Uterine and endometrial cancer are the most common gynecologic cancers. Risk factors include obesity, tamoxifen use, and certain genetic conditions. Diagnosis involves endometrial biopsy. Treatment typically involves hysterectomy with or without radiation or chemotherapy depending on risk factors like tumor grade and stage. New immunotherapies are showing promise for recurrent or advanced disease. Precision medicine approaches are helping to classify subtypes and identify targeted therapies.

1. Uterine and Endometrial
Cancer 101
Jason D. Wright, M.D.
Sol Goldman Associate Professor
Chief, Division of Gynecologic Oncology
Columbia University College of Physicians and Surgeons

2. Uterine and Endometrial Cancer

3. Uterine and Endometrial Cancer

4. Epidemiology
• Most common gynecologic cancer diagnosed in women
• Estimated new cases in 2015 61,880
• Estimated deaths in 2015 12,160
• Lifetime risk 1 in 37

5. Epidemiology
Average age
early 60’s

6. Epidemiology
•Incidence is highest in Caucasian women
• Lifetime risk of 2.88% compared to 1.69% risk for
African-American women
•African American women are more likely to
have:
• Non-endometrioid, high grade tumors
• More advanced stage of disease
• Nearly 2x the mortality rate

7. Risk Factors
•Endometrial hyperplasia
•Tamoxifen
•Obesity
•Age
•Reproductive factors
•Nulliparity, early menarche, late menopause
•Diabetes Mellitus

8. Endometrial Hyperplasia
• Proliferation of glands of
irregular size and shape
• Classification:
• Simple
• Complex
• Atypical
• 30-40% risk of cancer
associated with atypical
hyperplasia
• Bleeding

9. Tamoxifen and Endometrial
Cancer
• Selective estrogen receptor modulator (SERM)
• Treatment of breast cancer
• 6.4 to 7.5 fold increased risk
• National Surgical Adjuvant Breast and Bowel Trial B-14
(NASBP)
• 15/1220 patients on Tamoxifen developed uterine CA
• 2/1424 patients on placebo developed uterine cancer
• Breast cancer relapse rate for women treated with
tamoxifen was reduced from 227.8/1000 to 123.5/1000
• No routine screening

10. Obesity and Endometrial Cancer
• Rate of obesity rising rapidly in the U.S.
• Adipose cells (fat cells) secrete estrogen that stimulates the
endometrium
• Projected increase to 42 cases per 100,000 women by the
year 2030
• 55% increase over the 2010 endometrial cancer rates.

11. Protective Factors
• Weight loss/exercise
• Progestins
• Oral contraceptive pills
• Cigarette smoking

12. Signs and Symptoms
•Postmenopausal bleeding
• Abnormal vaginal discharge
• Pelvic pain/pressure
• Uterine enlargement
• Intermenstrual bleeding (perimenopausal women)

13. Diagnostic Evaluation
•History and physical examination
•Pelvic examination
•Pap smear
•Transvaginal ultrasound
•Endometrial sampling

14. Lynch Syndrome
•Hereditary nonpolyposis colon cancer (HNPCC)
syndrome
•Autosomal dominant
•Mismatch repair (MMR) genes
•MLH1, MSH2, MSH6, PMS2
•Tumors display microsatellite instability (MSI)
•9% of women <50 yo carriers
Aarnio M, Sankila R, Pukkala E, et al. Int J Cancer 1999;81:214-18.
Lu KH, Schorge JO, Rodabaugh KJ, et al. J Clin Oncol 2007;25:5158-64.

15. Lynch Syndrome
•Risk up to age 70
•Colon cancer 82%
•Endometrial cancer 60%
•Other tumors: ovary, stomach, biliary tract, ureter,
renal, CNS
•Screening Amsterdam criteria and Bethesda criteria
•Diagnosis: IHC, sequencing

16. Lynch Syndrome
• Screening
• Colonoscopy every other year beginning at age 20 and
annually after the age of 35
• Transvaginal sonogram, CA-125 and pelvic exama starting
at age 30.
• Prophylactic Hysterectomy/BSO once childbearing is
complete or after age 35

17. Classification of Endometrial
Carcinoma
• Endometrioid adenocarcinoma
• Mucinous carcinoma
• Serous carcinoma
• Clear cell carcinoma
• Squamous cell carcinoma
• Undifferentiated carcinoma
• Metastatic carcinomas

18. Patterns of Spread

19. Initial Treatment
•Hysterectomy
•Lymphatic evaluation (lymph node dissection)

20. Hysterectomy

21. Laparoscopy in Endometrial Cancer
• GOG LAP 2
– Randomized trial (n=2612) patients
• Laparoscopic staging
• Laparotomy
– Outcomes
– Fewer complications (14% vs. 21%)
– Similar intraoperative complications
– Longer operative times (204 vs. 130 min)
– Shorter LOS (> 2 days 52% vs. 94%)
– Less often performed LND (8% vs. 4% not performed)
Walker JL, Piedmonte MR, Spirtos NM, et al. J Clin Oncol 2009;27(32):5331-6.

