•Nivolumab and Pembrolizumab have been recently approved for advanced HNSCC.•PD-L1 correlates with improved efficacy to anti-PD-1 monoclonal antibodies.•Tumor mutational burden has been associated ...with immunotherapy (IO) response.•Interferon-γ signature has prognostic and predictive significance for response to IO.•Tumor microenvironment is a potential source for the identification of biomarkers.
Preclinical data suggest that head and neck squamous cell carcinoma (HNSCC) is a profoundly immunosuppressive disease, characterized by abnormal secretion of proinflammatory cytokines and dysfunction of immune effector cells. Based on landmark phase III trials, two anti-Programmed Cell Death-1 (PD-1) antibodies, pembrolizumab and nivolumab have been approved for HNSCC by FDA and EMEA in the recurrent/metastatic setting; in addition, pembrolizumab has recently received FDA and EMEA approval as first line treatment. In clinical practice, only a minority of patients with HNSCC derive benefit from immunotherapy and the need for the discovery of novel biomarkers to optimize treatment strategies is becoming increasingly more relevant. Although currently only PD-L1 is widely used as a predictive biomarker for response to immune checkpoint inhibitors in HNSCC, there are many ongoing trials focusing on the identification of new biomarkers. This review will summarize current data on emerging biomarkers for response to immunotherapy in HNSCC.
Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we ...evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.
Survival from head and neck cancers (HNCs) of the lip, oral cavity, pharynx, and larynx has increased by 10% over the past few decades. Little over half of patients who develop HNCs will survive ...beyond 5 years. Survival is lower for individuals in many countries where traditional risk factors such as tobacco smoking, alcohol drinking, and betel quid chewing are highly prevalent but tertiary health care center access is limited or unavailable. Early diagnosis of HNC is the most important prognostic factor for each tumor site. Molecular-based research on HNC tumors holds promise for early stage detection, screening, vaccination, disease follow-up, and progression. Future investments for HNC control must consider both effectiveness and sustainability for both high- and low-resource countries alike, with priority toward risk factor prevention and earlier diagnosis.
•Head and neck cancer patients are at high risk for sarcopenia, or low muscle mass.•Established cut-offs for sarcopenia are associated with poor chemotherapy tolerance.•Sarcopenia is associated with ...radiation treatment breaks greater than 1 week.•Sarcopenic patients with p16-negative disease have worse survival outcomes.
Sarcopenia is a predictor of poor prognosis in cancer patients. One potential mechanism for worse outcomes in sarcopenic patients is worse tolerance to treatment; this has not been investigated with regard to radiation treatment. We reviewed our institutional experience of head and neck cancer patients receiving concurrent chemoradiation and assessed outcomes with respect to sarcopenia.
Patients treated between 2012 and 2016 were reviewed. Sarcopenia was assessed from radiation planning computed tomography (CT) scans using muscles at the C3 vertebral body using previously published methods. Survival was calculated using the Kaplan–Meier method. Association between patient factors and outcome was calculated in univariate and multivariate analyses.
Two hundred and forty-six patients were included. Fifty-eight percent met criteria for sarcopenia. Thirty-seven percent experienced chemotherapy delays of >1 week and 14% had radiation treatment breaks >1 week. On multivariate analysis, concurrent smoking (HR 3.85, p < 0.01) and sarcopenia (HR 2.15, p = 0.01) were associated with chemotherapy toxicity and age >65 years (HR 2.94, p < 0.01) and sarcopenia (HR 2.99, p = 0.04) were associated with prolonged radiation breaks. Sarcopenia was associated with worse overall survival (HR 1.83, p = 0.03) and progression-free survival (HR 1.65, p = 0.03) in the overall cohort. When analyzed separately, sarcopenia was not associated with outcomes in p16-positive oropharynx cancers.
Sarcopenic patients receiving concurrent chemoradiation are more likely to require radiation treatment breaks and suffer chemotherapy toxicity than their non-sarcopenic counterparts. This may contribute to worse survival outcomes in head and neck cancer, with the exception of p16-positive oropharyngeal cancer.
Squamous cell carcinoma arises from multiple anatomic subsites in the head and neck region. The risk factors for development of cancers of the oral cavity, oropharynx, hypopharynx, and larynx include ...tobacco exposure and alcohol dependence, and infection with oncogenic viruses is associated with cancers developing in the nasopharynx, palatine, and lingual tonsils of the oropharynx. The incidence of human papillomavirus-associated oropharyngeal cancer is increasing in developed countries, and by 2020, the annual incidence could surpass that of cervical cancer. The treatment for early-stage squamous cell cancers of the head and neck is generally single modality, either surgery or radiotherapy. The treatment for locally advanced head and neck cancers is multimodal, with either surgery followed by adjuvant radiation or chemoradiation as indicated by pathologic features or definitive chemoradiation. For recurrent disease that is not amenable to a salvage local or regional approach and for metastatic disease, chemotherapy with or without a biological agent is indicated. To date, molecular testing has not influenced treatment selection in head and neck cancer. This review will focus on the changing epidemiology, advances in diagnosis, and treatment options for squamous cell cancers of the head and neck, along with data on risk stratification specific to oropharyngeal cancer, and will highlight the direction of current trials.
