Norah Guy Prize Winner - Anjali Gaston

 

 

Genomics and Cancer Treatment in Head and Neck and Thyroid: A Game Changer?

 

Introduction

Genomic medicine is a rapidly advancing interdisciplinary field that involves the study of an organism’s genome. The genome is defined as the complete set of information in an organism’s DNA, including both introns and exons. (1) Over the last decade genomic medicine has had a number of promising developments including the use of gene therapy, omics and precision medicine. The emerging field of gene therapy involves the use of genetic material to alter cells. The use of gene therapy in cancer treatment involves using the patient’s own chimeric antigen receptor (CAR) T-cells to attack tumour cells. This approach has the potential to revolutionise cancer treatment since CAR T-cells can selectively and efficiently recognise proteins expressed by tumour cells. Therefore, the tumour can be selectively targeted and destroyed without affecting the healthy cells in the body. New genome-editing technologies such as clustered regular interspaced palindromic repeat (CRISPR)-Cas9 are currently being used to improve CAR-T cell safety, efficacy and accessibility. (2) Omics includes several areas of study related to genomics such as transcriptomics, proteomics, and metabolomics. The use of omics in cancer treatment provides a more holistic understanding of the tumour, allowing pathways that may be vital for the detection and management of disease to be identified. (3) Whilst gene therapies and omics are both incredibly important in terms of transforming cancer treatment, it can be argued that precision medicine is likely to have the biggest impact on cancer treatment in the future. 

Precision medicine is defined as ‘The tailoring of medical treatment to the individual characteristics of each patient…to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment.’ (4, 5) Evidence suggests that single nucleotide polymorphisms (SNPs) in the population can be identified in order to determine individuals who are susceptible to various types of malignancies. (4) Genetic variants can also define prognosis, risk of developing a second primary cancer, treatment response and toxicity. (6, 7) A recent development in precision medicine is the use of next generation sequencing (NGS). NGS involves massive parallel sequencing of DNA -DNA is fragmented and multiple short segments are sequenced at the same time. (8) Using this method, thousands of genes to be sequenced in a relatively short time period. This approach has allowed genomic profiling of individuals to be done in a faster and more cost effective way in comparison to conventional serial single-biomarker analyses. (9) The consequence of this is that a personalised treatment approach for cancer is now becoming more feasible and has the potential to become the new standard of care.

Another novel way in which genomics has revolutionised cancer treatment is by mapping the molecular characteristics of the tumour that an individual patient possesses and using this sequencing to determine the best mode of treatment. This personalised approach has been shown to have major success in recent years. Furthermore, NGS and advanced computational data analysis approaches together have allowed for a much more detailed understanding of genes involved in oncogenesis. (10) The implication of this is the discovery of drug targets which are involved in the pathogenesis of cancer. For example, specific medications can be used to block expression of particular oncogenes and this can prevent the progression of a malignancy. Further, through the use of genomic profiling of the patient, SNPs that can result in resistance to certain medications can be identified. (9) This has the benefit of allowing treatments to be tailored to the individual’s needs, thereby preventing unnecessary treatment and adverse effects. Another advantage of NGS is that it can also be used on liquid biopsies. Not only are liquid biopsies more easily to obtain through minimally invasive procedures, the analysis of circulating tumour DNA can provide a more thorough understanding of heterogenous malignancies. (11) The potential to use precision medicine for head and neck cancers (HNCs)and thyroid cancers (TCs) which are notoriously heterogenous tumours could yield some very promising results. Therefore, the importance of genomics in future treatments for HNC and TC cannot be understated.

