p = 0.11). LDH was not associated with endpoints. Median OS for good, intermediate and poor LIPI groups were: 15.9mo, 8.9mo and 6.2mo, respectively (p=.03). In univariate analysis, Intermediate and Poor risk groups were associated with OS (HR:1.5 95%CI:1.1-2.2 and HR:2 95%CI:1.0-4. respectively ). There was trend to better objective response rate in the good risk group compared with intermediate and poor (36%, 22% and 18%, p = 0.09). Conclusions Baseline HN-LIPI is associated with worse OS for ICI in R/M SCCHN but not with PFS. Control cohort results and multivariate models will be further presented at the congress, which would elucidate the prognostic and/or predictive impact in R/M SCCHN population. Legal entity responsible for the study Neus Baste. Funding Has not received any funding. Disclosure V. Cristina: Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Ely Lilly; Advisory / Consultancy: Servier; Advisory / Consultancy: Celgene; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Merck-Serono. A. Garcia Castano: Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Pierre Fabre; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Pierre Fabre. R. Mesia Nin: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Nanobiotix; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: MSD. M. Taberna: Non-remunerated activity/ies: Merck Serono; Non-remunerated activity/ies: AstraZeneca; Travel / Accommodation / Expenses: Merck Serono; Travel / Accommodation / Expenses: Nanobiotics; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Bristol-Myers. B. Besse: Travel / Accommodation / Expenses: AbbVie; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Biogen; Travel / Accommodation / Expenses: Blueprint Medicine; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: GSK; Travel / Accommodation / Expenses: Ignyta; Travel / Accommodation / Expenses: IPSEN; Travel / Accommodation / Expenses: MERCK; Travel / Accommodation / Expenses: KGaA; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Nektar; Travel / Accommodation / Expenses: Onxeo; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Pharma Mar; Travel / Accommodation / Expenses: SANOFI; Travel / Accommodation / Expenses: Spectrum pharmaceuticals; Travel / Accommodation / Expenses: Tiziana Pharma; Travel / Accommodation / Expenses: Takeda. N. Baste-Rotllan: Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Nanobiotics; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: MSD. All other authors have declared no conflicts of interest.

Background VCN-01 is an oncolytic adenovirus with replication restricted to cells with a nonfunctional retinoblastoma pathway. Upon selective replication VCN-01 expresses the matrix remodeling-enzyme hyaluronidase to enhance virus spreading and tumor uptake of different therapeutics, including immune check-point inhibitors. In a phase I performed in pancreatic carcinoma VCN-01 reached tumors after systemic administration and induced CD8-infiltration, tumor inflammation and PD-1/PD-L1 up-regulation. We hypothesize these intratumor effects may help to overcome the observed resistance to Durvalumab and other PD-(L)-1 checkpoint inhibitors Trial Design NCT03799744 is a multi-center, open-label dose-escalation phase I study evaluating the safety, tolerability and efficacy of the combination of VCN-01 plus durvalumab in R/M HNSCC patients who have progressed on prior PD-(L)-1 checkpoint inhibitors. Patients need to have neutralizing antibodies levels against adenovirus ≤1/350 dilution to be included. The study follows a 3 + 3 design with two dose levels for VCN-01 (3,3.1012 & 1.1013 vp) combined with Durvalumab at a fixed dose of 1500mg intravenous (i.v.). Two treatment arms are explored: I) Concomitant single i.v. dose of VCN-01 with durvalumab on cycle 1 day 1 followed by durvalumab Q4W; II) Sequential single i.v. VCN-01 on cycle 1 day -14 plus durvalumab on cycle 1 day 1 followed by durvalumab Q4W. Patients continue durvalumab Q4W until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective of the study is to evaluate the safety and tolerability of VCN-01 with durvalumab in the two regimens of administration and to establish the recommended phase II dose. Secondary objectives are progression free survival, overall response rate by irRECIST /RECIST, VCN-01 pharmacokinetics and shedding in blood. Other exploratory biomarkers will be analyzed in tumor biopsies (immune markers), serum (hyaluronidase levels), stool (microbiome) and imaging (dynamic contrast-enhanced MRI, diffusion weighted imaging and T2 mapping). The study opened recruitment in April 2019 with 7 out of 18 planned patients enrolled at time of submission. Clinical trial identification NCT03799744. Legal entity responsible for the study Catalan Institute of Oncology (ICO). Funding VCN Biosciences, AstraZeneca. Disclosure M. Jove: Advisory / Consultancy: Boehringer Ingelheim. I. Brana: Advisory / Consultancy, Research grant / Funding (self): Orion Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (self): Celgene; Research grant / Funding (self): Gliknik; Research grant / Funding (self): GSK; Research grant / Funding (self): Janssen; Research grant / Funding (self): KURA; Research grant / Funding (self): MSD; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Shattuck; Research grant / Funding (self): Northern Biologics; Research grant / Funding (self): Rakutan Aspirian; Research grant / Funding (self): Naobiotics. M. Taberna: Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Merck; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy: Nanobiotics. E. Garralda: Leadership role, Research grant / Funding (institution): Novartis; Leadership role: Principia Biopharma Inc; Leadership role: Lilly, S.A; Advisory / Consultancy, Leadership role: Roche / Genentech Inc; Leadership role: Loxo Oncology Inc; Advisory / Consultancy, Leadership role: F.Hoffmann La Roche Ltd; Leadership role: Symphogen A/S; Speaker Bureau / Expert testimony, Leadership role, Travel / Accommodation / Expenses: MSD; Leadership role: Incyte; Leadership role: Pharma Mar; Leadership role: Kura Oncology; Leadership role: Macrogenics; Leadership role, Travel / Accommodation / Expenses: Glycotope; Leadership role: Pierre Fabre; Leadership role: Cellestia Biotech; Leadership role, Travel / Accommodation / Expenses: Menarini Ricerche; Leadership role: Blueprint Medicines; Leadership role: Beigene; Leadership role: Sierra Oncology; Leadership role: Genmab; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Janssen Global Services ; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: NeoMed Therapeutics; Advisory / Consultancy: SeaGen; Speaker Bureau / Expert testimony: ThermoFisher. G. Capella: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences. R. Alemany: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences; Research grant / Funding (institution): Lokon Pharma; Research grant / Funding (institution): Mologen. E. Blasi: Full / Part-time employment: VCN Biosciences. C. Blasco: Full / Part-time employment: VCN Biosciences. M. Cascallo Piqueras: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: VCN Biosciences. R. Mesia Nin: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. All other authors have declared no conflicts of interest.

