The Angiosarcoma Project: Generating the genomic landscape...

MichaelDunphy,EshaJain,ElanaAnastasio,MaryMcGillicuddy,RachelStoddard,BeenaThomas,SaraBalch,Kris>nAnderka,Ka>eLarkin,NiallLennon,Yen-LinChen,AndrewZimmer,EsmeBaker,SimoneMaiwald,JenHendrey,JasonHornick,ChandrajitP.Raut,GeorgeDemetri,EricLander,ToddGolub,NikhilWagle,CorriePainter

BroadIns*tuteofMITandHarvard,Cambridge,MA;Dana-FarberCancerIns*tute,Boston,MA;Massachuse@sGeneralHospital,Boston,MA;BrighamandWomen’sHospital,Boston,MA

The Angiosarcoma Project: Generating the genomic landscape of an exceedingly rare cancer through a nationwide patient-driven initiative

Abstract

Summary and Conclusions

The Patient Voice

Acknowledgements

Most tumor samples have not been readily available for study!

Only 5% of U.S. cancer patients are enrolled in

clinical trials!

Challenges of Studying Rare Patient Tumor Samples

Partnering Directly with Patients

And the Angiosarcoma Facebook group founded by Lauren Ryan, along with countless patients who have worked with us to develop

and implement this project.

ApproachOnline

ConsentMedical History

Tissue, Blood, Saliva

GenomicAnalysis

Reporting / Data Sharing

Electronic consent form asks for permission to obtain tumor tissue, blood, saliva, and medical records

Medical records are obtained by the study team and centrally reviewed and abstracted

Tumor blocks are requested from local pathology depts by the study team. Patients are sent saliva and blood kits

Patient specimens are characterized by ultra-low pass whole genome sequencing, whole exome sequencing and transcriptome sequencing

DataInterpretation

Genomic data is interpreted in the context of clinical data at the individual level and in aggregate across similar patients

De-identified genomic / clinical data shared widely with the research community. Overall findings regularly communicated directly to patients

GOAL: To empower patients and their families to accelerate research through sharing samples and clinical information

Over 300 women and men with angiosarcoma from 39 states have joined the ASCproject since our launch in March of 2017. Over 115 people have filled out information on behalf of a loved one who died from angiosarcoma

Participation in The Angiosarcoma Project to Date

We are grateful to all the patients with angiosarcoma cancer who are participating & have contributed their voices to this project.We thank the many patients, advocates, and advocacy groups who have worked with us to develop and implement this project.We thank our colleagues at the Broad Institute and Dana-Farber Cancer Institute for their contributions to designing, implementing, and running this project.

Twitter: @ASCa_project Facebook: Angiosarcoma Project Working Group Email: info@ascproject.org Phone: 857-500-6264

Patients have been involved from day 1 in conceiving, designing, implementing, testing, and refining this project. Patients have been partners in this project from the beginning.

98% submitted the 20-question survey

96% response rate to each question (all are optional)

294 participants have provided detailed clinical and demographic data, including information on treatments and responses

260 patients have consented to share medical records and allow next-generation sequencing on their tumor & saliva samples. 151 have returned saliva samples, 42 have returned blood biopsies

Disease Characteristics:•  Dates of initial diagnosis•  Primary site(s)•  Recurrence site(s)•  Other cancers

Treatment Response:•  Questions about treatment

modalities (therapies/surgeries/radiation)

•  Free text about treatments

Demographics:•  Year of birth•  Race and ethnicity

Free text about anything additional

Preliminary Sequencing Results

IRB approval for Pilot

1/6/17

First 10 saliva kits mailed

1/19/17

First SoMe of pts with saliva kits

1/26/17

First saliva kit arrived at Broad

2/1/17

First med record obtained

2/15/17

Public launch63 pts day 1

3/13/17

First tissue arrived at Broad

3/16/17

First blood biopsy kit received

4/24/17

85% of U.S. cancer patients are treated in

the community setting!

Sarcomas are only 1% of cancers; 80 angiosarcoma pts total in1 yr at DFCI,

MGH & BWH!

