Skip to 0 minutes and 14 seconds Lung cancer is the most commonly diagnosed cancer worldwide and is the leading cause of cancer-related death. More than half the cases, approximately 55%, occur in the developing world. The incidence in males is more than double that in females, with a ratio of about 2.5 to 1. As there is a strong correlation between tobacco smoking and incidence rate, it’s not surprising to see such high incidence rates with a time lag of about 20 to 30 years of smoking. At present, there is estimated to be more than one billion smokers worldwide. As this continues to rise without intervention, this will lead to large increases in the incidence of lung cancer in the coming decades.
Skip to 0 minutes and 53 seconds So what are the options for people diagnosed with lung cancer? If caught early enough, prior to invasion into other tissues, then combined chemotherapy and radiotherapy works well and generally has a good cure rate. However, most patients present with a much more advanced disease, around stage three to four, where the cancer has already spread throughout the body and to other tissue types. For these patients, there are three main options. Using platinum-based chemotherapy, which can prolong life from four to six months. Secondly, the use of kinase inhibitors against receptor tyrosine kinases, for example, erlotinib, which has been approved for use in Scotland since 2011. Thirdly, clinical trials, using a combined approach of chemotherapy and targeted approaches.
Skip to 1 minute and 40 seconds It is important to note that not all lung cancer is the same. There are distinct subtypes that can be identified using a variety of pathological techniques. Lung cancer can be broadly divided into small cell lung cancer, accounting for around 15% percent, and non small cell lung cancer, accounting for around 85% of cases. Recent studies into non small cell lung cancer have given us a better understanding of the molecular biology of the disease. This, in turn, has led to the identification of possible therapeutic targets. One such case is EGFR, which is a growth factor receptor found on the surface of cells. This growth factor pathway plays an important role in carcinogenesis and tumour progression.
Skip to 2 minutes and 22 seconds If EGFR is deranged, this can lead to cell growth, proliferation, invasion, and metastatic spread. As you can imagine, the EGFR is an interesting therapeutic target for the treatment of patients with non small cell lung cancer. Treatment therapies that block this receptor could slow down or stop the spread of cancer. There are two major classes of therapy. Firstly, antibodies that block the receptor-specific ligand. These tend to be larger molecules, administered by injection. This way, the drug has a longer half-life in the body. Secondly, EGFR tyrosine kinase inhibitors. The EGFR pathway is turned on when EGFR is activated by tyrosine phosphorylation, that is, the addition of a phosphate molecule onto a tyrosine residue.
Skip to 3 minutes and 8 seconds Tyrosine kinase inhibitors are drugs that block this phosphorylation event. These are smaller molecules that can be used for daily therapy and are distributed well within the body. A number of pharmaceutical companies have developed such inhibitors for use in non small cell lung cancer patients. So where do we come in? Well, the role of molecular diagnostics services has evolved over recent years. We now know from research studies that the “one size fits all” model for treatment doesn’t really apply anymore. The different responses to cancer treatment have raised some interesting questions, such as, why do some people with the same or similar cancer type respond well to treatment, whilst others respond poorly?
Skip to 3 minutes and 47 seconds We now know the underlying mutations in certain genes can predict treatment response. In non small cell lung cancer, about 5% to 10% of patients will have a mutation in their tumor that makes them more likely to respond to treatment with drugs such as erlotinib, which is an EGFR-tyrosine kinase inhibitor. So it’s important to first stratify patients based on their tumour type and mutation status prior to treatment. This is a perfect example of what we call Stratified Medicine. Working collaboratively with our colleagues from different disciplines, we’re able to target each newly diagnosed non small cell lung cancer patient to the appropriate treatment option. So how do we go about this?
Skip to 4 minutes and 29 seconds Well, we receive formalin-fixed paraffin-embedded tissue from the lung tumours from our pathology colleagues. This does rely on the correct tissue being selected from the tumor area. We want as many tumour cells as possible, as too many normal cells can skew our results. The tissue is then cut into very thin slices, and the DNA is extracted from the tissue. We then test the tumour DNA for mutations in EGFR using two different techniques. One of the techniques we use is traditional Sanger sequencing. This uses bidirectional sequencing to amplify the region of interest and detects any changes when compared against a reference, i.e., a normal sequence.
Skip to 5 minutes and 6 seconds The other technique we employ is a commercially available COBAS EGFR mutation test kit, which uses allele-specific PCR to detect 41 specific mutations. Results from both of these techniques are able to detect and identify common mutations in exons 18 to 21 of the EGFR gene. Mutations can either be described as sensitising, i.e., they’ll respond to EGFR tyrosine kinase inhibitor treatment, or resistant, where treatment would not work as well and do more harm than good in these patients. Working with our pathology colleagues, we issue a report within a strict five-day turnaround time, allowing the start of treatment as soon as possible after diagnosis and biopsy of the sample.
Skip to 5 minutes and 47 seconds If a patient is found to have no EGFR mutations, we will issue an EGFR negative report. This will state that the patient is unlikely to respond to treatment with EGFR tyrosine kinase inhibitors. This patient will then follow standard platinum-based chemotherapy, as any treatment with EGFR tyrosine kinase inhibitors would do more damage than good. When an EGFR sensitising mutation is identified, the patient will be placed on an EGFR tyrosine kinase inhibitor, such as erlotinib. This drug is administered daily, and the patient will have a better response than standard treatment. Studies have shown that appropriate treatment with erlotinib has increased the average cancer survival by four to five months when compared to standard platinum-based chemotherapy.
Skip to 6 minutes and 32 seconds To date, we have tested in excess of 600 samples in the West of Scotland and identified about 50 EGFR sensitising mutations and about six resistance mutations. We should ask, what does the future hold for molecular diagnostics in lung cancer? As mentioned in this talk, EGFR is only one of the many therapeutic targets identified in lung cancer patients. The future will be very different to the current testing strategy. At the moment, we’re using a relatively targeted approach, which is specific to EGFR changes. In the near future, we will be performing genetic profiling on tumour DNA using next-generation sequence technologies. This will involve testing a large panel of different genetic targets simultaneously, using a very small amount of DNA.
Skip to 7 minutes and 17 seconds This will allow us to build a specific picture of each affected individual tumour profile, and their treatment will be custom-built around this. Hopefully, in time, with the help of clinical trials and continued drug development, the prognosis for lung cancer patients will be a lot brighter.
Molecular diagnostics in lung cancer
Clinical Molecular Geneticist Aisha Ansari outlines how molecular stratification of lung cancer patients is beginning to aid treatment decisions.
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