Why Oncologists Should Feel Directly Involved in Persuading Patients with Head and Neck Cancer to Quit Smoking.

INTRODUCTION: Among the risk factors for squamous cell carcinoma of the head and neck, smoking is still the most important today. Several studies agree on the effect of smoking on tumor microenvironment, while the definition of former smokers and the time of smoking cessation on biologic effect differs among papers. METHODS: We conducted a narrative review on smoking effects in HNSCC. RESULTS: There is evidence that smoker patients have a poorer prognosis than never smokers and former smokers. Translational studies show a relationship between smoking status and gene expression and support the importance of smoking cessation, for instance, demonstrating an inverse relationship between tumor-infiltrating lymphocytes and smoking. CONCLUSION: Convincing data suggest that quitting smoking at any time may improve patient outcomes. We advocate smoking cessation also after cancer diagnosis.

Immune escape mechanisms in head and neck squamous cell carcinoma and implication for new immunotherapy approach.

PURPOSE OF REVIEW: The aim of this review is to describe the major steps leading to the immunosuppressive tumor microenvironment and to summarize some of the new immunotherapies that interfere with these mechanisms. RECENT FINDINGS: Immunotherapy has improved the outcome of relapsed/metastatic head and neck squamous cell carcinoma (HNSCC). However, most patients still do not respond to treatment and median overall survival remains short with a modest rate of long-term survivors. There is a growing awareness that tumor immune-escape is a complex process that involves many redundant mechanisms other than immune check-points. They interfere with the innate immune response, activation of adaptive immune response, homing of effector T cells, their clonal expansion, viability, and efficiency. This abundance of immunosuppressive mechanisms explains the limited results achieved by immune checkpoint inhibitors. Combined treatments targeting different mechanisms of escape are in development to further improve the outcome of patients with HNSCC. SUMMARY: Many mechanisms favor tumor immune-escape. Each tumor exploits preferably some of them and the challenge is to understand which are the best targets in each tumor. This knowledge is an important tool to design future combination strategies based on strong biological rationales, which could offer better results than simple empirical combinations.

Phase III Randomized Study of Induction Chemotherapy Followed by Definitive Radiotherapy + Cetuximab Versus Chemoradiotherapy in Squamous Cell Carcinoma of Head and Neck: The INTERCEPTOR-GONO Study (NCT00999700).

OBJECTIVES: Induction chemotherapy followed by cetuximab and RT (IBRT) (Arm A) was compared to cisplatin/RT (CRT) (Arm B) in a randomized phase III study. PATIENTS AND METHODS: Naïve patients with stage III-IVa, histologically proven locally advanced head and neck cancer (LASCCHN) were eligible. Arm A (IBRT): 3 TPF induction followed by cetuximab-RT (equivalent daily dose 2 Gy up to 70 Gy); Arm B: 3 cisplatin concurrent with the same RT scheduling. Due to slow accrual and incomplete data collection a futility analysis was performed. RESULTS: 236/282 patients were evaluable. Therefore, no formal analyses can be made between the two arms. OS was 45.2/53.6 months in Arm A/B. Complete responses were achieved in 64% of patients in both arms. Neutropenia and skin toxicity were significantly worse in Arm A and body weight loss was significantly worse in Arm B. Compliance with the planned drug administration was higher in Arm B (p = 0.0008). CONCLUSION: The study suggests that IBRT and CRT have similar efficacy, activity and toxicity.

Expression and subcellular localization of the bromodomain-containing protein 7 is a prognostic biomarker in breast cancer.

Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family. Previous studies suggest that BRD7 is predominantly localized in the nucleus, wherein it functions as a transcriptional regulator. Several lines of evidence imply a tumour suppressor function for BRD7. However, the importance of BRD7 in the pathogenesis of breast cancer is not well understood. We have investigated the expression, CpG island methylation and subcellular localization of BRD7 in breast cancer cell lines and clinical cases and thereby assessed its prognostic significance by correlating with clinical-pathological features and time-dependent clinical outcomes. We show that nuclear exclusion of BRD7 occurs commonly in breast cancer and is strongly associated with cases expressing wild-type p53. Moreover, clinical outcomes are significantly less favourable in cases with nuclear exclusion or loss of expression than those in which there is nuclear expression of BRD7. Methylation of the CpG island of BRD7 increases in breast cancer relative to normal breast tissue, but there is not an obvious correlation between methylation and reduced expression or between methylation and clinical outcomes. Overall, our results suggest that nuclear exclusion, rather than transcriptional silencing, is a common mechanism by which the tumour suppressor function of wild-type p53 is inhibited in breast cancer, and show that BRD7 is a promising candidate biomarker in breast cancer.

Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature.

Lenvatinib (LEN) is a multikinase inhibitor with antiangiogenic properties recently approved in radioactive iodine-refractory differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma in combination with everolimus. LEN-treated patients frequently have adverse events (AEs) that generally require such dose modifications, including drug discontinuation. Hypertension, diarrhea, weight loss, proteinuria, fatigue, and palmar-plantar erythrodysesthesia are reported among the most frequent AEs, often leading to discontinuations or dose modifications. This paper reports a case series focusing on the role of the immediate multidisciplinary approach to manage AEs.

Melanoma: the new perspectives from clinical and translational research.

The prognosis of metastatic melanoma has not changed throughout the 20th century. However, in the last decade, we have witnessed a continuous improvement in survival, with many long-term survivors. These results are largely because of the simultaneous development of the knowledge in the biology of metastatic malignant melanoma and of the relationship between the disease and the host's immune system that allowed the development of effective new treatments. In this overview, we summarize the therapies available today, their biological rationale, and the research field currently under investigation divided into three main chapters: target therapies, immunotherapies, and their combination.

Pros and Cons of the New Edition of TNM Classification of Head and Neck Squamous Cell Carcinoma.

The TNM classification is a worldwide standard staging system used to define the extent of cancer and is a major prognostic factor in predicting the outcome of patients. The TNM Classification of Malignant Tumours, 8th edition, has been used since January 1, 2018. In the area of head and neck cancer major modifications were produced: important updated T and N modification for oral cavity and nasopharyngeal cancer, the introduction of clinical and pathological stages for neck disease, and a new HPV-16-positive HNSCC classification. While until a few years ago the TNM staging system classified prognostic risk groups based on tumour size, the 8th edition responds to the need to categorize the prognosis of patients with similarly sized tumours but with very different clinical and biological behaviour. This review details TNM changes and the clinical need for these modifications, valuating possible limits in daily applicability.

Negative prognostic factors and resulting clinical outcome in patients with metastatic renal cell carcinoma included in the Italian nivolumab-expanded access program.

AIM: We report the outcomes observed with nivolumab in metastatic renal cell carcinoma patients with poor prognostic features enrolled in the Italian expanded access program. PATIENTS & METHODS: Nivolumab was available for patients who relapsed after at least one prior systemic treatment in the advanced or metastatic setting. RESULTS: Of 389 patients, 32 (8%) had brain metastasis, 129 (33%) had liver and 193 (50%) had bone metastasis. These subpopulations achieved a disease control rate of 53, 45 and 47%, respectively. Fifty-one patients had G4 tumor, and they showed 23% objective response rate. The safety profile of the subgroups was in line with the expanded access program population. No new safety signals were reported. CONCLUSION: Patients with poor prognostic features may derive relevant benefits from nivolumab.

MicroRNAs role as potential biomarkers and key regulators in melanoma.

Malignant melanoma (MM) is a highly aggressive skin cancer with high incidence worldwide. It originates from melanocytes and is characterized by invasion, early metastasis and despite the use of new drugs it is still characterized by high mortality. Since an early diagnosis determines a better prognosis, it is important to explore novel prognostic markers in the management of patients with MM. microRNAs (miRNAs) are small (∼22 nucleotides) single-stranded non-coding RNAs that negatively regulate the expression of more than 60% of human genes.miRNAs alterations are involved in several cancers, including MM, where a differential expression for some of them has been reported between healthy controls and MM patients. Moreover, since miRNAs are stable and easily detectable in body fluids, they might be considered as robust candidate biomarkers useful to identify risk of MM, to diagnose an early lesion and/or an early metastatic disease. This review highlights the importance of miRNAs as risk factors, prognostic factors and their role as molecular regulator in the development and progression of MM. © 2016 Wiley Periodicals, Inc.

Elevated basal antibody-dependent cell-mediated cytotoxicity (ADCC) and high epidermal growth factor receptor (EGFR) expression predict favourable outcome in patients with locally advanced head and neck cancer treated with cetuximab and radiotherapy.

