precision medicine and cancer

8/9/2019 Precision Medicine and Cancer

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• Probably no area of modern medicine where

the Precision Medicine Approach has had such

an impact as in cancer medicine.

• Many current examples in cancer medicine:

Molecular Dia!nosis

"creenin! Pro!nosis

#herapy

Precision Medicine and Cancer

on Medicine and Cancer


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Advances in Cancer Genomics

Timeline:


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Advances in Cancer Genomics

•$e can se%uence D&A 'relati(ely inexpensi(ely)

any !i(en tumor within se(eral wee*s

+ Panel ',--- !enes)

+ /xome 'transcribed portion of 0-1 !enes)

+ 2enome '/(erythin!)

•3ther technolo!ies 'R&Ase%4 5low sortin!4

Comparati(e 2enome 6ybridi7ation4 /pi!enomics)• Ad(ances in Bioinformatics


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• &ational Cancer 8nstitute '&C8)

• &ew 8nitiati(es

• 5undin!

• &C8 Cancer Centers

• 8nfrastructure

• Multiin(esti!ator teams

• Mayo Clinic Cancer Center 'MCCC)




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&C8 2enomic 8nitiati(es

• #C2A + #he Cancer 2enome Atlas

+ Brain4 Breast4 284 29&4 6ead &ec*4 6eme4 "*in4

#horacic4 ;rolo!ic

• C#D0 + Cancer #ar!et Disco(ery


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MCCC Contributions to #C2AMolecular Dia!nosis

• Chapman MA4 =awrence M"4 1eats >>4 et al: 8nitial !enome

se%uencin! and analysis of multiple myeloma. Nature. 0-??@

?:0. (MCCC members from the Hematologic Malignancy

Program and Myeloma SPORE contributed to this manuscript.)

• Cancer 2enome Atlas &etwor*. 8nte!rated !enomic analyses of

o(arian carcinoma. Nature. 0-??@ :-?,. (MCCC members

from the omen!s Cancer Program and the O"arian Cancer SPORE

contributed to this manuscript.)

• Cancer 2enome Atlas &etwor*. Comprehensi(e molecular portraits

of human breast tumours. Nature. 0-?0@ -'?):?-. (MCCC

members from the omen!s Cancer Program and the #reastCancer SPORE contributed to this manuscript.)


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MCCC Contributions to #C2AMolecular Dia!nosis

• Bian*in AE4 $addell &4 1assahn 1"4 et al: Pancreatic cancer

!enomes re(eal aberrations in axon !uidance pathway !enes.

Nature. 0-?0@ ?:F-,. (MCCC researchers from the $ER%

and $& Cancer Programs and the Pancreatic Cancer SPORE

contributed to a pooled analysis of ' patients that led to the no"el

disco"ery of a*on guidance path+ay gene mutations in pancreatic

adenocarcinoma.)

• #he /sopha!eal Adenocarcinoma 2enetics Consortium: Common

(ariants at the M6C locus and at chromosome ?%0.? predispose

to BarrettGs esopha!us. Nat Genet. 0-?0@ :??F???F. (MCCC

in"estigators from the $& Cancer Program contributed samples from

a registry and tissue ban, at Mayo Clinic).


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$hy is #his 2enomic 8nformation

8mportantH

• Cancer is !enetically abnormal

• Molecular Dia!nosis4 "creenin!4 and Pro!nosis

• De(elopment of #herapies tailored for fre%uent

!enetic e(ents + BRA5 'melanoma)

+ BCRAB= 'CM=)

+ /25R '=un!)

+ 6er0 'Breast4 !astric)

• $e *now that these tar!etable lesions occur in

low fre%uencies in other tumor types


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Cancer 2enome 3bser(ations

3ne tumor type many different dri(er !enes


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Many tumor types per !ene4 per pathway4 per dru!