Advocacy Partners

When I saw the delivery, I cried ~ I’m so excited to be part of this genomics project for angiosarcoma. It’s a privilege. Let patients benefit from what is learned from this research ~ Pepperrell, MA !

Like electing people to the school board who never had children, or building a retirement community without input from retired people. You have walked in our shoes by asking for our input. ~ Kernersville, NC!

I see my daughter in this research and it’s both heartbreaking and makes me proud that she wanted to be a part of the solution and give back.!~ Marlborough, MA

I didn’t choose this cancer. It chose me! And since it did, we are continuously mounting a large and dedicated war against it!~ Lansing, MI !

•  A direct-to-patient approach using social media & patient/advocate partnerships enabled rapid identification of large numbers of angiosarcoma patients willing to share tumors, blood, saliva, and medical records.

•  Remote acquisition and sequencing of patient samples from the USA and Canada is feasible and ongoing.

•  Genomic analysis of saliva and cell free DNA from blood biopsies to study resistance, tumor evolution, and heterogeneity is underway.

•  All de-identified clinically-annotated genomic data from 14 samples from 12 patients are now publicly available.

•  This study may serve as a model for patient-driven research in other cancer types.•  This study serves as proof of principle that direct-to-patient genomics efforts can democratize cancer

research for exceedingly rare cancers, which to date have been understudied.

ScantoviewASCprojectdataoncBioPortal.org:

Angiosarcoma(AS)isanexceedinglyraresoK*ssuesarcoma,withanincidenceof300cases/yranda5-yeardisease-specificsurvivalof30%.Thelowincidencehasimpededlarge-scaleresearcheffortsthatmayleadtoimprovedclinicaloutcomes.Toaddressthis,welaunchedana*onwideclinical-genomicsstudyinordertoempowerpa*entstoaccelerateresearchbysharingtheirclinicalinforma*onandsamplesremotely.Pa*entscanaccessthestudythroughanonlineportal(ASCproject.org).Enrolledpa*entsaremailedsalivaandblooddrawkits.ThestudyteamobtainsmedicalrecordsandstoredFFPEtumorsamples.AllreceivedFFPEsamplesareexaminedbyanexpertpathologisttoconfirmadiagnosisofangiosarcoma.Inordertovalidatethatourprocesseswouldenablethegenera*onofarobustdatasetfrom*ssuesacquiredfrommul*pleins*tu*ons,wesoughttocharacterizepreviouslydescribedgenesknowntobealteredinangiosarcoma(e.g.,TP53,NF1,KDR,BRCA2,MET,ARID1A,POT1,BRCA1,ASXL1,KDM6A,BRAF,SETD2,PTPRB,NRAS).Atotalof251pa*entshaveenrolledsincetheprojectlaunchedinMarchof2017.Primaryloca*onsofASareprimarybreast59(25%),breastwithpriorradia*on45(19%),head/face/neck/scalp52(22%),bone/limb26(11%),abdomen5(2%),heart5(2%),lung2(1%),liver1(1%),lymph1(0.4%),mul*pleloca*ons25(11%),andotherloca*ons12(5%);107(52%)reportedbeingdiseasefreeatthe*meofenrollment.Todate,wehavereceived129salivakits,106medicalrecords,19bloodsamples,and36*ssuesamples.Whole-exomesequencing(WES)wasperformedon21FFPE/salivamatchedpairswithagoalmeantargetcoverageof150xfortumors.Ultra-lowpasswhole-genomesequencing(0.1x)wasperformedoncellfreeDNA(cfDNA)fromplasmainordertodeterminetumorfrac*on.Of10cfDNAsamplessequenced,4samplesmetcriteriatoperformWES.Addi*onally,transcriptomesequencingwasperformedon9FFPEsamples.Sequencedataprocessingandanalysishasbeencompletedonthefirst10samplesandisinprogressforthesubsequentsamples.Altera*onsweredetectedingenespreviouslydescribedtobeaffectedinangiosarcoma.Recurrentmuta*onsinTP53weredetectedin50%(5/10)ofanalyzedsamples,comprising3missensemuta*ons,1frameshiKdele*on,and1frameshiKinser*on.Altera*onswereseeninatleastonesampleinallothergenesselectedforthisini*alanalysis.Thisini*a*vedemonstratesthefeasibilityofstudying*ssuesfromgeographicallydispersedpa*entsandservesasproofofconceptthatpa*ent-drivengenomicseffortscandemocra*zeresearchforexceedinglyrarecancers.Enrollmentiss*llinprogress,andaddi*onalsampleswillbesequencedandanalyzedatscale.Thedatageneratedfromthesestudieswillbedepositedintothepublicdomaininsix-monthintervals.

