Estrogen can play a role in uterine cancer in a number of ways. Many uterine cancer tumor types are considered to be hormonally driven, especially endometrioid tumors. Obesity is a strong risk factor as it increases and produces additional estrogen levels in our bodies. Uterine cancer treatments are evolving, and today experts can treat estrogen related uterine cancers with some of the same therapies used to treat breast and ovarian cancer. Join Dr. Kristen Zeligs, Gynecologic Oncologist at Mt. Sinai Hospital, as she discusses these and other links between estrogen and uterine cancer. She will also review the latest treatment information as well as risk reduction strategies.

1. Kristen P. Zeligs, MD, FACOG
Assistant Professor
Icahn School of Medicine at Mount Sinai
Division of Gynecologic Oncology
Understanding the Relationship
Between Estrogen and
Endometrial Cancer

2. Disclaimer &
Disclosures
• Answers to incoming questions represent
personal opinion based upon the current
and usual practices in the field. Every effort
is made to ensure the accuracy of the
information provided.
• I have no financial disclosures.

3. Learning Objectives
• At the conclusion of this session, attendees
will be able to:
• Summarize the current state of
endometrial cancer
• Better understand the role of sex
steroids in the development,
prevention, and treatment of
endometrial cancer
• Discuss targeted treatment options for
endometrial cancer

4. Endometrial
Adenocarcinoma
• Most common gynecological
malignancy in the developed World
• 1/32 lifetime risk (3.1%)
• Mean age at diagnosis = 63
https://seer.cancer.gov

5. Endometrial
Cancer
Classification
Type I
• Endometrioid, low-grade
• Associated with obesity,
estrogen exposure
• Perimenopausal women
• Frequent ER and PR +
• Favorable prognosis, early
stage at presentation
• Precursor lesion = EIN
Type II
• High-grade and non-endometrioid
(serous, clear cell)
• Older age
• Not associated with hormone
exposure; thin
• Increased risk in African-
Americans
• Poor prognosis, late stage at
presentation
• Associated with endometrial
atrophy

6. Endometrial
Cancer
Incidence
Rising in the
US
Lortet-Tieulent J, et al. JNCI (2017) 110(4):djx214

7. Risk Factors for
Type I
Endometrial
Adenocarcinoma

8. Estrogen
• Estrogen is a hormone that
promotes the development and
maintenance of female
characteristics and sexual
functions
• Types of Estrogen
• Steroidal (Endogenous)
• Estradiol (E2)
• Estrone (E1)
• Estriol (E3)
• Non-steroidal (Exogenous)
• Natural xenoestrogens
(phytoestrogens,
mycoestrogens)
• Synthetic xenoestrogens

9. The
Influence of
Estrogen
https://www.endonews.com/estrogen-receptors-
and-endometriosis-what-do-we-know-now

10. Role of Estrogen in Development of Endometrial Cancer

11. Balancing Estrogen and Progesterone

12. Role of Obesity in Development of
Endometrial Cancer
• Obesity if associated with an increased incidence of endometrial
cancer
• Case control studies have demonstrated a 200-400% linear increase in
risk of endometrial cancer in individuals with a BMI > 25

13. Role of Progesterone in Treatment of Endometrial Cancer

14. HRT use after menopause
• Systemic unopposed estrogen therapy increases
the risk of endometrial cancer by up to 20-fold,
with the increasing risk correlating with the
duration of use
• Concomitant progestin administration mitigates
this risk
• When progestins are administered continuously,
intermittently (at least 10 days/month), or though
a levonorgestrel-releasing intrauterine device, the
risk is reduced to below that of women not
receiving HT

15. Selective Estrogen
Receptor
Modulators

16. Tamoxifen and Endometrial Cancer
• Rate of EmCA is 1.6/1,000 patient-years for women on tamoxifen
(compared with 0.2)
• Risk decreases with treatment discontinuation
• Small long-term increased risk of uterine sarcomas
• ACOG recommends annual gyn exams for women on Tamoxifen
• Routine annual transvaginal ultrasound or endometrial sampling
in asymptomatic patients taking tamoxifen has not been associated
with increased detection of endometrial cacner
• For women who have AUB on Tamoxifen, endometrial sampling
should be completed irrespective of endometrial thickness on
imaging

17. Role of Estrogen Therapy for Management of Menopausal
Symptoms in Survivors of Endometrial Cancer
• 25% of women undergoing hysterectomy with BSO for endometrial carcinoma are premenopausal
• Traditionally women w/ endometrial carcinoma have been denied estrogen because of the concern for
increased risk of cancer recurrence
• In patients with early-stage endometrial cancer there is insufficient high-quality evidence to support a
determinantal effect
• Decision should be individualized
• Estrogen therapy for the management of menopausal symptoms in the survivors of early-stage endometrial
cancer can be considered after thorough counseling about the risks and benefits
1. NAMS 2017 statement. Menopause 2017;24:728-753.
“May be considered following surgical treatment of early
stage, low risk endometrial cancer if non-hormonal options
are not effective” 1

18. Her2/neu in Endometrial Cancer: A Promising
Therapeutic Target
DOI: 10.1200/JCO.2017.76.5966 Journal of Clinical Oncology 36, no. 20 (July 10, 2018) 2044-2051.
Published online March 27, 2018.
• Uterine serous carcinoma is a molecularly
distinct entity from the more commonly
diagnosed endometrioid carcinoma
• The dysregulation of Her2/neu oncogene
has been reported in ~27% of USC in
studies performed by TCGA network
(Levine, DA, Nature 2013)
• Trastuzumab (Herceptin) is a humanized
monoclonal antibody against Her2/neu

19. Timeline of HER2-targeted therapies in different tumor types

20. HER2 Testing in Endometrial Serous Carcinoma
Buza, N. (2021). HER2 Testing and Reporting in Endometrial Serous Carcinoma: Practical Recommendations for HER2 Immunohistochemistry and Fluorescent In Situ Hybridization: Proceedings of
the ISGyP Companion Society Session at the 2020 USCAP Annual Meeting. International Journal of Gynecological Pathology, 40 (1), 17-23. doi: 10.1097/PGP.0000000000000711.

21. Hormone Therapy for Management of
Recurrent Disease
• Summary of hormonal options confirms 20 – 30% RR
Protocol Agents N PFS
(months)
RR
(%)
RR (%)
Grade 1
RR (%)
Grade 2
RR (%)
Grade 3
NCIC Letrozole 32 NR 9 NR NR NR
GOG 121 MA 800mg daily 58 2.5 24 37% 23% 9%
GOG 153 Alternating every three
weeks: MA 80mg BID, T
20mg
56 2.7 27 33% 24% 22%
GOG 119 T 20mg BID, MPA
100mg intermittent
weekly
58 3.0 33 NR NR NR

22. Hormone Therapy for Management of Recurrent
Disease
§ ER+ = 25% RR, PR+ = 37% RR, neg ER/PR = 7% RR
§ Low dose progestin MPA 200 mg/day vs 1000
mg/day showed low dose with higher RR (25% vs
15%) with improved OS 11 vs 7 mo
§ Tamoxifen alternating with MPA lead to 33% RR
with favorable toxicity and PFS/OS
§ Trial of MPA showed 37% RR in grade 1, 23% grade
2 and 9% grade 3 endometrioid tumors Whitney CW et al Gynecol Oncol 2004; Thigpen JT et al J Clin Oncol 1999; Singh M et al
Gynecol Oncol 2007 ; Fiorica JV et al Gynecol Oncol 2004
Hormone therapy with progestins are more likely to be
effective in grade 1 or 2 endometrioid tumors that are ER and
PR positive

23. Questions?