Howard Lim, MD, PhD, FRCPC

Chair, Gastrointestinal Tumour Group

Program Director, Medical Oncology Residency Training Program

Clinical Associate Professor, University of British Columbia

Division of Medical Oncology, BC Cancer Agency

How PET and Personalized

Onco-Genomic (POG) Trial

are Able to Create Patient –

Centered Care

Disclosures

• Received honorariums from Eisai, Taiho,

Roche, Lilly, Amgen, and Leo for

consultant work

• Investigator on trials with Bayer, BMS,

Lilly, Roche, Astra-Zenca and Amgen

• Have investments with marijuana stocks

Objectives

• Understand the use of genomic based

testing in oncology

• Examine the use of PET for genomic

based testing

• Review the pitfalls of genomic based

testing

Comprehensive molecular characterization of GC - TCGA

Genomic testing

• Many different levels of testing

• Panels:

– Look presence of known cancer genes

– Fast and relatively inexpensive

• Exome sequencing

• Whole genome sequencing (DNA & RNA)

Approaches (how much is enough?)

POG Primer 8BCCA Confidential - For Research Purposes Only

Non-coding RNAs Proteomics MetabolomicsEpigenomics

Personalized Cancer Therapy

15BCCA Confidential - For Research Purposes Only

Lung Cancer

Crizotinib

Gefitinib

Molecular profiling(genomic analysis) Adapted from: https://pct.mdanderson.org/#/home

Identify disease characteristics and predictive biomarkers

ALK fusion positive

EGFR positive

POG Primer

Population-Based Personalized

Oncology

POG Clinical

Trials

Genome

Sciences

Centre

Collaborative

Research

Innovative

Collaborative

Achievable

GSC Sequencing Capacity and Throughput

• Total data

generated to

date: 609 Tb

• Platform

upgrade in

progress →14

HiSeq 2500

1Tb model

• Annual

capacity 600Tb• 6,500 human

genomes/year

What does this entail?

• Whole genome sequencing = 6 billion bits of information

• Compare cancer to normal cells

• Patterns of RNA expression

• Analyze abnormalities and search for their function in databases

• Sift through scientific literature for evidence to link pathways to specific drugs

Types of information

• Evolution of cancer as a response to treatment

• Biological explanation of why a specific agent works in one type of cancer and not another

• Identification of pathways leading to drugs that would not have otherwise been used with excellent clinical results

• Completely changed the diagnosis of rare cancers

Genomic Alterations in Cancer

BCCA Confidential - For Research Purposes Only 22

POG - Breast Cancer

AR

[100%]

ERBB4

[93%]

WNT7B

[72%]

NRAS

[80%]

MAP2K4

[0%]

MAPK3

[98%]

MAP2K2

[82%]

ELK1

[89%]

ERBB2

[59%]

ERBB3

[25%]

FGFR3

[48%]

FGFR4

[96%]

RET

[69%]

BIRC5

[95%]

WNT

Pathway

Gene Regulation

PICK3CA

[8%]GoF

BRCA1

[99%]

BRCA2

[88%]

APOBEC3B

[76%]

DNA damage

CD274

[70%]

[PD-L1]

MUC1

[31%]

TOP2A

[85%]

Inhibition of apoptosis

MAPK

Pathway

CDK1

[99%]

E2F1

[96%]

RB1

[43%]

CCNB1

[74%]

CDKN3

[82%]

MYCN

[77%]

AURKA

[90%]

AURKB

[72%]

BRD4

[80%]

TOP1

[89%]

Cell

Cycle

TGF-beta

Pathway

POG[TC=45%] TETRAPLOID

FC vs. Compendium Normal breastPercentile vs. BRCA (TCGA)

copy number loss(es)

copy number gain(s)

Tumour Sup.

Activation Inhibition Indirect

Underexpressed

Overexpressed

[%] percentile

Drug Target

Copy numbers show relative to estimated PLOIDYOne start per copy, copy gains with 5+ are in large stars

GoF activating mutationLoF inactivating mutationVUS unknown mutation

TP53

[8%]

PIK3-Akt

Pathway

VUS

CHD4

[0%]LoF

6

FGF10

[100%]

18

CCND1

[68%]

14

5

CDK6

[20%]

CDK4

[3%]

PDPK1

[47%]

5

FGF3

[88%]

14FGF4

[98%]

14FGF19

[83%]

14

FGFR2

[1%]

CCNA2

[92%]

TYMS

[99%]

6

673 SNV = hypermutated

Genomic based treatment

• Hypothesis Generating

• Each patient is their own clinical trial

• Lack power

• Need an efficient manner to evaluate

response – CT scans q 8 weeks tend to

be standard

• Use PET/CT in certain cases

POG130 – colonic adenocarcinoma

• Stage III colon cancer– toxicity with adjuvant 5FU/oxaliplatin

with neuropathy and neutropenia

• Relapsed retro-peritoneum– Resected

• Relapsed in L spine– XRT twice

• Palliative resection– Analyzed for POG

POG Primer 25BCCA Confidential - For Research Purposes Only

FFPE section

Frozen section (used for POG)

POG130 expression outlier analysis

• Outlier expression analysis in POG130 indicated the AP-1 transcriptional complex (FOS/JUN) as an upregulated axis potentially acting as a central driver to disease progression in this patient.

