|Year : 2013 | Volume
| Issue : 1 | Page : 1-2
Molecular markers in the head and neck cancers: Are we there yet?
Department of Radiotherapy, AIIMS, New Delhi, India
|Date of Web Publication||10-Apr-2013|
G K Rath
Department of Radiotherapy, AIIMS, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Rath G K. Molecular markers in the head and neck cancers: Are we there yet?. J Can Res Ther 2013;9:1-2
India accounts for 20-25% of 6.4 lakh cases of head and neck cancers diagnosed world-wide every year. Majority of them were present in the advanced stage (60-80%). The treatment of head and neck cancers continues to evolve, both in terms of understanding of the disease, therapeutic technologies and more recently understanding of the molecular pathways and biology of the disease. Even with the modern day multimodality therapies, loco-regional failures occur in around 20-40% of the patients. The methods of detection of recurrences also rely on clinical and radiological examination, which are not adequate and sensitive enough to detect them all. Hence, there is a pressing need to explore the role of molecular and bio-markers, for better patient outcomes.
There is a remarkable diversity both in anatomy, tumor morphology, and biology of the head and neck. The evolution and progression of this cancer are thought to result from multiple stepwise alterations of cellular and molecular pathways in the squamous epithelium. Loss of chromosomal region 9p21 is found in 70-80% of cases, thus, representing the most common genetic alteration seen in squamous dysplasia and head and neck squamous cell carcinoma. p16 inactivation, p53 mutation, alterations of the epidermal growth factor receptor (EGFR) axis, hypoxia inducible factor (HIF)-1 α, and alterations of the PI3-K/AKT/mTOR pathways are the other common alterations. The recent information about the role of human papilloma virus (HPV) and EGFR have generated both enthusiasm and hopes for further development in this arena.
The updated results of the landmark trial by Bonner et al.  showed not only a survival benefit at 5 years in the Cetuximab arm of ~10% but also showed statistically significant increase in survival in patients who had at least grade 2 acneiform rash, thus, guiding ways to identify robust and inexpensive indirect markers for the molecular therapies. Several studies including Eastern Cooperative Oncology Group (ECOG) 5397 and extreme trial have also shown benefit of Cetuximab in recurrent and metastatic head and neck cancers. However, have we really achieved a breakthrough? In the last decade, apart from the Bonner trial, no trial has shown such robust survival benefit with Cetuximab. Unlike other cancers like breast where the targeted therapies are based on individualized tumor assays, the need for assays and quantification of EGFR expression has not been explored. A study by Burtness Barbara et al.  showed less favorable response with high EGFR expression, necessitating more research in this field.
Several pathways mediating resistance to EGFR directed therapies have emerged including EGFRvIII (produced by the rapid proliferation of receptors and shedding of their external domain), STAT3 pathways, Aurora kinase etc., which needs to be studied to bridge the gaps in the understanding of the pathways. Several EGFR directed therapies including, Panitumumab, Zaltumumab, Nimotuzumab,  Gefitinib, and Erlotinib are actively being investigated in various phase II/III trials and needs to be carefully followed and interpreted.
The other development in the biology of head and neck cancers, which has revolutionized the molecular landscape is HPV. , Smoking and alcohol consumptions are the established risk factors for head and neck cancers. However, recently there has been an upsurge of squamous cell carcinoma in young population with no or limited history of tobacco use and distinct sexual behaviour, most of which are oropharyngeal squamous cell cancers (OPSCC) and HPV positive.  These subgroups of patients not only have distinct demographics but also very favorable outcomes (e.g., 5-year overall survival rate of >80% vs.~40% for patients with stage III-IV tumors), and hence they are more likely to experience chronic therapy-induced morbidity. Therefore, changes in evaluation, staging, and treatment are needed for this patient group. In view of their favorable outcome with standard radiotherapy/chemo-radiotherapy, the focus is now more on treatment de-intensification in order to reduce treatment related morbidities in this younger group of patients.
Recent studies have explored the significance of tobacco exposure history as a variable, along with tumor and regional node stage as predictors of risk of recurrence and death in the patient with HPV-associated OPSCC who is treated with radiation therapy.  Recently O'Sullivan et al.  reported the results of a large, retrospective, institutional review of 505 patients treated uniformly by stage with radiotherapy alone or concurrent cisplatin and radiotherapy. The HPV-positive cohort could be segregated into low-risk (T1-3, N0-2C) and high-risk (T4, N3). Among the low-risk HPV-positive cohort, subgroups of patients with N2b (particularly those with ≥10-pack-year tobacco exposure) and N2c were found to have a higher rate of distant relapse when treated with radiotherapy alone (the majority with accelerated radiotherapy schedules) compared with patients treated with concurrent chemoradiotherapy. Thus, modifying or eliminating chemotherapy as a de-intensification strategy may be most reasonably tested in patients with HPV-positive T1-3 and N0-2a stage disease, which would encompass all stage III cancers and most stage IV cancers with low-volume regional nodes. Several studies including ECOG 1308, RTOG 1016 and studies at Dana Farber are prospectively studying the de-intensification strategies and holds promises to resolve the issue in very near future.
Several predictive molecular markers have appeared on the horizon including ERCC1  (as a surrogate marker of cisplatin sensitivity), RRM1 (gemcitabine sensitivity), β-Tubulin-II  (taxane sensitivity). HPV status for oropharyngeal cancer and EBV quantification may emerge in the future as strong prognostic factor.
The scope of molecular markers have definitely widened and it has been applied not only in diagnosis (EBV for nasopharyngeal cancers and HPV for oropharyngeal cancers in tumor samples), tailoring treatment (HPV status for oropharyngeal cancers), and predicting response to therapy. It also has opened up new avenues of research including work on stem cell markers (CD44 laryngeal cancers), (epithelial to mesenchymal transition) and research on epigenetic modifications.
We have come a long way but still several questions remain unanswered and several gaps unfilled. Is there an association between HPV status and EGFR targeting? How to best combine chemotherapy, radiotherapy and targeted therapy? How to best select patients based on the biomarkers?
The quote by Sir Winston Churchill aptly applies to the revolution in the molecular landscape of head and neck cancers:
"This is not the end. It is not even the beginning of the end. This is, however, the end of the beginning"
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