Urothelial cancer in Lynch syndrome Mef Nilbert, MD, PhD, prof Oncology Lund University, Sweden and Copenhagen University, Denmark Lynch syndrome 400 Lynch families; 200 unique alterations Population incidence 1/400, estimated 24 000, 400 fam x 6 =2400 - 10% detected 15% of the families fulfill the Amsterdam criteria Strong support for universal testing – CRC, endometrial, upper uro, sebaceous tumors? Identification of MMR defects for -Lynch syndrome diagnostics -Prognostic impact in colorectal cancer -Application of immunotherapy Gene and gender-based surveillence programs 2/3 of cancer-related deaths from extracolonic cancer, mean age 63 Immunotherapy – a revolution for dMMR tumors and patients with Lynch syndrome Lagerstedt et al. Oncol Rep 2016 Pylvänäinen et al., Fam Cancer 2012 Lynch – a multi-tumor syndrome Morkk et al., Lynch Syndrome: A Primer for Urologists and Panel Recommendations. J Urol. 2015 Jul;194(1):21-9. Incidence rates for extracolonic cancer in Lynch syndrome Therkildsen et al., submitted MMR protein immunostaining for all UTC of the upper urinary tract? Lynch, 5% of bladder cancer, 10-15% of upper UTC cancer Denmark: • 48 ureter cancers, 34 renal pelvic cancers and 54 urinary bladder cancers • 78% developed in a family without a prior history of the disease • Synchronous UTC in 16%, metachronous UTC in 12% • 78% had a previous cancer outside of the urinary tract • MSH2 mutations in 73% • Mean age 61, 55% female • 70% high grade tumors • Loss of MMR protein staining in 93% (MSI in 20-30%) Cleveland: • MMR protein loss in 7% of total upper tract urothelial carcinomas • Intratumoral lymphocytes, pushing tumor-stromal interface • MLH1/PMS2 little utility, MSH2/MSH6 loss sensitive and specific for Lynch syndrome. Joost et al., Urology etl., 2015 Immunotherapy Hypothesis: • Mutations generate neo-antigens that can be recognized and targeted by the immune system • Average tumors have dozens of mutations, dMMR tumors have thousands • Immune augmentation by PD-1 blockage may be highly effective in dMMR tumors PD1-inhibition dMMR CRC pMMR CRC dMMR non-CRC OR 55% 0% 55% DCR 90% 16% 72% Le et al., NEJM 2015 PD1-inhibition 2nd line Advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab mOS 10.3 months vs 7.4 months (HR 0.73). PD-L1 score >10% 8.0 months vs 5.2 months (HR 0.57) Fewer treatment-related adverse events and toxicities in the pembrolizumab group (15.0% vs. 49.4%) Pembrolizumab was associated with significantly longer overall survival and with a lower rate of treatmentrelated adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. Bellmunt et al., NEJM 2017 Status nationellt-internationellt • I USA (NCCN resp USMSTF) rekommenderas årlig analys för mikroskopisk hematuri med start i ålder 25-35 år hos alla mutationsbärare (Girardello et al., 2014). • I de Europiska riktlinjerna (INSIGHT) rekommenderas kontroll av mikroskopisk hematuri hos MSH2-mutationsbärare inom forskningsprojekt eller med systematisk insamling av effektdata (Vasen et al., 2013). • I Sverige rekommenderas screening i familjer med Lynch syndrom där fall av urotelial cancer har förekommit. Problemet med denna strategi är att de flesta (75-80%) uroteliala cancrar uppträder i familjer utan tidigare kända fall. Föreslagen strategi • • • Familjeanamnes för Lynch syndrom upptas vid (övre) urotelial cancer Kolorektalcancer och endometriecancer hos förstagradssläktingar inger misstanke om Lynch syndrom och motiverar remiss för onkogenetisk utredning Individer Lynch syndrom bör informeras om en ökad risk för urotelial cancer, uppmärksamhet på symtom och makroskopisk hematuri samt betydelsen av rökfrihet. • Vid sjukdomsorsaknade variant i MSH2-EPCAM erbjuds kontrollprogram för urotelial cancer MLH1, PMS2 eller MSH6 erbjuds kontrollprogram om urotelial cancer hos en förstagradssläkting • • Årlig urinanalys med av cytologi samt analys med UroVysion från 50 års ålder Cxbladder (MDK, HOXA13, CDC2, IGFBP5, and CXCR2) • Koordineras i respektive region, rapporteras till det onkogenetiska kvalitetsregistret (NOGA)