New Developments in Uterine Cancer

Matthew A. Powell, MD Professor & Chief Division Gyn Oncology

Washington University School of Medicine

St. Louis, Missouri, USA

Only major cancer with Incidence and Mortality Rates for Uterine Cancer Have Been Rising

• Over the last 10 years, rates of new cases have been rising 1.3%, andrates of deaths have been rising 1.6% on average each year1

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• Increased obesity and aggressive endometrial cancer subtyperates in the United States may be contributing to the rise inuterine cancer incidence and mortality2

US population-based cancer data published by the Surveillance, Epidemiology, and End Results (SEER) program include all cancers of the uterine corpus, inclusive of endometrial cancers.

Uterine cancer prevalence in the US2

727,200 5% of the 15 Million cancer survivors

in US

61, 880 new cases* 12,160 deaths*

53,000 endometrioid 6,070

40,800 Grade 1-2 2,840

12,200 Grade 3 3,250

5,500 Serous 3,800

1,400 Clear cell 660

1,200 Sarcoma/Carcinosarcoma

800

* Siegel et al. Cancer Statistics2019

Population of interest

Risk Factors for Endometrial Cancer: Can we identify a phenotype = genetic disease? Risk Factors Protective Factors

Circulating estrogen Obesity Never

having children

Late menopause Tamoxifen

Lynch/ other genetic syndromes2

Postmenopausal estrogen

Polycystic ovary

syndrome

Pregnancy Oral

contraceptives

Physical activity

Risk factors related to increased estrogen exposure Other risk factors

1. American Cancer Society. Cancer Facts & Figures 2018. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed January 1,2019. Published January 8, 2019. 2. National Cancer Institute. Endometrial Cancer Treatment (PDQ)-Health Professional Version. https://www.cancer.gov/types/uterine/hp/endometrial-treatment-pdq#section/all. Updated January 19, 2018. Accessed January 8, 2019.

Promise of molecular “personalized” “predictive” biomarkers: Endometrioid TCGA subgroups

GOG 210 Endometrioid (Cosgrove 2018)

.

SUBGROUP INCIDENCE Cancer Mortality

TP53/Serous-like/copy number altered

8% 19%

No Specific Mol.Profile /low copy number variant/ copy # stable

49% 5%

MSI+/MMR-deficient

39% 7.6% POLE 4% 2.6%

Potential therapeutic impact of TGCA classification

POLE MSI Copy-number low

Copy-number high

MSI/MLH methylation

Mixed MSI high Low, stable

MSI high MSI stable MSI stable

Molecular profile

POLE (100%) PTEN (94%) PIK3CA (71%) FBXW7 (82%) ARID1A (76%) KRAS (53%) PD1/PD-L1 overexpression

PTEN (88%) RPL22 (37%) KRAS (35%) PIK3CA (54%) ARID1A (37%) PD1/PD-L1 overexpression

PTEN (77%) CTNNB1 (52%) PIK3CA (53%) ARID1A (42%) FGFR2 (10.9%)

TP53 (92%) PPP2R1A (22%) FBXW7 (22%) PIK3CA (47%) PTEN (11%) FGFR (7%) HER2 (25%)

Potential drugs

PI3K/PTEN/AKT/mTOR pathway PARP-I

Anti-PD1/PD-L1 Hormones

PI3K/PTEN/AKT/mTOR pathway PARP-I

Anti-PD1/PD-L1 Hormones

PI3K/PTEN/AKT/mTORpathway PARP-I

Hormones FGFR-I

HER2- I PI3K- I PARP-I Wee-1 I

FGFR-I

GOG=249: XRT vs VBT+PCx3

Chemo vs PXRT :Summary of Data Study Arms PFS Events OS Events Maggi 2006

Chemo PXRT

66 59

59 59

Susumu 2008

Chemo PXRT

30 33

22 26

GOG 249 VCB/C PXRT

43 44

23 18

Totals Chemo PXRT

139/666= 20.8% 136/660=20.1%

104/666= 15.6% 103/660= 15.5%

Both Chemo and XRT work equally well (or poorly) as adjuvant therapy for stage I/IIEC

A phase III Trial of postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate or high risk endometrial cancer. 