BACKGROUND: Antibody-dependent cell-mediated cytotoxicity (ADCC) may contribute to the antitumor activity of cetuximab. However, the extent of this contribution is unclear. In this study, we investigated the impact of baseline ADCC on the outcome of patients with locally advanced squamous cell carcinoma treated with cetuximab and radiotherapy. METHODS: We determined baseline ADCC in 28 patients treated with cetuximab and radiotherapy and in 15 patients treated with chemoradiation. We linked the values observed with complete response and with overall survival. We also considered the role of epidermal growth factor receptor (EGFR) expression and studied the combined effect of EGFR and ADCC. RESULTS: We observed a wide range of baseline values of ADCC. Complete response did not correlate with either ADCC or EGFR expression. However, when ADCC and EGFR were considered together using a mixed score, they significantly correlated with achieving a complete response (p = 0.04). High baseline ADCC significantly correlated with outcome compared to low (p = 0.03), but not in patients treated without cetuximab. Patients showing high baseline levels of both ADCC and EGFR3+ achieved the best outcome compared to the others (p = 0.02). CONCLUSIONS: In this study, patients treated with cetuximab and radiotherapy, showing high baseline of both ADCC and EGFR3+, have significant higher probability of achieving a complete response and a long overall survival compared to the others.

Eribulin in advanced breast cancer: safety, efficacy and new perspectives.

Eribulin is a synthetic analog of halichondrin B belonging to microtubule-targeted agents with a distinct mechanism of inhibition of microtubule dynamics. This molecule has multiple nonmitotic effects on tumor biology, exhibiting effects on epithelial-mesenchimal transition and tumor vasculature. We review here preclinical and clinical studies on eribulin. The mitotic and nonmitotic effects together with its favorable safety profile make eribulin a unique drug with high potential in the treatment of metastatic breast cancer. The new emphasis of eribulin mechanism of action on vascular remodeling, microenvironment modifications and reversal of epithelial-mesenchimal transition paves the way to rethinking the use of the drug in an immunological perspective.

Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis.

BACKGROUND: Platinum-based concurrent chemoradiation (CCRT) improves locoregional control and overall survival of locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) when compared to radiotherapy alone, but this approach is hampered by significant toxicity. Therefore, alternative ways to enhance the radiation effects are worth investigating. Gemcitabine (2',2'-difluorodeoxycytidine), in addition to its activity against a variety of solid tumors, including SCCHN, is one of the most potent radiosensitizers, and it has an overall favorable safety profile. In this paper, the clinical experience with gemcitabine-based chemoradiation in the treatment of patients with LA-SCCHN is reviewed. METHODS: We conducted a review of the literature on the clinical experience with radiotherapy combined with either single-agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN. We also searched abstracts in databases of major international oncology meetings from the last 20 years. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate and grade 3-4 acute mucositis rate. RESULTS: A total of 13 papers were eligible for the literature review. For schedules using a gemcitabine dose intensity (DI) below 50 mg/m(2) per week, the complete response rate was 86% (95% CI, 74%-93%) with grade 3-4 acute mucositis rate of 38% (95% CI, 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year overall survival of 50%. Compared with DI ≥50 mg/m(2) per week, there was no difference in the complete response rate (71%; 95% CI, 55%-83%; p = .087) but a significantly higher (p < .001) grade 3-4 acute mucositis rate of 74% (95% CI, 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year overall survival, 27%-63%). Late toxicity comprising mainly dysphagia was generally underreported, whereas information about xerostomia and skin fibrosis was scarce. CONCLUSION: This review highlights the radiosensitizing potential of gemcitabine and suggests that even very low dosages (less than 50 mg/m(2) per week) provide a sufficient therapeutic ratio and therefore should be further investigated. Refinements in radiation schemes, including intensity-modulated radiation therapy, in combination with low-dose gemcitabine and targeted agents, such as cetuximab, are currently being investigated. IMPLICATIONS FOR PRACTICE: Cisplatin-based concurrent chemoradiation (CCRT) has become the standard treatment of locally advanced head and neck cancer (LAHNC). This approach is hampered by significant toxicity. This paper reviews the studies using gemcitabine as an alternative radio-sensitizer for CCRT in patients with LAHNC. In this capacity, despite its mild intrinsic toxicity, gemcitabine comes with high rates of severe mucositis when used in dosages exceeding 50 mg/m(2) per week. CCRT with low-dose gemcitabine provides a sufficient therapeutic ratio, combining clinical activity, similar to the higher-dose regimens, with lower toxicity. Further investigation is warranted.

Schedule-dependent interaction between temsirolimus and cetuximab in head and neck cancer: a preclinical study.

