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
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
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
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?