Urothelial cancer in Lynch syndrome

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
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•
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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
•
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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)