For patients with colorectal cancer
Anti-EGFR antibody based therapies such as cetuximab & panitumumab are commonly used in the routine treatment of metastatic colorectal cancer. However, if a patient’s tumour contains certain mutations, these therapies simply won’t work very well, if at all. Thus it is important to try to identify these mutations as early as possible in order to start alternative treatment options without delay.
Many clinicians only use a combination of two single gene tests to analyse KRAS and NRAS (collectively referred to as RAS) for common activating mutations, as these alone account for the majority of colorectal patients who are unlikely benefit from anti-EGFR therapy. Both these genes (common and rare variants) are included in all our DNA based NGS test (MGP-4 DNA), but so are many others, such as BRAF, ERBB2, PIK3CA and PTEN – all of which can be important when considering colorectal cancer treatment options. This information can help you avoid putting patients through a treatment that is unlikely to work. Also, if there are no licensed or approved therapies which are optimal for your patient, mutations or copy number gains in these additional genes may be able to direct them onto a suitable clinical trial. Finally, if we don’t find any oncogenic mutations with our DNA panel, you may wish to consider additional screening with our MGP-4 RNA panel for the latest generation of therapies which target gene rearrangements (fusions) like RET and NTRKs. Although generally rare, the incidence of these aberrations becomes much more appreciable once all the ‘usual suspects’ (KRAS etc.) have been excluded, especially if further filtered by characteristics such as the patient’s DNA miss-match repair status (see our MSI assay below).
Please note that colorectal cancers are associated with Lynch Syndrome, and in addition to the options detailed above for targeted therapy use, we also offer both MSI and MLH1 promoter analysis in order to help stratify the risk of Lynch Syndrome. In accordance with current NICE guidelines, such risk screening should be undertaken in all new CRC patients at diagnosis.
For patients with lung cancer
With non-small cell lung cancer, many patients are unfortunately still only tested for the minimum set of therapeutic bio-markers recommended in current guidelines, namely EGFR, ALK, ROS1 and PDL1. Only the first three of these comprise genetic changes associated with specific targeted therapies, and collectively they account for only about 20% of non-small cell lung cancer cases in the UK. This means that the remaining 80% or so are treated without any idea of what is actually driving their lung cancer. Of course, even if the primary genetic defects could be identified in all cases, for many there may still be no associated treatments, but this is certainly not always the case and a significant number of other genetic markers do have associated therapies, either already approved for use or undergoing clinical trials. Individually, these additional markers are all quite rare, which can make screening for them separately uneconomic at a population level. Collectively however, they can form a significant subset of patients. Consequently, tests based on technologies like NGS, that can look at these at the same time as the ‘basic’ markers, for little or no extra cost, really come into their own. Even if such tests only identify non-actionable tumour specific events, at least there is some piece of mind in knowing that potentially actionable events have not been missed. Indeed, in a world where biopsies are increasing becoming smaller, less invasive and consequently more challenging for laboratories to analyse reliably, this is an often overlooked benefit in more comprehensive testing strategies.
If your patient has previously only received single bio-marker tests, which did identify an actionable mutation (in EGFR, ALK or ROS1), our NGS test can still be useful as their disease progresses. This is because in time, such patients will unfortunately go on to develop resistance to first line Tyrosine Kinase Inhibitor (TKI) therapy. In some cases, this will be due to the acquisition of additional mutations in the originally mutated gene, such as a change from Threonine to Methionine at codon 790 (often just referred to as T790M) of EGFR; something which can be detected by most EGFR single gene tests and treated with a 3rd generation TKI. However, in the same way that not all lung cancers are initially driven by EGFR mutation, not all EGFR TKI resistance is driven by acquisition of T790M, and tests that only analyse this can give no other information that may help guide options in the majority of first line EGFR TKI resistant patients, who are T790M negative.
For patients with melanoma
BRAF and MEK inhibitors are drugs of choice in treating metastatic melanoma. However, their routine use is only indicated in patients whose tumours contain mutations at one specific site (codon 600) of the BRAF gene. Consequently, clinicians often request a single gene BRAF test that can identify the mutations at codon 600 only. Unfortunately though, less than half of patients will possess this mutation, leaving few alternative options for the remainder.
In addition to BRAF codon 600, our multi-gene NGS test also assesses activating BRAF mutations at other codons as well as looking other genes like KIT, NRAS, ERBB2, MAP2K1, PIK3CA, PTEN, GNA11 and GNAQ, which can also help stratify patients for other approved therapies (e.g. KIT inhibitors) or potential off-label treatment/clinical trial options.
For patients with breast cancer
Although potentially less relevant at initial diagnosis, our NGS test can be useful for breast cancer patients who have already been through endocrine or other standard therapies and are now considering more molecularly targeted options, potentially even in a clinical trial context. In this setting the identification of alterations in PIK3CA, ERBB2, PTEN and other genes can all be of relevance.
2. Getting answers fast from appropriate* use of our rapid turnaround tests
Metastatic Colorectal (mCRC) Screen: Mutations in KRAS are the cause of many colorectal cancers. We can test KRAS quickly to identify whether your patient has an activating KRAS mutation and consequently will not benefit from anti-EGFR antibody therapy. If KRAS mutation is NOT the primary driver of your patient’s cancer, it’s obligatory (in order to meet UK best practice guidelines) that we reflex at least to analysis of NRAS, though we also include BRAF – as collectively these account the majority of patients who would likely not respond or potentially only respond poorly to anti-EGFR therapy. Please note that KRAS positive patients will not routinely be tested for NRAS/BRAF as well.
Melanoma Screen: BRAF & MEK inhibitors are key drugs of choice in treating metastatic melanoma. However, their routine use is only indicated in patients whose tumours contain mutations at one specific site (codon 600) of the BRAF gene. To enable suitable patients to access this treatment fast we offer codon 600 only analysis in rapid turn-round format. Note that if MEK inhibitors are being considered in relation to NRAS mutation, please request our MGP-4(DNA) panel.
Non-Small Cell Lung Cancer (NSCLC): Tyrosine Kinase Inhibitors (TKIs) are often the drugs of choice for treating NSCLC. However, their routine use is only indicated in patients whose tumours contain specific mutations or gene rearrangements. To enable suitable patients to access these treatments as fast as possible, we offer analysis of the most commonly observed changes in two rapid turn-round format assays. The first of these is for EGFR mutations and the second for rearrangements in the ALK, ROS1, RET & MET genes.
Micro-Satellite Instability (MSI): High microsatellite instability is an indicator of defective DNA mismatch repair with a tumour and is a predictive biomarker for potential benefit from immune checkpoint inhibitor therapy in a number of cancer types.
With all our rapid turn-round single gene test options, we will deliver the results within 2 working days, subject to the supplied sample being directly suitable for testing.
*Given that these rapid turnaround tests are inherently less comprehensive that our multi-gene options, they should ideally only be used when circumstances mean that time is critical. Furthermore, in certain cancer types you may still need to consider reflex to additional testing (in order to meet best practice requirements) in the event that the requested rapid analyses prove uninformative.