PLSD Database Update and the New Lynch Syndrome Guidelines: An Interview with Toni Seppälä

An interview by Zoe Garoufalia 

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ESCP dedicated this November to raising awareness for hereditary colorectal cancer syndromes and genetics.

Lynch syndrome is probably the most common predisposition to cancer. It is characterised by predisposition to colorectal, endometrial, and other cancers, and is caused by autosomal dominant inherited pathogenic variants affecting the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2.

Dr. Toni Seppälä, a colorectal surgeon and Associate Professor at Helsinki University Hospital, speaks to Zoe Garoufalia to update us on the Prospective Lynch Syndrome Database (PLSD), and the European guidelines for surveillance and management of Lynch Syndrome.

Zoe Garoufalia: Dr. Seppälä thank you very much for agreeing to this interview. Last year, you kindly introduced ESCP audience to the PLSD, which is maintained and curated by European Hereditary Tumor Group (EHTG). This database is aiming to provide age and organ-specific cancer risks, according to gene and gender, estimates of survival after cancer and information on the effects of interventions. One year later - what is new?
Toni Seppälä: We have finished the curation of the Version 4 of the PLSD and preparing first reports from the update. The PLSD is now nearly 9000 pathogenic MMR variant carriers under prospective observation for over 74 000 follow-up years, enabling more accurate estimates with narrower confidence intervals for

ZG: How is PLSD changing the treatment approach to patients with Lynch syndrome?
TS: Based on the results of the PLSD, we have understood that the underlying assumption of healthcare that the colonoscopy surveillance in Lynch syndrome prevents cancer, is largely false. Continuing colonoscopy surveillance is very important to improve survival by early detection, but does not seem to be very effective in preventing cancers. Early diagnosis at non-advanced stage is achieved with regular colonoscopies with any interval of 1 to 3 years, with no difference in stage distribution or survival.

ZG: Has PLSD changed our views on Lynch Syndrome cancer risk?
TS: Indeed, it has. It has widened our perspective about the differences in cancer spectrum and penetrance between different genes. Lynch syndrome is no longer just one entity, but four very different phenotypes.

ZG: Regarding diagnosis and management of extra-colorectal cancers in patients with Lynch Syndrome, has PLSD any new insights to provide?
TS: It looks like the practices that are applied especially on preventive gyneacological surgery are not entirely guided by observed risk. For example, premenopausal salpingo-ovariectomy does not seem to be warranted in most cases to reduce mortality from ovarian cancer. Time window to prevent uterine cancer when the colorectal cancer is diagnosed is often missed, leading to repeated procedures. Urothelial cancers are very tightly associated with path_MSH2 variants, which may open opportunities for targeted surveillance in the future.

ZG: Another interesting finding revealed from PLSD was that surveillance colonoscopies did not prevent all colorectal cancers in these patients. Any updates regarding surveillance colonoscopy in Lynch Syndrome patients?
TS: We are preparing a study comparing the incidence of CRC under surveillance to a contrast group mainly NOT under colonoscopy surveillance. We have previously raised concerns of over-diagnostics of CRC in LS, which nobody believed would be possible, so this will be very interesting to look into.

ZG: Recently the new European Guidelines from the EHTG and ESCP for Lynch syndrome were published in the British Journal of Surgery. What is different from previous Mallorca guidelines?
TS: Subtotal colectomy is advocated as a very effective way of reducing metachronous CRC, but functional aspects should be considered, and especially ileosigmoidal anastomosis may help in preserving function without increasing the risk, but yet enabling convenient endoscopic surveillance and possibly less anastomotic complications than ileorectal anastomosis. The use of extended surgery may be limited to MLH1 and MSH2, as the risk of metachronous cancer is less in MSH6. In PMS2, prospectively observed CRC risk is low, and it may be considered that they undergo surveillance only every 5 years. We have also acknowledged the fact that the evidence supporting very frequent endoscopy surveillance is extremely weak, so 3-yearly intervals are just fine for carriers without previous CRC. In MSH6 and PMS2, the surveillance can be initiated at 35, ie. later than in MLH1 and MSH2.

ZG: Is evidence-based personalised medicine feasible for these patients?
TS: The guidelines for the first time stratify the recommendations between the four genes, but there is indeed a lot of variation in the risk also within each gene, that could be tackled in the future. Like in all precision approaches, there is great promise that the risk could be stratified to target more intensive surveillance to those at highest risk. Tools for this are not entirely ready, but research is ongoing in non-invasive biomarkers, but also the traditional risk factors can be applied.

ZG: Do you have any messages to convey to the ESCP audience regarding diagnosis or treatment of patients with Lynch Syndrome?
TS: Universal MMR or MSI screening of all CRCs and endometrial cancers should be routine by now. I would advise to perform these tests already from the CRC biopsies before multi-disciplinary decision-making, as the quality is actually very high and can be utilized for many aspects of the care, e.g. when planning the extent of surgery, but also pre- and postoperative oncological therapies. Checkpoint inhibitor therapies have made the medical oncologists very interested in the MMR status, and it is also an important prognostic factor, no matter if the dMMR is caused by a pathogenic germline variant or not.

ZG: Thank you for your time and insights.

Read the updated European guidelines from the EHTG and ESCP for Lynch syndrome here.


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