POG130 pathway analysis 26BCCA Confidential - For Research Purposes Only

Gene IDCopy

numberFold change

(vs. normal colon tissue)Percentile expression (within colon cancer)

RPKM value Curated cancer gene

BRI3BP 2 5 85 19.97 proto-oncogene

CCND1 2 7 79 79.26 proto-oncogene

CDT1 2 23 93 41.01 proto-oncogene

CSF1R 2 5 78 11.48 proto-oncogene

ELAC2 2 3 80 18.74 proto-oncogene

ELF4 2 4 82 22.45 proto-oncogene

FOS 2 11 98 516.74 proto-oncogene

JUN 2 4 100 383.25 proto-oncogene

MAFB 2 4 71 6.55 proto-oncogene

MDM2 2 4 92 17.02 proto-oncogene

NCKIPSD 2 2 88 15.69 proto-oncogene

PIM3 2 2 82 62.01 proto-oncogene

SPI1 2 3 84 14.09 proto-oncogene

STIL 2 4 66 4.44 proto-oncogene

TPM3 2 5 64 47.62 proto-oncogene

WHSC1 2 5 84 8.66 proto-oncogene

Table shows filtered transcriptome data from POG130 assessing the transcriptional activity of known oncogenes

Angiotensin II pathway

POG130 pathway analysis 27BCCA Confidential - For Research Purposes Only

Shown to reduce JUN levels at both RNA and Protein level

Angiotensin inhibitors (aka blood pressure meds)

Pre-treatment PET/CT (Nov 2014) Post-treatment (4 Weeks – Jan 2015)

SPINE MET

POG Primer 28BCCA Confidential - For Research Purposes Only

POG005

• 32 year old male presented with large ethmoid sinus mass

• Biopsy suggested “poorly differentiated squamous cancer”

• Received neoadjuvant cisplatin-docetaxel followed by radiation with concurrent cisplatin.

• Recurred within 6 months. Cis-doce tried again, no response.

• Biopsied for study Dec 2012.

POG Primer 29BCCA Confidential - For Research Purposes Only

POG005

POG Primer 30BCCA Confidential - For Research Purposes Only

Many chromosomes have no somatic copy number changes

Small deletions on 2,3,5,9,12,13,17 (not p53)

Larger deletions on 8,11,22 with one homozygous

deletion event on 22q SMARCB1

Diagnostic of pediatric cancer – atypical teratoid

rhabdoid tumor (ATRT); median age of this

sarcoma is 9 months.

Panel entirely normal

ch17

ch22

ch1 ch21

Pre- and Post- POG PET images

JAN 22 – 2013Baseline

FEB 25 – 2013After 1.5 cycles of

“sarcoma” directed chemo

POG Primer 31BCCA Confidential - For Research Purposes Only

Biopsies are critical

• Source material for analysis

• Biomarker analysis is dependent on the

quality of the tissue

• Need a tumor content of around 20-30%

• Treatment affects viability

• Directly related to the biopsy

• Key Factors:

– Tumor Heterogeneity

– Temporal Heterogeneity

• Evolution of the tumor

Use of functional imaging???

• Typically biopsy

the safest lesion –

not necessarily the

most biologically

relevant lesion

• Consider use of

PET/CT to

determine which

lesion to biopsy

What to biopsy?

• Metastatic CRC to

liver

• Plan – receive

chemotherapy and

consider surgical

resection

Pre-treatment PET/CT

After 4 cycles of chemo

Progression???

• Patient was being

considered for POG

if evidence of

progression

• Did a PET/CT to

assess response

and viable lesion to

biopsy

Case

• Patient had complete response on

PET/CT

• Went for surgery – liver – necrotic

lesions

• So biopsy would have no yield

• PET/CT – changed treatment

management

Assessing for biopsy

• Metastatic adenoid

cystic cancer to the

lung

• Enrolled in POG

• Only accessible lesion

was a pleural lesion

that had undergone

XRT

• Is there viable tissue?

Summary

• Genomic profiling is becoming increasingly more complex – mutations, expression panels, and proteomics

• Patients should be aware of the pitfalls of testing– Does it really affect health outcomes?

