Endometrial Cancer: Are we about to face a major problem? Faina - - PowerPoint PPT Presentation

Endometrial Cancer: Are we about to face a major problem?

Faina Linkov, PhD, MPH

Associate Professor Associate Professor Magee Womens Research Institute University of Pittsburgh School of Medicine March 18 2014 March 18, 2014

Endometrial cancer: what’s known and what s known and what’s not?

– Most common malignancy of the female genital tract in the US – 49,560 new cases/year and over 8190 deaths – Obese women (BMI >30 kg/m²) are at increased risk of developing this malignancy – Prevention of EC through weight loss received much attention but not explored thoroughly – Reversal of premalignant endometrial lesions through intentional weight loss has been reported, but not explored in large scale investigations – Several studies reported the link between inflammatory markers and EC development, but there is no single marker or panel of markers that can predict EC risk

Analysis of future EC trends

The best-fitting model based on multivariate regression projected an increase to 42.13 EC cases per 100,000 by the year 2030, a 50% increase over 2010 EC rates (provisionally accepted at future oncology)

Overview of my research at MWRI Overview of my research at MWRI

Area 1: Endometrial cancer today and Area 1: Endometrial cancer today and tomorrow: Projecting rates into the year 2030 Area 2: Biomarker and biobehavioral marker Area 2: Biomarker and biobehavioral marker changes occurring with weight loss Area 3: Endometrium changes occurring with Area 3: Endometrium changes occurring with weight loss Area 4: Endometrial cancer and adipose tissue Area 4: Endometrial cancer and adipose tissue Area 5: Endometrial cancer survivors and weight loss decisions loss decisions

Unifying theme: Prevention

“ f h d f ”

Adipose Tissue

“An ounce of prevention is worth a pound of cure”

• Benjamin Franklin

Endometrial Cancer Projections Endometrial Pathology Decision Support Biomarkers

Can any of these pathways be altered or influenced in a positive way by intentional weight loss?

Prospective studies of cancer risk

O j k C ti t i One major maker: C-reactive protein

Heikkila et al., 2009

Endometrial Cancer: T I/II C t Type I/II Concept

• Type I

– Estrogen Related Estrogen Related – Younger and heavier patients – Low grade – Background of Hyperplasia

What if we could prevent these cancers through intentional weight

g yp p – Perimenopausal – Exogenous estrogen

• Type II (~10% of total cases)

intentional weight loss?

yp ( )

– Aggressive – High grade – Unfavorable Histology – Unrelated to estrogen stimulation – Occurs in older & thinner women

• Familial/genetic (~15% of total cases)
• Lynch II syndrome/HNPCC
• Familial trend

My research interests: My research interests:

Building bridge between obesity, g g y, inflammation, biobehavioral factors, and cancer and ultimately design interventions ultimately design interventions targeting multiple mechanisms that cause malignancies Endometrial cancer risk reduction in the context of weight loss through bariatric surgery through bariatric surgery

What types of bariatric surgeries h ld should we target?

Bariatric surgery/obesity reduction as a model for cancer prevention in patients at high risk?

Aims of Ongoing Barimark Study Work in progress: stay tuned! Work in progress: stay tuned!

(funded by American Cancer Society)

Aim 1 Examine the effects of weight loss surgery on a selected set of biomarkers associated with the risk of endometrial and other obesity-linked cancers 6, 12, and 24 months following surgery Aim 2 Investigate the relationships between the magnitude of the weight loss achieved at 6, 12, and 24 months following surgery and the quantitative measures of the biomarkers on the obesity-linked cancer risk panel. Aim 3 Aim 3 To explore the possible additional contribution of changes in physical activity levels and psychological factors to the changes in quantitative measures of the biomarkers on the obesity-linked cancer risk panel.