 

Head and Neck and Thyroid Cancer Overview

As the sixth most common type of cancer and the most prevalent type of endocrine malignancy respectively, HNC and TC pose a significant impact on morbidity worldwide. (12, 13) HNC encompasses a heterogenous group of malignancies of the pharynx, larynx, and oral cavity. (6, 14) More than 90% of these malignancies are head and neck squamous cell carcinomas (HNSCC) which are derived from the mucosal epithelium. (15, 16) Treatment for HNC has previously mostly involved surgery or chemoradiotherapy or a combination of both. Despite the fact that this treatment strategy yields a high percentage of cure in those with early stages of the disease, both high doses of chemoradiotherapy and surgery required for late-stage cancer can have significant detrimental effects. (17) 

For those with pathologic high risk HNSCC, standard of care is concurrent cisplatin-radiation therapy. Cisplatin carries the risk of systemic upset, for example nausea, vomiting and hearing loss, as well as a higher risk of infection due to a lower white blood cell count. (18) Furthermore, surgery can have a highly detrimental psychological impact on patients; HNSCC survivors have second highest rate of suicide compared to all cancer survivors. (19) Surgery also carries the risk of postoperative infections which can lead to a higher chance of mortality. (16) Perioperative treatment related causes of death include acute heart failure, respiratory failure, and cardiopulmonary arrest; previous chemotherapy and radiotherapy are risk factors for these complications. (18, 20, 21) Due to the aforementioned complications, more importance is currently being placed on ascertaining the risk factors for HNC in order to find and treat patients at an earlier stage of malignancy. Major environmental risk factors for HNC include HPV infection, smoking, and alcohol consumption. (22) However, not all patients exposed to these risks will develop HNC. This is where recent advances in genomics can have a profound impact in determining those who are susceptible.

Personalised medicine is also becoming much more widely used in the treatment of thyroid cancer. Thyroid cancer (TC) is divided by histology into differentiated (DTC), undifferentiated and medullary thyroid cancer. (23) The most common type of thyroid cancer is DTC which can be further divided into papillary TC and follicular TC. Papillary DTCs comprise the majority of TCs and are highly curable with an excellent prognosis following treatment. However, 10-15% of TCs will undergo progression into more aggressive variants which have a much higher mortality rate. Prognosis of TC depends highly on age of the patient and histological grade of the tumour. Undifferentiated TC is much more rare than DTC. The largest group of undifferentiated TC is anaplastic thyroid cancer (ATC) which makes up roughly 2% of all TCs. (24) ATCs are one of the most aggressive malignancies, they are uniformly fatal with a median survival of 3-5 months after diagnosis. (25) Metastatic and poorly differentiated DTCs also have a poor prognosis. There is currently no treatment to prolong survival for patients with ATC or highly advanced DTC. (26)

Similarly to HNC, management of TC has previously mostly involved a combination or surgery, chemotherapy and radiotherapy. (24) However, more recently, treatment has involved immunotherapy. Immunotherapy alone has not shown major success in the more aggressive forms of TC. However, sequencing the genome of TCs can identify specific genomic alterations that promote the progression of TC. By sequencing the tumour of an individual and then targeting the immunotherapy based on these findings it is hoped that effective treatment for advanced DTC and ATC could be developed. (26)

 

Genomic Alterations and Treatment Strategies

NGS assays include whole genome sequencing, whole exome sequencing and sequencing a targeted panel of genes.  Whole genome sequencing involves sequencing almost all nucleotides in the genome, whereas whole exome sequencing focuses purely on protein-coding regions (roughly 1% of the genome). Targeted panel sequencing involves interrogating specific genes to look for certain mutations. Whilst each technique has its advantages, whole genome and whole exome sequencing tend to be used more in research, whereas targeted panel sequencing has more clinical applications. Targeted panel sequencing is particularly useful when looking at cancer somatic mutation because it can cover different mutations with variable allelic frequencies in more depth. (8)

Panel sequencing has recently been used to identify gene mutations in TC. TC predominantly involves both tumour suppressor and oncogene mutation. The genes that are thought to drive both ATC and advanced DTCs are the oncogenes BRAFV600E and RAS. (26) Alterations in BRAF and RAS affect cell cycle and progression through mitogen-activated protein kinase pathway (MEK). BRAF mutations are common in TC and are related to metastasis and extrathyroidal expansion. The presence of BRAF mutation could help to decide whether the thyroid gland should be surgically removed; if BRAF mutation is present the chances of the patient having TC are close to 100%. (27) BRAFV600E inhibitor (vemurafenib) and MEK inhibitor (selumetinib) have been trialled in in vivo models. The results of this are promising, inhibition of tumour growth and metastasis as well as cell cycle arrest were seen in the study. (28) However, limitations of immunotherapy include high costs and the possibility of developing resistance (which is closely related to tumour heterogeneity). (29)

