The first ever joint session between the European Hereditary Tumour Group (EHTG) and ESCP focussed, perhaps unsurprisingly, on hereditary colorectal cancer and featured global experts in the field, John Burn, Matthias Kloor and Toni Seppälä.
ESCP Secretary, Gabriela Möslein from Germany and Evangelos Xynos from Greece chaired the session.
MSI, HNPCC, Lynch syndrome and immunotherapy
Matthias Kloor (Germany) provided an update on MSI, HNPCC, Lynch syndrome and immunotherapy.
He started by asking why use immunotherapy in Lynch syndrome? He went on to explain how some cancers metastasize and take a very aggressive clinical course. In such instances immune checkpoint blockade can be an option.
He underlined that regular colonoscopy can miss non-polypous cancers in Lynch syndrome. For extracolonic tumors, the availability of screening is limited but that there may be a place for preventive vaccines.
MSI tumor evolution favours clones with recurrent mutations. Recurrent mutations lead to recurrent neoantigens. It has been found that there are FSP-specific T-cell immune responses in MSI cancer patients and those with Lynch syndrome (as opposed to people with either no cancer or MSS cancer).
Kloor talked of how immune checkpoint blockade is a very promising therapy option in metastasized MSI cancers. He referenced the Micoryx phase I/IIa trial which looked at evidence of functional significance as driver mutations. The results revealed significant T cell and humoral immune responses in all patients vaccinated per protocol. They also showed no systemic side effects. Additionally there was local injection site reactions in six patients, reflecting strong immunogenicity of the FSP antigens. Pre-existing immune responses against FSPs trigger injection site reactions.
He went on to question whether host immune factors may determine tumor risk and outcome. The immune system controls pre-cancerous cell clones in Lynch syndrome. As such Lynch syndrome is an ideal model for proving the efficacy of neoantigen-based vaccines for tumor prevention.
The role of epigenetic factors
John Burn (UK) interrogated the role of epigenetic factors. Epigenetics effects are heritable changes in gene expression. DNA Methylate, is essentially a biomarker epigenetic states. Methylation can go wrong. Sometimes methylation doesn’t get turned off and is passed on.
Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumours not least explained by the fact we contain more bacterial genomes than human genomes.
John went on to highlight the latest data into the long term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer (ASPREE, ASCEND, ARRIVE, seafood, ASPECT + Rothwell). Firstly that using a low dose aspirin doesn’t work in big people. It has also been evidenced that GI bleeds are much more dangerous and rise exponentially in old people without specific risk factors. The data indicates that in the first few years after starting aspirin, cancer rates and deaths rise - particularly in relation to older and more obese people.
He went on to explain the working hypothesis is that big people need more than 100mg of Aspirin due to a reduced anti platelet effect. Also, while aspirin helps destroy early neoplasms and reduce metastasis it can promote more advanced lesions locally. As such people at increased risk should consider taking aspirin in the decade before retirement, earlier in Lynch syndrome.
Clinical aspects: from phenotype to genotype and back
Toni Seppälä (Finland) covered clinical aspects, looking at the phenotype to genotype and back. Firstly Seppälä walked us through the short history of Lynch Syndrome from family ‘G’ in 1913 to hereditary Cancer was practically forgotten when it was widely considered to being acquired disease until 1971 when Henry Lynch revisited Family G finding the primary cancers were CRC, endometrium and stomach and establishing autosomal dominant inheritance.
After this first registries were founded and materials collected based on family phenotype. Cancer Family Syndrome became Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and surveillance for cancer began.
However, there were assumptions about HNPCC.
Seppälä stressed that it has been found that it is not all about phenotype. There is not only one Lynch Syndrome but different affected genes and different variants within genes. As such he advocated that we need to start being systematic and screen almost universally all tumors. We should look at functional MMR testing, better (body fluid -based) screening tools, immune-based prevention and chemoprevention, increase uptake of genetic testing.