Change in BMI, depression, and quality f l f

• f life

Case control investigation of markers implicated in endometrial cancer Gynecologic Oncology, 2007

Collaboration with RENEW investigators

Collaboration with Lora Burke

Endometrial Changes Occurring with Endometrial Changes Occurring with Weight Loss

Two parallel studies are conducted at the University of Minnesota and the the University of Minnesota and the University of Pittsburgh

Study 1 Examine the effects of weight loss surgery on a selected set of biomarkers associated with the risk of endometrial and other obesity- linked cancers at 12 months following gastric ed ca ce s at

• t s o o

g gast c bypass surgery in asymptomatic women (focus of this presentation) S d 2

Argenta, PI

Study 2 Examine the effects of weight loss surgery on a selected set of endometrial tissue markers associated with the risk of endometrial and

Argenta, PI

associated with the risk of endometrial and

• ther obesity-linked cancers 6-12 months

following any bariatric surgery in symptomatic and asymptomatic women

Linkov, PI

Overall aim Overall aim

To explore and characterize differences in p endometrial tissue occurring with weight loss We hypothesize that endometrial tissue markers associated with endometrial cancer development will normali e as patient intentionally loses weight will normalize as patient intentionally loses weight approaching the biomarker level of normal weight individuals individuals

Methods (University of Minnesota) Methods (University of Minnesota)

• 59 asymptomatic, morbidly obese women underwent

y p , y endometrial sampling before bariatric surgery in the

• perating room

46 (78%) f th t d l t ft di

• 46 (78%) of these returned one year later, after a median

weight loss of 41kg, and underwent repeat biopsy.

• Duplicate core samples from these specimens were

Duplicate core samples from these specimens were arranged randomly in a tissue microarray and scored for expression of estrogen receptor (ER), progesterone receptor (PR) androgen receptor (AR) Ki67 CD3 CD20 receptor (PR), androgen receptor (AR), Ki67, CD3, CD20, and PTEN by two pathologists (University of Pittsburgh)using a semi-quantitative scores.

Results Results

• The incidence of occult hyperplasia pre-operatively was

yp p p p y 7% overall (3 cases of simple and 1 case of complex, all without atypia) Similar hyperplasia rates have been

• bserved at the University of Pittsburgh
• bserved at the University of Pittsburgh.
• Approximately 50% (27/59) of women had adequate

tissue available at both assessments.

• 3 hyperplasia cases resolved after bariatric surgery
• Tendency towards decreased expression levels from

baseline status was observed for CD20

• ER expression decreased for patients who experienced

resolution of hyperplasia resolution of hyperplasia

Early Results from the University of Pittsburgh (b li d f 24 f l b li bi i ) (baseline data for 24 successful baseline biopsies)

20% of patients had subclinical endometrial pathology 35% failed pipelle biopsies

Conclusions Conclusions

• Morbidly obese patients have a high incidence of
• ccult hyperplasia, characterized by relatively high

hormone receptor expression, even when asymptomatic. y p

• Up to 20% of bariatric surgery patients may have

unrecognized pathology of the endometrium (expected healthy population pathology rate =0). healthy population pathology rate 0).

• These molecular changes may normalize with weight

loss. Th d i l l f i hi

• These data suggest a potential role for screening this

population as well as the possibility that weight loss may be a valid treatment strategy for risk reduction.

Future directions Future directions

• EC is a growing burden locally and globally,

EC is a growing burden locally and globally, need to learn more about future trends of EC

• EC might be preventable through weight loss,

EC might be preventable through weight loss, but we need to know what populations to target

• Bariatric surgery could be explored as a model

for EC prevention through weight loss

• Mind-body connection may be important to

investigate in relation to EC development

Acknowledgements Acknowledgements

Bariatric Surgery Practice: Ramesh Ramanathan, Anita Courcoulas, William Gourash Kelly Kaufmann Giselle Hamad Carol McCloskey and many others Gourash, Kelly Kaufmann, Giselle Hamad, Carol McCloskey, and many others Gynecologic Oncology group: Robert P. Edwards, John Commerci, Karen Lyle Plastic Surgery Group: Peter Rubin Kacey Marra Lauren Kokai M Aamir Sheikh Plastic Surgery Group: Peter Rubin, Kacey Marra, Lauren Kokai, M. Aamir Sheikh UPCI: Dana Bovbjerg, Anna Lokshin, William Bigbee CTRC Center: Kathy Laychack, Cindy Schatzman, Tony Thompson, Mary McQuinn Mentors: Ronald LaPorte, Robert Edwards, Dana Bovbjerg, and James Roberts Project coordinator: Kyle Freese Funding sources: American Cancer Society Mentored Research Award, Scaife Foundation, DOD ,

Questions? ll b Collaborations?

Please contact Faina Linkov at linkfy@mail magee edu linkfy@mail.magee.edu

I would like to thank the organizers and sponsors for having me at this conference! having me at this conference!