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

Faina Linkov, PhD, MPHAssociate ProfessorAssociate Professor

Magee Womens Research InstituteUniversity of Pittsburgh School of Medicine

March 18 2014March 18, 2014

Endometrial cancer: what’s known andwhat 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 MWRIOverview of my research at MWRI

Area 1: Endometrial cancer today andArea 1: Endometrial cancer today and tomorrow: Projecting rates into the year 2030Area 2: Biomarker and biobehavioral markerArea 2: Biomarker and biobehavioral marker changes occurring with weight lossArea 3: Endometrium changes occurring withArea 3: Endometrium changes occurring with weight lossArea 4: Endometrial cancer and adipose tissueArea 4: Endometrial cancer and adipose tissueArea 5: Endometrial cancer survivors and weight loss decisionsloss 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 riskO j k C ti t iOne major maker: C-reactive protein

Heikkila et al., 2009

Endometrial Cancer:T I/II C tType I/II Concept

• Type I– Estrogen RelatedEstrogen Related– Younger and heavier patients– Low grade– Background of Hyperplasia

What if we could prevent these cancers through intentional weightg 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, biobehavioralfactors, and cancer and ultimately design interventionsultimately design interventions targeting multiple mechanisms that cause malignancies

Endometrial cancer risk reduction in the context of weight loss through bariatric surgerythrough bariatric surgery

What types of bariatric surgeries h ldshould we target?

Bariatric surgery/obesity reduction as a model for

cancer prevention in patients at high risk?

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

(funded by American Cancer Society)Aim 1Examine 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 2Investigate 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 3Aim 3To 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 fof life

Case control investigation of markers implicated in endometrial cancerGynecologic Oncology, 2007

Collaboration with RENEW investigators

Collaboration with Lora Burke

Endometrial Changes Occurring withEndometrial Changes Occurring with Weight Loss

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

University of PittsburghStudy 1Examine 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 o t s o o g gast cbypass surgery in asymptomatic women (focus of this presentation)

S d 2 Argenta, PIStudy 2Examine 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 other obesity-linked cancers 6-12 months following any bariatric surgery in symptomatic and asymptomatic women

Linkov, PI

Overall aimOverall aim

To explore and characterize differences in pendometrial tissue occurring with weight loss

We hypothesize that endometrial tissue markers associated with endometrial cancer development will normali e as patient intentionally loses weightwill normalize as patient intentionally loses weight approaching the biomarker level of normal weight individualsindividuals

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

• 59 asymptomatic, morbidly obese women underwent y p , yendometrial sampling before bariatric surgery in the operating room46 (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 wereDuplicate 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 CD20receptor (PR), androgen receptor (AR), Ki67, CD3, CD20, and PTEN by two pathologists (University of Pittsburgh)using a semi-quantitative scores.

ResultsResults

• The incidence of occult hyperplasia pre-operatively was yp p p p y7% overall (3 cases of simple and 1 case of complex, all without atypia) Similar hyperplasia rates have been observed at the University of Pittsburghobserved 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 hyperplasiaresolution 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 pathology35% failed pipelle biopsies

ConclusionsConclusions• Morbidly obese patients have a high incidence of

occult 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 directionsFuture 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

AcknowledgementsAcknowledgementsBariatric Surgery Practice: Ramesh Ramanathan, Anita Courcoulas, William

Gourash Kelly Kaufmann Giselle Hamad Carol McCloskey and many othersGourash, 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 SheikhPlastic 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, ScaifeFoundation, DOD,

Questions? ll bCollaborations?

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

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