ENGOT-EN2-DGCG / EORTC55102

NCT01244789

Supported by

n=678

Endometrioid:StageI-G3;II

Non-endometrioid:StageI-II

ChemotherapyCarbopla?n-Paclitaxelx6+ Brachytherapy

Observa?on+ Brachytherapy

1:1randomiza?on

mansoor@rh.regionh.dk

Sponsor:DGCGPI:Mirza/Amant

Beyond GOG 249

Final results of the PORTEC-3 trial

Presented By Stephanie de Boer at 2017 ASCO Annual Meeting

PORTEC 3

Overall population

Stage III

Stephanie de Boer: Lancet Oncology: Vol 19, N3, p295–309, March 2018

Matei et al. NEJM. June 2019

WhatChemotherapyshouldwebeusing?PhaseIIITrials-AdvancedRecurrentDisease

AC AT TAP TC

A GOG 107

AC GOG 139

GOG 163

GOG 177

TAP GOG 209

A=doxorubicin, AC= doxorubicin + cisplatin, TAP= paclitaxel + doxorubicin + cisplatin, TC= paclitaxel + carboplatin

Control A

rm

Experimental Arm

How can we do better????

GOG 0261: Primary Outcome Uterine Cohort: OS

Dr.MaBhewA.Powell,MD

• 37 mo PC vs. 29 mo PI• Adjusted treatment death hazard ratio is 0.87• The 90% CI 0.70 to 1.075.• p-value < 0.01. Rejects the null hypothesis:

inferiority• Superiority: Not significant (p=0.14); one-tailed

GOG 0261: Secondary Outcomes Uterine Cohort: PFS

Dr.MaBhewA.Powell,MD

16.3 mo PC vs. 11.7 mo PI HR=0.735 (95% CI: 0.58 to 0.93) The p-value <.001. The test rejects the null hypothesis of inferiority. PFS (superiority) was statistically significant (p<0.01).

How do we improve? Targets: • Anti-Angiogenesis• EGRF• mTOR/PI3K/AKT• DNA repair• Immunotherapy• Combinations

GOG 86P: Adding ”targeted therapy” n= 349

• Biomarker?

• When compared to a matched group from GOG protocol 209 (CP arm), the tripletregimen of CP + bevacizumab showed a significant improvement in OS (34 vs. 22.7months; p<0.039).

Arm Median Point Estimate 1 34.0 (p<0.039)

2 25.0

3 25.2

Reference 22.7

Utility of anti-angiogenic therapy: GOG 86P (N=349)

Randomize Phase II : MITO End-2

How do we improve? Targets: • Anti-Angiogenesis• EGRF• mTOR/PI3K/AKT• DNA repair• Immunotherapy• Combinations

Phase II Clinical Trials With EGFR Family in Women With Endometrial Cancer

Drug N RR SD PFS> 6 Months PFS

EGFR inhibition: Small-molecules

Erlotinib (Oza 2008) 34 12.5% 46.9% - -

Gefitinib (Leslie 2009)

26 3.8% 27.2% 15.4% -

Lapatinib (Leslie 2012)

30 3.3% 23.3% 10% -

EGFR inhibition: Monoclonal antibodies Trastuzumab (Fleming 2010)

34 0% 58.8% - 1.8

months

Ras/Raf/MEK/ERK inhibition Selumetinib (AZD6244) (Coleman 2015)

52 5.7% 25% - 2.4

months

Oza AM, et al. J Clin Oncol. 2008;26(26):4319-4325. Leslie KK, et al. J Clin Oncol. 2009;27(suppl): Abstract e16542. Leslie KK, et al. Gynecol Oncol. 2012;127(2):345-350. Fleming GF, et al. Gynecol Oncol. 2010;116(1):15-20. Coleman RL, et al. Gynecol Oncol. 2015;138(1):30-35.

***Carcinosarcomas & Consider in Serous like endometrioids