Personalised medicine in action

Susmita Chowdhury

6 June 2017

Back in February, the National Institute for Health and Care Excellence (NICE) published their official evidence-based recommendations for patients diagnosed with colorectal cancer (CRC) to be tested for Lynch syndrome (LS), a hereditary form of the disease. Colorectal cancer, also called bowel cancer, is the fourth most common cancer in the UK, and though LS accounts for no more than 5% of CRCs, affected individuals carry up to 80% lifetime risk of developing CRC and other cancers at an average age of only 46 years. Detecting those at risk is therefore important.

The new NICE guideline recommends universal testing for Lynch syndrome to all patients newly diagnosed with colorectal cancer. Currently, LS is an under-recognised, underdiagnosed and undermanaged condition. The expectation is that adopting a universal approach to Lynch syndrome screening of all colorectal cancer patients will increase the numbers identified as being at risk, who can then be offered germline genetic testing and associated counselling. This can significantly boost the numbers of cancer patients identified as having inherited LS, as well as family members who may also be affected and at increased risk of cancer. These people can then be offered increased surveillance, which can reduce mortality by 72%; through earlier diagnosis and treatment. For the health community, this is an exciting example of personalised medicine in action, where biomedical testing will be used to identify a high risk population, which can then be offered appropriate testing and personalised prevention measures.

Identifying Lynch Syndrome and outcomes

Lynch syndrome is the most common cause of hereditary bowel cancer, and patients with it have an increased risk of developing other cancers, including womb, ovarian, and stomach cancer. It is caused by germline mutations but 95% of individuals who carry the faulty genes are not genetically diagnosed, due largely to the lack of a systematic approach to testing.

At present, general identification of LS on the basis of age and family history alone inaccurately identifies eligibility for Lynch syndrome screening or testing in 25% -70% of cases.

We know that inherited mutations in DNA mismatch repair (MMR) genes lead to an increased risk of Lynch syndrome. Risk-reducing interventions can thus be offered to individuals with known LS-causing mutations. Though the mutations can be identified by comprehensive testing of the MMR genes, it would be prohibitively expensive to use this approach in the general population. However, tumour-based biomolecular tests such as microsatellite instability (MSI) and MMR immunohistochemistry (IHC) can be effectively and practically used in CRC patients to identify those individuals at high risk of LS,  in whom genetic testing is appropriate.

Positive IHC or MSI test results indicate that the individual has malfunctions in the genes that are connected to Lynch syndrome. Performing these initial molecular tests helps to identify potential LS patients (and hence also their families) who don't meet the usual criteria for genetic testing.

The NICE guideline is now recommending an evidence based approach to offer either an MSI test (to identify tumours with deficient DNA mismatch repair) or an IHT (for mismatch repair proteins) to newly diagnosed CRC patients, for the purpose of identifying those patients at high risk of having LS. The results of these tests guide the decision to test for Lynch syndrome by genetic testing of germline DNA. The NICE Diagnostic Assessment Report states that with this method: ’Life expectancy for individuals with Lynch syndrome is improved by 1.2 years for probands and 2.1 years for relatives. Over 300 colorectal cancers are expected to be prevented over the lifetime of each annual cohort’.

The complexities of implementation

The Lynch syndrome screening process ticks boxes for the ‘four P’s of personalised medicine’ - prediction, precise diagnosis and targeted personalised prevention. Although clinicians have long been tailoring interventions to people’s individual health needs, there are few illustrations of nationwide systematic implementation of novel approaches such as biomolecular diagnostic tests to stratify the population for more precise intervention. The new NICE guidelines  on screening for Lynch syndrome is an excellent opportunity to implement personalised medicine at the population level. 

Improved screening is likely to increase the patient cohort requiring genetic investigation and clinical management, stretching further the already stretched capacity of and potentially compromising patient safety.

Nevertheless, this is still only a national guideline for health professionals. Such guidelines may be the principal means of disseminating best practice, but , as ever, there are challenges :

Firstly addressing existing variation in access, quality and frequency of colonoscopic screening  will require a united effort from CRC multidisciplinary teams (MDT) to identify and resolve the operational gaps  and ensure the effectiveness of the pathway.  Local  ‘Clinical Champions , for example, could be assigned to lead  a consistent approach to the referral, examination, personalised management and counselling of LS gene mutation carriers .

Secondly, a new screening pathway indicates the need for an initial investment in the infrastructure and capacity in order to establish the process. Clinicians will need appropriate training. Furthermore,  improved screening is likely to increase the patient cohort requiring genetic investigation and clinical management, stretching further the already stretched capacity of  and potentially compromising patient safety. This consequently brings up the wider issue of the need for a growth in clinical workforce, supported by an increase in resources and facilities. Where possible, existing services must be used, but commissioners may need to guarantee that funding is in place for the new requirements arising from the NICE guidance, including an increased capacity for bio-molecular pathology, imaging and biopsy, genetic testing and counselling.

Finally, high quality clinical audits will provide answers to whether the Lynch syndrome screening pathway recommended by NICE is being consistently provided in line with recognised standards, and help identify the scope for improvements to ensure equity of access to best practice for patients across the country.

Inherited conditions like LS have a devastating impact on families, where multiple generations are affected. Until now, the process of identifying such families was markedly inefficient. The new NICE recommendations for LS screening of colorectal cancer patients using biomolecular testing (followed by genetic testing where appropriate) is a classic example of the utility of personalised intervention to identify, predict and prevent disease families with this inherited condition. It is important that we should act on these opportunities as part of the move towards more personalised healthcare.

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