Background The etiologic role of human papillomavirus (HPV) in oropharyngeal cancer (OPC) is well established and it explains the increase of young patients (pts) affected with OPC. This is an observational study representing a real-world experience evaluating clinicopathologic features and prognosis in young ( Methods We conducted a retrospective cohort study of pts diagnosed with OPC in four Catalonian hospitals from 1991 to 2017. Data was collected from medical records. Unconditional logistic regression was used to compare age groups and Proportional hazards model (Cox regression) and Cumulative Incident Function (CIF) to analyze OPC-specific survival (OPC-sS) in locally advanced cases. Results A total of 865 pts were included, 49 in the young group (median age 42; range 28.5-45.0) and 816 in the old group (median age 61; range 45.1-93.9). There were no differences between age groups in terms of sex, anatomic subsite, toxic habits, HPV status (positivity defined as double p16/DNA positivity) or stage at diagnosis. There were more non-smokers HPV-related (HPV+) OPC pts than HPV-negative (HPV-) ones (p-value Conclusions HPV is the most important prognostic factor in OPC independent of age. Legal entity responsible for the study ICO (Catalan Institute of Oncology). Funding The Instituto de Salud Carlos III-ISCIII (Spanish Government) co funded by EDER funds/ European Regional Development Fund (ERDF) - a way to build Europe (References: PI1102096, PI1401918, PI1500500, PI1501205, RD12/0036/0056, CIBERESP, CIBERONC). Disclosure M. Nieva: Travel / Accommodation / Expenses: Takeda; Travel / Accommodation / Expenses: Merck. S. Tous: Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK.: GSK; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK.: Seegene; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK.: Merck. M. Mena: Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: GSK; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Merck; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Seegene. R. Mesia Nin: Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: AZ; Advisory / Consultancy: Roche; Advisory / Consultancy: Nanobiotix. L. Alemany: Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: GSK; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Seegene; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Merck. M. Taberna: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AZ; Advisory / Consultancy: Nanobiotics; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Bristol Myers. All other authors have declared no conflicts of interest.

Background The objective of the present study is to assess differences in the competing causes of death in patients with oropharyngeal carcinoma (OPC) as a function of the human papillomavirus (HPV) status. Methods We studied retrospectively 423 patients with OPC with known HPV status. Among the patients included in the study, 53 (12.5%) were HPV-positive. We analyzed overall survival and competing causes of mortality according to the HPV status of the patients. Results Patients with HPV-negative tumors had lower OPC cancer-specific survival (P = .0001), second primary neoplasm survival (P = .0001), and noncancer-related causes survival (P = .13) than patients with HPV-positive tumors. This resulted in significant differences in overall survival depending on HPV status (P = .0001). Conclusion Conclusion: HPV-positive OPC has a better overall survival than HPV-negative OPC. Patients with HPV-positive tumors presented a significant lower OPC cancer-specific and second primary neoplasm mortality and a marginally nonsignificant lower noncancer mortality as compared to HPV-negative tumors.