We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus (HPV) and p16 protein expression status with outcomes in patients with oropharyngeal ...carcinoma (OPC) receiving radiotherapy (RT) plus cetuximab or RT alone.
In the IMCL-9815 study, patients were randomly allocated to receive RT plus weekly cetuximab or RT alone. A subpopulation of patients with p16-evaluable OPC was retrospectively evaluated on the basis of locoregional control (LRC), overall survival (OS), and progression-free survival (PFS). Evaluable samples from patients with p16-positive OPC were also tested for HPV DNA.
Tumor p16 status was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study; 41% were p16 positive. When treated with RT alone or RT plus cetuximab, p16-positive patients had a longer OS than p16-negative patients (hazard ratio, 0.40; 95% CI, 0.21 to 0.74 and hazard ratio, 0.16; 95% CI, 0.07 to 0.36, respectively). The addition of cetuximab to RT increased LRC, OS, and PFS in both patients with p16-positive OPC and those with p16-negative disease. Interaction tests for LRC, OS, and PFS did not demonstrate any significant interaction between p16 status and treatment effect (P = .087, .085, and .253, respectively). Similar trends were observed when patients with p16-positive/HPV-positive OPC (n = 49) and those with p16-positive/HPV-negative OPC (n = 14) were compared.
p16 status was strongly prognostic for patients with OPC. The data suggest that the addition of cetuximab to RT improved clinical outcomes regardless of p16 or HPV status versus RT alone.
To construct an immune-related gene prognostic index (IRGPI) for head and neck squamous cell carcinoma (HNSCC) and clarify the molecular and immune characteristics and the benefit of immune ...checkpoint inhibitor (ICI) therapy in IRGPI-defined subgroups of HNSCC.
On the basis of The Cancer Genome Atlas HNSCC immune dataset (
= 546), 22 immune-related hub genes were identified by weighted gene coexpression network analysis. Three genes were identified to construct an IRGPI by using the Cox regression method and validated with the Gene Expression Omnibus (GEO) dataset (
= 270). Afterward, the molecular and immune characteristics and the benefit of ICI therapy in IRGPI-defined subgroups were analyzed.
The IRGPI was constructed on the basis of
,
, and
genes. IRGPI-high patients had a better overall survival than IRGPI-low patients, consistent with the results in the GEO cohort. The comprehensive results showed that a high IRGPI score was correlated with DNA repair-related pathways; low
mutation rate; high infiltration of CD8 T cells, CD4 T cells, and M1 macrophages; active immunity and less aggressive phenotypes; and more benefit from ICI therapy. In contrast, a low IRGPI score was associated with cancer and metastasis-related pathways; high
and
mutation rate; high infiltration of B cells, M0 macrophages, and M2 macrophages; suppressive immunity and more aggressive phenotypes; and less benefit from ICI therapy.
IRGPI is a promising biomarker to distinguish the prognosis, the molecular and immune characteristics, and the immune benefit from ICI therapy in HNSCC.
Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy ...represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours' aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.
Poor oral hygiene has been proposed to contribute to head and neck cancer (HNC) risk, although causality and independency of some indicators are uncertain. This study investigates the relationship of ...five oral hygiene indicators with incident HNCs.
In a pooled analysis of 8925 HNC cases and 12 527 controls from 13 studies participating in the International Head and Neck Cancer Epidemiology Consortium, comparable data on good oral hygiene indicators were harmonized. These included: no denture wear, no gum disease (or bleeding), <5 missing teeth, tooth brushing at least daily, and visiting a dentist ≥once a year. Logistic regression was used to estimate the effects of each oral hygiene indicator and cumulative score on HNC risk, adjusting for tobacco smoking and alcohol consumption.
Inverse associations with any HNC, in the hypothesized direction, were observed for <5 missing teeth odds ratio (OR) = 0.78; 95% confidence interval (CI) 0.74, 0.82, annual dentist visit (OR = 0.82; 95% CI 0.78, 0.87), daily tooth brushing (OR = 0.83, 95% CI 0.79, 0.88), and no gum disease (OR = 0.94; 95% CI 0.89, 0.99), and no association was observed for wearing dentures. These associations were relatively consistent across specific cancer sites, especially for tooth brushing and dentist visits. The population attributable fraction for ≤ 2 out of 5 good oral hygiene indicators was 8.9% (95% CI 3.3%, 14%) for oral cavity cancer.
Good oral hygiene, as characterized by few missing teeth, annual dentist visits, and daily tooth brushing, may modestly reduce the risk of HNC.
PDF