Aberrant epidermal growth factor receptor (EGFR) signaling is associated with tumor growth in head and neck squamous cell carcinoma (HNSCC) and is a major focus of targeted therapy. The phosphatidylinositol-3-kinase/AKT/mammalian target of the rapamycin (PI3K/AKT/mTOR) signaling pathway is frequently mutated in HNSCC and is involved in disease progression and resistance to EGFR inhibitors. The aim of this study was to assess the antiproliferative effects of mTOR inhibition (temsirolimus) combined with the anti-EGFR monoclonal antibody cetuximab, administered according to different combination schedules. Antiproliferative effects of the combination of temsirolimus and cetuximab were determined on the representative HNSCC CAL33 cell line (PI3KCA H1047R mutated and K-RAS wild-type). In addition, key proteins related to the EGFR pathway (pEGFR/EGFR, pAKT/AKT) and the mTOR pathway (p-p70S6K1, p4E-BP1) were determined to explain the cytotoxic effects. Temsirolimus and cetuximab showed a synergistic effect when administered in combination. Supra-additive effect was lost when the two drugs were administered sequentially, irrespective of which drug was administered first. Synergistic effect of the combination was corroborated by a marked downregulation of pEGFR, significant downregulation of pAKT expression, and a marked diminution of p70S6K1 and p4E-BP1 expression. Our study demonstrated a synergistic effect of temsirolimus and cetuximab administered in combination, well illustrated by a simultaneous blockade of intracellular signaling pathways regulating cell proliferation and survival. These results establish the notion of a schedule dependency for the combined treatment, which can be of importance at the clinical level.

Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial.

BACKGROUND: Panitumumab is a fully human monoclonal antibody that targets EGFR. We aimed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS: In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (three cycles of cisplatin 100 mg/m(2)) or panitumumab plus chemoradiotherapy (three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2)) using stratified randomisation with a block size of five. All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary endpoint was local-regional control at 2 years, analysed in all randomised patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00500760. FINDINGS: Between Oct 26, 2007, and March 26, 2009, 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68% (95% CI 54-78) in the chemoradiotherapy group and 61% (50-71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3-4 adverse events were dysphagia (17 [27%] of 63 patients in the chemoradiotherapy group vs 35 [40%] of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 [24%] vs 48 [55%]), and radiation skin injury (eight [13%] vs 27 [31%]). Serious adverse events were reported in 20 (32%) of 63 patients in the chemoradiotherapy group and in 37 (43%) of 87 patients in the panitumumab plus chemoradiotherapy group. INTERPRETATION: In patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed. FUNDING: Amgen.

The effect of paclitaxel and nab-paclitaxel in combination with anti-angiogenic therapy in breast cancer cell lines.

Taxanes represent a treatment of choice for metastatic breast cancer. Their combination with bevacizumab improved response rate and progression-free survival. We studied in vitro the effect on cell survival of the combination of either paclitaxel or nab-paclitaxel with bevacizumab and we investigated the biological factors involved in the response to treatments. We used two breast cancer cell lines, MCF7 (ER+/HER2-) and MDA-MB-231 (ER-/HER2-), co-cultured with or without HUVEC cells. We analysed cell survival by MTT test, VEGF secretion by ELISA and VEGFR, SPARC, MDR1 expression by western blot. Doses of both taxanes causing a 50 % growth inhibition were higher in MCF7 than MDA-MB-231, suggesting that taxanes are more effective in ER- cell lines. When both cell lines were grown as single culture, the combination bevacizumab+paclitaxel showed a similar anti-proliferative effect compared to paclitaxel alone. The association bevacizumab+nab-paclitaxel was more effective than nab-paclitaxel alone. An increased anti-proliferative effect of bevacizumab+paclitaxel was observed when MDA-MB-231 cells were cultured with HUVEC. We detected an induction of VEGF secretion when MDA-MB-231 cells were treated with either taxanes. Paclitaxel caused a reduction of VEGF in MCF7. SPARC resulted up-regulated in both cell lines treated with bevacizumab+nab-paclitaxel. Nab-paclitaxel seems to play an important role in inhibiting tumor proliferation through albumin-SPARC bound in association with bevacizumab compared to taxanes alone in both breast cancer cells. The addition of bevacizumab to paclitaxel increased its activity only in ER- cells. This difference might be due to their ER status.

Treatment effect of buparlisib, cetuximab and irradiation in wild-type or PI3KCA-mutated head and neck cancer cell lines.