Background: The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. Methods: We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16(INK4a)/pRb/p53/Cyclin-D1 immunohistochemistry. HPV-DNA positive and a random sample of HPV-DNA negative cases were subjected to HPV-E6*I mRNA detection. Demographic, tobacco/alcohol use, clinical and follow-up data were collected. Multivariate models were used to evaluate factors associated with HPV positivity as defined by four different HPV-relatedness definitions. Proportional-hazards models were used to compare the risk of death and recurrence among HPV-related and non-related OPC. Results: 788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16(INK4a), HPV-DNA, HPV-DNA/HPV-E6*I mRNA, and HPV-DNA/p16(INK4a), respectively. Being nonsmoker or non-drinker was consistently associated across HPV-relatedness definitions with HPV positivity. A suggestion of survival differences between anatomic sub-sites and treatments was observed. Double positivity for HPV-DNA/p16(INK4a) showed strongest diagnostic accuracy and prognostic value. Conclusions: Double positivity for HPV-DNA/p16(INK4a), a test that can be easily implemented in the clinical practice, has optimal diagnostic accuracy and prognostic value. Our results have strong clinical implications for patients' classification and handling and also suggest that not all the HPV-related OPC behave similarly.

BACKGROUND: Given the different nature and better outcomes of oropharyngeal carcinoma (OPC) associated with human papillomavirus (HPV) infection, a novel clinical stage classification for HPV-related OPC has been accepted for the 8th edition AJCC TNM (ICON-S model). However, it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. MATERIAL AND METHODS: The aim of this study was to compare different staging system models proposed for HPV-related OPC patients: 7th edition AJCC TNM, RPA stage with non-anatomic factors (Princess Margaret), RPA with N categories for nasopharyngeal cancer (MD-Anderson) and AHR-new (ICON-S), according to different HPV-relatedness definitions: HPV-DNA detection plus an additional positive marker (p16INK4a or HPV-mRNA), p16INK4a positivity alone or the combination of HPV-DNA/p16INK4a positivity as diagnostic tests. RESULTS: A total of 788 consecutive OPC cases diagnosed from 1991 to 2013 were considered eligible for the analysis. Of these samples, 66 (8.4%) were positive for HPV-DNA and (p16INK4a or HPV-mRNA), 83 (10.5%) were p16INK4a positive and 58 (7.4%) were double positive for HPV-DNA/p16INK4a. ICON-S model was the staging system, which performed better in our series when using at least two biomarkers to define HPV-causality. When the same analysis was performed considering only p16INK4a-positivity, RPA stage with non-anatomic factors (Princess Margaret) has the best classification based on AIC criteria. CONCLUSION: HPV-relatedness definition for classifying HPV-related OPC patient do impact on TNM classification and patients' survival. Further studies assessing HPV-relatedness definitions are warranted to better classify HPV-related OPC patients in the era of de-escalation clinical trials. This work was partially supported by grants from the Instituto de Salud Carlos III-ISCIII (Spanish Government) cofunded by FEDER funds/European Regional Development Fund (ERDF) - a way to build Europe (PI14/01819, PI15/00500 and PI11/02096); Ayudas Merck Serono-Fundación Salud 2000 de investigación 2015; Agéncia de Gestió d’Ajuts Universitaris i de Recerca, AGAUR (2017SGR1085 and 2017SGR1718), European Commission 7th Framework Programme COHEAHR (Health-F3-2013-603019) and Rio Hortega-SEOM (ISCIII-Spanish Society of Medical Oncology) (personal grant to MT). The funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Objectives: It has been reported that patients with HPV-positive oropharyngeal cancer (OPC) have a lower risk of appearance of second primary neoplasm (SPN) than HPV-negative OPC patients. The aim of our study was to analyze the risk of developing SPN in a large group of patients with OPC according to HPV status in the primary tumor. Materials and methods: We included 412 OPC patients treated at our center from 1991 to 2014 for which the HPV DNA positivity was evaluated by PCR in available tumor specimens. HPV DNA positive samples were further tested for HPV E6*I mRNA detection and/or p16(INK4a) immunohistochemistry. We estimated the incidence of SPN in all cancer sites and in cancer sites related to tobacco and alcohol consumption according to the HPV status in the primary tumor. Results: Fifty-one (12.4%) out of 412 OPCs included in the study were HPV-related. Five-year SPN-free survival for HPV-negative versus HPV-positive OPC patients was 57.0% and 89.0% (P < 0.001), respectively. Corresponding estimates for 10-year SPN-free survival were 35.2% versus 78.5% (P < 0.001). When restricting the analyses to tobacco/alcohol-related SPNs, the corresponding survival rates where 62.0% versus 97.6% (P < 0.001) and 42.2% versus 97.6%, (P < 0.001), for 5-year and 10-year survival rates, respectively. HPV status and previous toxic habits might allow classifying patients regarding the risk of tobacco/alcohol-related SPNs. Conclusion: HPV-related OPC patients have a significant lower risk of SPN development, particularly in those locations related to tobacco use or alcohol consumption. (C) 2016 Elsevier Ltd. All rights reserved.