This document discusses Lynch syndrome and its relationship to endometrial cancer. The key points are: 1) Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, is an inherited condition that increases the risk of endometrial and colorectal cancer due to a mutation in genes responsible for DNA mismatch repair. 2) Individuals with Lynch syndrome have a higher lifetime risk of developing endometrial cancer, ranging from 25-60%. Screening strategies like endometrial biopsy every 1-2 years starting at age 30-35 can help with early detection. 3) For those diagnosed with endometrial cancer, universal screening of tumor tissue looks for mutations in mismatch repair

1. Dario R. Roque, MD
Endometrial Cancer &
Lynch Syndrome

2. Endometrial Cancer 2020
Estimated New Cases

3. Early Detection Makes a
Difference

4. Endometrial Cancer Risk Factors
Chronically increased
estrogen levels
• Unopposed estrogen therapy
• Tamoxifen
• Anovulation
• Obesity
• Estrogen secreting tumors
• Early onset menses or late
menopause
Hereditary Factors
• Lynch Syndrome

5. Lynch Syndrome (aka Hereditary Non-
Polyposis Colorectal Cancer (HNPCC)
• Inherited changes in
genes that affect DNA
mismatch repair
(MMR) during DNA
replication
• Autosomal Dominant
Inheritance
HAVING LYNCH SYNDROME DOES NOT
MEAN YOU HAVE CANCER OR THAT
YOU WILL DEFINITELY DEVELOP CANCER

6. Lynch Syndrome & Risk of
Endometrial Cancer

7. • Surveillance & Prevention Strategies
– Prompt reporting and evaluation of any
abnormal uterine bleeding
– Consider screening with endometrial biopsy
every 1-2 years starting at age 30-35
– Hysterectomy as risk reducing option if
completed childbearing
Lynch Syndrome & Risk of
Endometrial Cancer

8. What if I Already Have Endometrial
Cancer?
• Universal screening on all endometrial cancers
– Analysis of tumor for presence of 4 genes that are
known to malfunction/mutated in Lynch syndrome
• MLH1, MSH2, MSH6, and PMS2
• If all genes are expressed (normal)  Unlikely that a Lynch
related pathogenic MMR deficiency is present
• If one (or more) of the genes are not expressed  Consider
germline testing
– Unless defects in MLH1/PMS2  Hypermethylation tumor testing
– Microsatellite Instability (MSI)
• Changes in DNA sequence between normal tissue and tumor
tissue
• Presence of MSI suggests malfunction in MMR genes
• Majority of microsatellite unstable tumors ARE NOT due to
Lynch Syndrome

10. Why Screening and Testing for
Lynch Matters?

12. Emma Barber, MD, MS
Immunotherapy for
Endometrial Cancer

13. Immune System and Cancer

14. Lynch Syndrome =
Mismatch Repair Deficient

15. Mismatch Repair Deficient
• Missing proteins that help the body repair
DNA
• Cell accumulates many mistakes
– High mutation burden
– Microsatellite unstable
– Hypermutator phenotype
• Immune system more likely to recognize
things that are unlike it

16. Immune Check Point Inhibitors
CTLA-4
Ipilimumab
tremelimumab
PD-1
Nivolumab
Pembrolizumab
PD-L1
Atezolizumab
Avelumab
Durvalumab

17. Clinical Trial Results
• KEYNOTE-028
– 24 women with PD1 positive recurrent
endometrial cancer
– 13% ORR
– 13% SD
• KEYNOTE-158
– 49 women with MMR deficient
endometrial cancer
– ORR 57%
– Median PFS 25 months

18. Immunotherapy for non-biomarker
selected endometrial cancer
• Breakthrough FDA designation, now FDA
approved
• Lenvatinib and Pembrolizumab
– 54 patients
– 40% ORR

19. Ongoing Clinical Trials
• NRG GY-018 – Chemotherapy and
pembrolizumab for women with stage III/IV
(measureable disease) or recurrent
endometrial cancer
• NRG GY-020 – Pembrolizumab and radiation
therapy for high intermediate risk endometrial
cancer
• Molecular subtyping of endometrial cancer –
does immunotherapy replace chemotherapy?

20. Thank you