Loved One Survey Data

Technology, social media, and cultural changes now provide a new opportunity

to engage cancer patients and directly partner with them in this research!

ASCproject.org enables patients in the US and Canada to participate directly in genomics research regardless of where they live!

Pilot Phase

Cumulative Enrollment

Saliva Kits Received

Blood Bx Received

SitesofSpread(N=261)SpreadLoca>on CountLung 64Liver 42Bone/Limb 26Abdominal 24Brain 23Lymph 23Spleen 17Don'tKnow 15Heart 7Head/Face/Neck/Scalp 6NoSpread 6NotReported 6Breast 1Other 1

6 Institutions with > = 10 pts (117 pts total)

226 Institutions with only 1 pt represented

Counts

Fra

ctio

ns

Angio−ASCProject_0098−Tumor−SM−DAE57

Angio−ASCProject_0134−Tumor−SM−DAE6G

Angio−ASCProject_0113−Tumor−SM−DADXW

Angio−ASCProject_0055−Tumor−SM−DAE3X

Angio−ASCProject_0059−Tumor−SM−DADIT

Angio−ASCProject_0007−Tumor−SM−DAE1F

Angio−ASCProject_0026−Tumor−SM−DADGX

Angio−ASCProject_0167−Tumor−SM−DAE4K

Angio−ASCProject_0167−Tumor−SM−DADTI

Angio−ASCProject_0067−Tumor−SM−DADRM

Angio−ASCProject_0179−Tumor−SM−DACKI

Angio−ASCProject_0006−Tumor−SM−E76O4

Angio−ASCProject_0003−Tumor−SM−DADQD

Angio−ASCProject_0145−Tumor−SM−E76MF

Angio−ASCProject_0164−Tumor−SM−DADWN

Angio−ASCProject_0167−Tumor−SM−DAE22

Angio−ASCProject_0026−Tumor−SM−E76O8

Angio−ASCProject_0011−Tumor−SM−DADLY

Angio−ASCProject_0030−Tumor−SM−DADSQ

Angio−ASCProject_0066−Tumor−SM−DADKP

Angio−ASCProject_0044−Tumor−SM−E76O5

Angio−ASCProject_0007−Tumor−SM−DAE2O

0

250

500

750

1000

0.00

0.25

0.50

0.75

1.00

Samples

Sig

na

ture

Activitie

s

factor(Signature) W1 W2 W3

Siganture Activities in ASC_all

ASCproject.org enabled the upcoming launch of GECproject.org

A B C

March 2018

EachSankeyDiagramdetailstheprimarysiteandsitesofspreadofangiosarcomaasreportedthroughtheLovedOneSurveyonbehalfofsomeonewhodied

First data release on cBioPortal.org

A Co-occurrence of Genomic Alterations in Angiosarcoma Samples B Distribution of Signature Scores per Sample

C Distribution of Genomic Alterations in Angiosarcoma Cohort

Sig. 1+6: Age/MMROther Sig.

Sig. 7: UV light

Breast,70,24%

Head/Face/Neck/Scalp,63,21%

Breast(previousradia>on),58,

20%

Mul>ple,31,11%

Bone/Limb,27,9%

Other,14,5%

Heart,10,3%

Abdominal,8,3%Liver,5,2%

Lung,4,1%

Spleen,3,1% Lymph,1,0%

Angiosarcoma Diagnosis Location (N=294)

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