Introduction In complement to anti-EGFR therapy, the targeting of PI3K/AKT/mTOR signaling pathway is of particular interest in the management of Head and Neck Squamous Cell Carcinoma (HNSCC). Here, we assess the effects of PI3K inhibition combined with anti-EGFR monoclonal antibody cetuximab and/or irradiation (RT). Material and methods Anti-proliferative effects of the combination of buparlisib (a specific PI3K inhibitor), cetuximab and RT was determined in two HNSCC cell lines (CAL33, PI3KCA H1047R-mutated and CAL27, PI3KCA wild-type). We examined biochemical factors related to proliferation, apoptosis (caspases), DNA repair (ERCC1, XRCC1) and the PI3K pathway (pEGFR/EGFR, pAKT/AKT, p-p70, p4EBP1). Results The best synergistic combined treatment in inhibiting cell proliferation was sequence 2 (cetuximab followed by buparlisib) in both cell lines. Addition of RT increased sequence 2 anti-proliferative effect only in CAL27. Data on protein expression indicated a possible activation of mTORC2 complex and caspases proteins in CAL27 not seen in CAL33. In CAL33, the synergistic anti-proliferative effect of the two drugs may derive from the higher sensitivity of mutated cells to PI3K targeting. Conclusions Our study demonstrates a synergistic effect of cetuximab followed by buparlisib in both PI3KCA wild-type and mutated cells, even with different intracellular signaling cross-talk depending on mutational status.

Real-world study of everolimus in advanced progressive neuroendocrine tumors.

Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs.

State-of-the-art and emerging treatment options in the management of head and neck cancer: news from 2013.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer death worldwide. Its treatment is complex and evolving. In general, early-stage disease may be managed with single-modality treatment while an advanced stage (about 60% of clinical presentation) needs a multidisciplinary approach. In this setting concurrent chemoradiation has been associated with improvement in locoregional control and organ preservation, but at the cost of significant acute and chronic toxicity. Molecular target therapies specially directed to epidermal growth factor receptor (EGFR) might improve the outcomes and reduce toxicities. In recurrent-metastatic (R/M) HNSCC, cetuximab, a monoclonal antibody against EGFR, plus platinum-based chemotherapy (CT) allow an overall survival (OS) of about 10 months. However, the prognosis for R/M-HNSCC remains dismal and additional efforts are needed. At the 2013 American Society of Clinical Oncology (ASCO) Meeting, data on induction CT, anti-EGFR inhibitors, innovative molecular targets and predictor factors were reported. Further results on target therapies were presented at the European Cancer Congress (ECC) 2013, where a large study also showed that hyperfractionated radiotherapy (RT) improve OS rates compared with standard RT. The aim of this review is to discuss current standards and emerging therapies by considering recent new updates. © 2014 S. Karger AG, Basel.

Association of a gene-expression subtype to outcome and treatment response in patients with recurrent/metastatic head and neck squamous cell carcinoma treated with nivolumab.

BACKGROUND: Immune checkpoint inhibitors have been approved and currently used in the clinical management of recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. The reported benefit in clinical trials is variable and heterogeneous. Our study aims at exploring and comparing the predictive role of gene-expression signatures with classical biomarkers for immunotherapy-treated R/M HNSCC patients in a multicentric phase IIIb trial. METHODS: Clinical data were prospectively collected in Nivactor tiral (single-arm, open-label, multicenter, phase IIIb clinical trial in platinum-refractory HNSCC treated with nivolumab). Findings were validated in an external independent cohort of immune-treated HNSCC patients, divided in long-term and short-term survivors (overall survival >18 and <6 months since the start of immunotherapy, respectively). Pretreatment tumor tissue specimen from immunotherapy-treated R/M HNSCC patients was used for PD-L1 (Tumor Proportion Score; Combined Positive Score (CPS)) and Tumor Mutational Burden (Oncopanel TSO500) evaluation and gene expression profiling; classical biomarkers and immune signatures (retrieved from literature) were challenged in the NIVACTOR dataset. RESULTS: Cluster-6 (Cl6) stratification of NIVACTOR cases in high score (n=16, 20%) and low score (n=64, 80%) demonstrated a statistically significant and clinically meaningful improvement in overall survival in the high-score cases (p=0.00028; HR=4.34, 95% CI 1.84 to 10.22) and discriminative ability reached area under the curve (AUC)=0.785 (95% CI 0.603 to 0.967). The association of high-score Cl6 with better outcome was also confirmed in: (1) NIVACTOR progression-free survival (p=4.93E-05; HR=3.71, 95% CI 1.92 to 7.18) and objective-response-rate (AUC=0.785; 95% CI 0.603 to 0.967); (2) long survivors versus short survivors (p=0.00544). In multivariate Cox regression analysis, Cl6 was independent from Eastern Cooperative Oncology Group performance status, PDL1-CPS, and primary tumor site. CONCLUSIONS: These data highlight the presence of underlying biological differences able to predict survival and response following treatment with immunotherapy in platinum-refractory R/M HNSCC that could have translational implications improving treatment selection. TRIAL REGISTRATION NUMBER: EudraCT Number: 2017-000562-30.

Essential data variables for a minimum dataset for head and neck cancer trials and clinical research: HNCIG consensus recommendations and database.

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website.