Extensive Surgery in LS factoring in gene and gender. Gabriela Möslein

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1 Extensive Surgery in LS factoring in gene and gender Gabriela Möslein

2 Where we are coming from.

3 Non polyposis colon cancer Recommend subtotal colectomy at the time of the first colon cancer Recommend prophylactic hysterectomy 1977/78

4 LS carriers confirmed All genes pooled together 3-year interval Mortality down by 65% CRC incidence down by 62% compared to not screened Carcinogenesis shown to be accelerated leading to short intervals Jass J Anticancer Res 1994

5 POST-GENOMIC ERA 2000S Registries evolve Confidence in shared dmmr phenotype despite the affected gene Patients pooled together in the studies as a one common entity Even shorter surveillance intervals recommended Belief that removal of adenomas would prevent from having CRC Extended surgery recommended and shown to reduce risk over segmental resections Natarajan et al, Dis Colon & Rectum 2010 Toni Seppälä

6 Extensive surgery in LS : AIMS 1. Reduce the risk of metachronous CRC 2. Improve survival 3. Consider other prophylactic measures 4. Retain QoL Personalized risk assessment based on current knowledge

7 Extensive surgery in LS : At the event of CRC Endoscopic prevention Risk of colonoscopies Impact on QoL Removal of target organ Risk of surgery Impact on QoL

8 Missed considerations Colon Rectum

9 Extensive surgery: Colon Cancer in LS Oncological resection Extended surgery right hemicolectomy left hemicolectomy sigmoid resection Subtotal colectomy all: one anastomosis similar rate of surgical complications (You et al. Dis Colon Rectum 2008;51: ) 2. Bergisches Sympoium für Gynäkologie und Senlogie

10 Extensive surgery: Rectal Cancer in LS

11 Risk of metachronous CRC at first Colon Cancer Conclusions: This result suggests that extended colectomy reduces the risk of mcrc by over four-fold compared with segmental resection

12 Risk of metachronous CRC at first Rectal Cancer 54% (90% CI) after a median of 20 years (Möslein 1998) 17% (3/18) after a median of 203 months (Lee 2001) 15,2% (5/33) after a median of 72 months (Kalady 2010) 19 % (95 % CI 9 31 %) after 10 years 47 % (95 % CI %) after 20 years 69 % (95 % CI %) after 30 years (Win 2013)

13 DATABASES IN 2010S FRUITS FROM THE NATIONAL REGISTRIES No clinical benefit from short colonoscopy intervals Recommended colonoscopy intervals in Lynch syndrome Germany 1-yearly The Netherlands 1-2-yearly Finland 2-3-yearly Outcome in 2747 patients No reduction of CRC risk or tumor stage with shorter intervals Engel, Vasen, Seppälä et al. Gastroenterology 2018, In Press

14 2. Bergisches Sympoium für Gynäkologie und Senlogie

15 Missed considerations High penetrance Genes MLH1 MSH2 Colon Low penetrance Genes MSH6 Rectum PMS2

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20 Recommendations: LS patients with 1. Colon Cancer

21 Recommendations: LS patients with 1. Rectal Cancer

22 Extensive Surgery: Special considerations High penetrance Genes MLH1 MSH2 Low penetrance Genes MSH6 PMS2

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25 Manchester Consensus Thus MSH6 pathogenic variant carriers may consider undergoing risk-reducing surgery after the age of 40 years, while women with pathogenic variants in either MSH2 or MLH1 may consider risk-reducing surgery at around 35 years of age assuming their childbearing is complete. Risk-reducing surgery at 40 years of age is a cost-effective strategy. The risk of gynecological cancer in PMS2 carriers is low; however, patient representatives with PMS2 pathogenic variants felt strongly that they should be offered risk-reducing surgery alongside other women with Lynch syndrome.

26 LS Patients presenting with CRC in the vast majority of cases not be aware of the underlying genetic disposition

27 Lynch-Syndrom und HNPCC Vilkin A et al. Human Pathology 2015: Reflex testing via IH staining - biopsies Immunohistochemistry staining for PMS2 on endoscopic biopsies and surgical specimens from the same tumor

28 Precision (individualized) Medicine

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30 Wuppertal