22. Laparoscopic Surgery
•Recurrence (3 year): 11.4% laparoscopy vs. 10.2%
laparotomy
Walker JL, Piedmonte MR, Spirtos NM, et al. J Clin Oncol 2012;30(7):695-700.

23. Robotic Surgery
Surgeon Console
Patient Cart (“Robot”)
Video Cart

24. Robotic Surgery

25. Pelvic Lymphadenectomy

26. Sentinel Lymph Node Biopsy

27. Surgery Caveats
•In young women occasionally treated with non-
surgical options (preserve fertility)
•Young women may consider ovarian conservation
•Women with significant underlying medical
problems may require alternative management
• Vaginal hysterectomy
• Radiation therapy

28. What to Do Next: Adjuvant
Therapy
•Low risk
• IA grade 1-2
• IB grade 1
•Intermediate risk
• IA grade 3
• IB grade 2, 3
• II
•High risk
• III/IV
• High risk histologies
No Treatment
Chemotherapy and radiation
? Radiation

29. Study N Inclusion Treatment Locoregional
recurrence
Overall survival
Norwegian
Radium
Hospital
540 Stage I Brachytherapy vs.
Brachytherapy/EBRT
7% vs. 2%
P<0.01
89% vs. 91%
NS
PORTEC-1 715 Stage IB (G2, 3)
Stage IC (G1, 2)
Observation vs.
EBRT
14% vs. 4%
P<0.0001
85% vs. 81%
NS
GOG-99 392 Stage IB, IC
Stage II (occult)
Observation vs.
EBRT
12% vs. 3%
P=0.007
86% vs. 92%
NS
ASTEC 905 Stage IA, IB (G3)
IC, IIA
Observation vs.
EBRT
6% vs. 3%
P=0.02
84% vs. 84%
NS
PORTEC-2 427 IC (G2, 3, >60)
IB (G3, >60)
Stage IIA
Brachytherapy vs.
Pelvic radiation
5% vs. 2%
P=0.42
86% vs. 82%
NS
Radiation for Intermediate Risk
Disease

30. PORTEC
Creutzberg CL, van Putten WLJ, Koper PC, et al. Lancet 2000;355:1404-11.
Control 14%
Radiation 4%
Recurrence Survival
Radiation versus observation

31. Radiation
Whole pelvic radiation Vaginal brachytherapy

32. Adjuvant Therapy for Stage III
Endometrial Cancer
•Historically whole pelvic radiation
•2000’s importance of chemotherapy recognized
•Combination therapy

33. • N=686
• Stage IB (G3 or LVSI), II, III or
stage I-III (UPSC or CC)
• WPRT vs. WPRT and
chemotherapy (weekly
cisplatin then
carboplatin/paclitaxel x4)
• 5-year OS
• 81.4% combination vs. 76.1% RT
(P=0.03)
• HR=0.70
• Toxicity (>G3)
• 8% combination vs. 5% RT (P=0.24)
PORTEC-3
De Boer S, Powell ME, Mileshkin L, et al. Lancet Oncol 2019;20:1273-85.

34. Recurrent Endometrial Cancer
• Treatment palliative
• Progestational agents classically considered first line
• Variable response to cytotoxic agents
• Surgery rarely indicated

35. Progestins
• Predictors of
response:
• Low grade
• PR positive
• Long disease free
interval
• Overall 20-25%
• Median duration: 4
months
Agent Response Range
Hydroxyprogesterone 24% 9-34 %
Medroxyprogesterone 22% 14-53 %
Megestrol Acetate 20% 11-56 %
Tamoxifen 18% 0-53 %

36. Precision Medicine for
Endometrial Cancer
-Cluster 1
-Only 0.5% genomic alteration
-Cluster 2
-Cluster 3
-More frequent 1q amplifications
-Cluster 4
-Serous, grade 3, 5% grade 1-2
-Very high SCNA
-MYC and ERBB2 amplifications
-FGFR3 and SOX17
amplifications
-90% P53 mutations (rare PTEN)
The Cancer Genome Atlas Research Network. Nature 2013;497:67-73.

37. Targeted Therapy for
Endometrial Cancer

38. Immunotherapy
MMR deficiency in 12,019 tumors
Le DT, Durham JN, Smith KN, et al. Science 2017;357(6349):409-13.

39. Novel Immunotherapy Strategies
• 70% of endometrial cancers
MSS
• Recurrent endometrial cancer
• Pembrolizumab (anti-PD-1
antibody)
• Lenvatinib multikinase
inhibitor (VEGFR1-3, FGFR1-4,
PDGFRa, RET, KIT)
Makker V, Rasco D, Vogelzang NJ, et al. Lancet Oncol 2019;20:711-18.

40. Conclusions
•Endometrial cancer has a very favorable prognosis
overall
•Surgery has improved with minimally invasive
options
•Adjuvant therapy remains controversial
•Treatment for recurrent endometrial cancer is
improving