Transcriptomic analysis of TC using RNA sequencing has shown that DTC can be sub classified into BRAFV600E-like and RAS-like. This could be important in predicting disease progression since BRAFV600E-like DTCs display more aggressive clinical characteristics than RAS-like DTCs. (30) Another molecular marker that has been found to have prognostic value in TC is the promoter mutation of the oncogene TERT. TERT mutations are strongly related to a poor prognosis. For those patients without TERT mutations, the approach of a lobectomy of the thyroid gland rather than a total thyroidectomy may be indicated. (31) This would have the advantage of preventing overtreatment and reduce chances of postoperative complications that can have both physical and psychological impacts on patients.  

Unlike TC, in which mutations occur frequently in multiple oncogenes such as RAS, the only oncogene that has been shown to be mutated regularly in HNSCC is PIK3C. Therefore, HNSCC is thought to be driven by loss of tumour suppressors. (15) Whole exome sequencing has identified that tumour suppressor genes such as TP53, TP63, TP73, CDKN2A and NOTCH1 are the most commonly altered genes in HNSCC. (32) Gene alterations that occur in HNSCC are largely impacted by whether the patient is HPV-positive. HPV-positive HNSCC and HPV-negative HNSCC have clear differences in gene expression as well as immune profiles. In HPV-negative HNSCC, alterations in tumour suppressor genes are associated with a poor prognosis. TP53 (the gene that encodes p53) is often deleted or mutated. The inactivation of TP53 usually occurs early in the pathogenesis of HNSCC and plays a role in the development of cellular dysplasia. TP53 mutations are clinically associated with shorter survival time and more resistance to radiotherapy and chemotherapy. Therefore, TP53 may be useful in predicting clinical response in HPV-negative HNSCC patients. (33) This is only significant in cases of HPV-negative tumours as HPV positive tumours cause degradation of TP53 so mutations in the gene cannot occur. 

HPV 16 and HPV 18 are the strains that tend to cause HPV- positive HNSCC. The viral genome in HPV infection tends to be integrated at a single site. E6 and E7 viral genes are essential in cancer formation in the host. E6 causes proteasomal degradation of TP53. (34) E7 causes the degradation of retinoblastoma protein (pRB) which causes upregulation of a protein called p16INK4A (encoded by CDKN2A tumour suppressor gene). (35) Upregulation of p16INK4A causes cell cycle dysregulation which then leads to carcinogenesis. HPV testing in oropharyngeal cancers involves using immunohistochemistry for p16INK4A which indicates levels of the E7 oncoprotein. (36) Studies have shown that HPV-positive HNSCC is more susceptible to radiation and anticancer drugs and has a more favourable prognosis. (37) The implications of this are that treatments can be chosen based on whether the patient HPV-positive or HPV-negative and therefore which gene mutations they are more likely to have. As well as this, there is potential for doses of chemoradiotherapy to be reduced in those with HPV-positive HNSCC – this could lead to equally as effective treatment with improved quality of life. (38)

CDKN2A loss is an important prognostic factor in HPV- negative HNSCC. CDKN2A inactivation occurs very early in the pathogenesis of HNSCC and is a key event in causing the normal mucosa to develop into hyperplasia. In HPV-negative HNSCC CDKN2A copy number loss was associated with poor prognosis regarding both disease progression and overall survival. (39) Tumour suppressors TP53 and CDKN2A were also frequently altered in ATC. CDKN2A loss has been associated with poor prognosis and increased mortality in both ATC and advanced DTC patients. CDKN2A loss involved in TC has several therapeutic implications. Firstly, cell lines with CDKN2A loss have been shown to respond CDK4/6 inhibitors. (26) CDKN2A loss has also been shown to be involved with resistance to BRAFV600E-selective inhibitors. Therefore, the use of genomics can have significant implications on effective treatment choice in ATC. Although the aforementioned findings are relating to ATC specifically, since the pathogenesis of HPV-negative HNSCC also involves CDKN2A loss, it is likely that CDK4/6 inhibitors may be an effective treatment for some HNCs as well.  As well as this, CDKN2A loss has been associated with up regulation of CD274 and PDCD1LG2 in ATCs. (40) These genes are known targets for immunotherapy. The personalised medicine approach of mapping the tumour of each individual could therefore be key in determining whether to target CD274, PDCD1LG, CDK4/6 or a combination of these as the most effective treatment strategy.