• Most genomic testing should be done in the context of trials and informed consent

• The results are complex for both patient and physician – should be tests that physician directed versus consumer driven

Summary

• How do we assess success? Does a metabolic response translate into clinically meaningful benefit such as survival

• The acquisition of tissue is key for analysis

• Therefore biopsies are a critical component for genomic based testing

• PET/CT can help in ensuring quality of biopsy samples and in some cases spare patients from procedures

• Given the heterogeneous nature of cancer –PET/CT may also determine which lesion is the biologically relevant sample versus obtaining from the safest site

Acknowledgements

43All patients & their families

Medical Oncologist Janessa Laskin Deepa Wadhwa Anna Lee Pinaki Bose Gregg MorinAbdul Al-Tourah Lyly Le Tamana Walia Lawrence Lee Simon Chan Ryan Morin

Helen Anderson Christopher Lee HuiLi Wong Hector Li Chang Carolyn Ch'ng Andy MungallVanessa Bernstein Ursula Lee Muhammad Zulfigar Pedro Farinha Richard Corbett Brad Nelson

Sylvie Bourque Jenny Ko Ann Tan Malcolm Hayes Eric Chuah Cydney Nielsen

Barbara Campling Christian Kollmannsberger Sara Taylor Tadaaki Hiruki An He Julie NielsenAngela Chan Caroline Lohrisch Anna Tinker Hugo Horlings Martin Jones Jacquie ScheinTheresa Chan Nicol Macpherson Dorothy Uhlman David Huntsman Steven Jones Colin SchlosserSylvia Cheng Barb Melosky Neurologist Diana Ionescu Katayoon Kasaian Sohrab Shah

Winson Cheung John Paul McGhie Brian Thiessen Hoang Lien Ji-Young Kim Liz StarksKim Chi Corey Metcalf Medical Geneticist Nikita Makretsov Sreeja Leelakumari Yongjun Zhao

Stephen Chia Deepu Mirchandani Linlea Armstrong Nissreen Mohammad Jake Lever Social ScientistJoseph Connors Nevin Murray Ian Bosdet Greg Naus Yvonne Li Anita ChartersJanine Davies Sujaatha Narayanan Gillian Mitchell Tony Ng William Long Peter Chow-White

Rebecca Deyell Thao Nguyen Sean Young Torsten Nielsen Yussanne Ma Dung HaThuan Do Conrad Oja Intan Schrader Tomo Osako Karen Mungall Dean Regier

Bernhard Eigl Gary Pansegrau Clinical Ethicist Amir Rahemtulla Brandon Pierce Deirdre Weymann

Susan Ellard Maryse Power Alice Virani David Schaeffer Erin Pleasance Project Coordinator/ ManagerXiaolan Feng Bradley Proctor Radiologist Brandon Sheffield Cara Reisle Leslie AlfaroDavid Fenton Sanjay Rao Francois Bernard Sona Sihra Yaoqing Shen Charlene Appleby

Daygen Finch Rod Rassekh Colin Mar Brian Skinnider Greg Taylor Balvir Deol

Paul Galbraith Daniel Renouf Montgomery Martin Graham Slack Nina Thiessen Nancy FergusonKaren Gelmon Paul Rogers John Myo Peyman Tavassoli Tina Wong Colleen Fitzgerald

Alina Gerrie David Sanford Pharmacist Basile Tessier-Cloutier Wei Zhang Cathy Fitzpatrick

Sharlene Gill Delia Sauciuc Shirin Abadi Tom Thomson Eric Zhao Alexandra FokKarmjit Gill Kerry Savage Pathologist Tracy Tucker Amir Zadeh Colleen JantzenAnagha Gurjal Ravinder Sawhney Yazeed Alwalaie Emilija Todorovic Kelsey Zhu Jas Kandola

Edward Hardy Asif Shaikh Daiana Becker-Santos Dirk van Niekerk Genome Scientist Julie Lorette

Jason Hart Wen Wen Shan Ian Bosdet Suzanne Vercauteren Sam Aparicio Katherine MuiCheryl Ho Tamara Shenkier Kathy Ceballos Carlos Vilamil Scott Brown Jessica Nelson

Donna Hogge Christine Simmons Andy Churg Joanne Wright Robin Coope Robyn RoscoePaul Hoskins Kevin Song Bakul Dalal Stephen Yip Peter Eirew Payal Sipahimalani

Michael Humphreys Caron Strahlendorf Christopher Dunham Chen Zhou Bruno Grande June Song

Bal Johal Sophie Sun John English Bioinfomatician Martin Hirst Isabel TrapagaAvancena

Hagen Kennecke Isabella Tai Patrice Eydoux Jianghong An Rob Holt Peggy Tsang

Koo Khoo Joanna Vergidis Anthony Karnezis Dustin Bleile Christopher Hughes

Meg Knowling Diego Villa Aly Karsan Melika Bonakdar Marco MarraDoran Ksienski Helga Klein-Parker Morgan Bye Richard Moore