CAR-T cell immunotherapy has the potential to play an important role in the treatment of both HNSCC and TC. Dysregulated signally of ErbB family of receptor tyrosine kinases has been shown to be involved in the pathogenesis of HNSCC. The ErbB family includes epidermal growth factor receptor (EGFR). Over expression of EGFR which is found in 80-90% of HNSCCs is associated with resistance to radiotherapy and increased chance of metastasis. (41) The EGFR monoclonal antibody cetuximab is often used with radiation for treatment of HNSCC if comorbidities mean that chemotherapy is contraindicated or if there is recurrent disease. (15) The success of cetuximab in treatment of HNSCC has led to investigations into the use of CAR T-cell immunotherapy in targeting ErbB. CAR-T therapy could have a large impact on HNSCC treatment as it has the potential to target specific tumour cells thereby decreasing the risk of the tumour evading the immune system. It is currently surmised that a combination approach of chemotherapy and CAR-T therapy should be used since chemotherapy can sensitise the tumour to the T cells. (41) CAR-T immunotherapy is also hypothesised to be an effective treatment of patients with medullary metastatic thyroid cancer (MTC) for which there is currently no cure. Bhoj at al are currently developing a clinical trial to test CAR-T cells directed against glial derived neurotrophic factor receptor alpha 4 (GFRα4) which is over expressed in MTC. (42)

 

Conclusion

The genetic evaluation of the patient and their tumour in both HNC and TC is becoming more crucial in diagnosis and treatment. (43) The incidence of TC has been rising rapidly in recent years. Well differentiated thyroid cancer is predicted to be the fourth most common cancer by 2030. (44) HNC is already the sixth most common cancer and has a high mortality rate of approximately 271,000 patients per year. (13) Through the use of genomic medicine developments such as NGS, tumour DNA can be screened at a large scale in an efficient and cost-effective manner. This has led to the identification of molecular markers for diagnosis, risk stratification and treatment targets. Finding key gene alterations involved in the pathogenesis of HNC and TC allows for better informed treatment decisions for patients and therefore better outcomes. Over recent years, a better understanding of genomics has also enabled the development of gene therapy use in cancer treatment. The ability of CAR-T cells to target and destroy tumour cells could result in effective treatment whilst avoiding the typical side effects of more traditional therapies such as chemotherapy or radiation. Therefore, it is arguable that genomics certainly has the potential to be a game changer in the treatment of HNC and TC. 

However, for this potential to revolutionise cancer treatment by using a personalised approach to become a reality, changes beyond the scope of genomics will have to take place. Firstly, despite the fact that targeted immunotherapy has the greatest potential therapeutic advantage, it is also highly expensive. The BRAF inhibitor vemurafenib which has the potential to treat both HPV negative HNC and TC costs approximately £37,700 per patient per year. (45) The combined costs of NGS techniques and immunotherapy mean that the personalised medicine approach may not have the largest impact on HNC and TC treatment on a global scale. Data sharing to global knowledgebases, increased access to clinical trials and education of both clinicians and patients could help to overcome some of the obstacles that are preventing widespread uptake of personalised medicine. (9) Modification of risk factors is also hugely important in HNC specifically. The role of worldwide HPV vaccination schemes in HNC prevention cannot be understated. It is thought that most cases of HNSCC could be prevented with global HPV vaccination and smoking cessation combined. (15) Reducing the number of cases of both HNC and TC could mean that a personalised treatment approach would be more feasible in the future. Therefore, whilst genomics is revolutionising cancer treatment, a holistic approach of using genomic medicine alongside traditional cancer therapies and public health campaigns is most likely to be a game changer in HNC and TC moving forwards. 

 

 

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