Ar!ues for offlabel use of dru!s based on !enomic typin!

rather than histopatholo!ical typin!

e.!.4 8matinib '2lee(ec)


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#umors are hi!hly combinatoric for dri(er !enes

Additional !enetic combinatorics from

metastasis

treatment side effect allele

resistance

/stimated we need to learn from ?-, + ?- cases

#C2A is only ,-- cases of each histolo!ictype

Re%uires a different approach


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&C8 Precision Medicine Approaches

Exceptional RespondersInitiative

Phenotype to Genotype


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/xceptional Responders 8nitiati(e: Pilot "tudy

• ??-I of patients respond well to dru!s that do not!o on to recei(e 5DA appro(al for that indication

• Molecular mutations or chan!es in !ene expression

may explain these Jexceptional responsesK

• J8nacti(eK dru!s are sometimes acti(e in a subset of

patients

• Could lead to de(elopment of predicti(e assays

• 8mpro(e biolo!ic understandin! for bettertherapeutics


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/xceptional Responders

• Complete response lasting at least 6 months• Drug did not go on to FDA approval in that

indication due to insufcient activity

• issue + Pre!er "ust #e!ore drug treatment$ other%ise any

prior

+ &'( tumor

+ FFPE) Fro*en) core accepta#le

+ +ormal, #lood or other


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"olicitation of /xceptional Responders Cases

• "olicit #issue "amples and Clinical Data =etters

to C#/P in(esti!ators for identified /R cases

+Pharma

+ Cooperati(e 2roups4 ;-? and &-? !rants

+ Cancer Centers

• "ites will be reimbursed for effort


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Preparation

Central .iorepository, +ation%ide Children/s

0ospital

-iteReceives-amples

D+A trans!erred tose1uencing center

R+A 2 additionaltissue #an3ed

-e1uencing and Analysis o!-amples

Contract Existing CGA -e1uencing Center-ite

Receives-amples

-e1uencing

Analysis

Datasu#mitted

to

data#ase


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-creening o! Potential ERCases

-ites su#mit data through the C-4/s 5PE+ Eligi#ility -tage

Internal+CI

revie%

-ynopsis,•Response• reatmentin!o

•Copy o!consent!orm•Pathologyreports

-u#mittedthroughC-4 5PE+

Case isnot

exceptional

Case isexceptio

nal

Responseletter to

su#mittin

ginvestigat

orRe1uestsample

and data


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+CI Precision 7edicineApproaches

Molecular Analysis for #herapy Choice'&C8MA#C6)

2enotype to Phenotype


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+CI87AC0

• ;mbrella protocol for multiple4 sin!learm phase 88trials

+ /ach molecular sub!roup matched to a tar!eted a!ent

• 8&D for protocol template arms could be added or

deleted without affectin! other arms + 8nitially focused on sin!lea!ents 'commercial or

experimental) Combinations will be considered for

tar!ets that ha(e (alidated combination tar!eted therapy

+ &eed minimum dose


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&C8MA#C6

• 8dentify mutations


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&C8MA#C6 /li!ibility

• "olid tumors and lymphomas that ha(e pro!ressedfollowin! at least one line of standard therapy

+ /xclude histolo!ies from a !i(en arm if already 5DA

appro(ed for that indication or lac* of efficacy documented

• #umor accessible for biopsy and patient willin! tounder!o biopsy

• At least ? years of a!e

• Performance status /C32 -0

• Ade%uate or!an function


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&C8MA#C6

Patient population considerations

• #ar!et: at least 0,I of total enrollment to be

patients who ha(e JrareK tumors

• JCommonK defined as breast4 &"C=C4 colon4

prostate

• #erminate enrollment to an arm if accrual on pace

to re%uire L , years to accrue


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Geneticse1uencin

g

Actiona#le

mutationdetected

-tudyagent

-ta#leDisease9-D:; !or

6months

Drugholida

yPD

-tudyagent

-ta#ledisease or

#etter<

Continueon study

agent untilprogressio

n

Completeor partialresponse9CR=PR:;

Continueon

studyagentuntil

progression

PD

Progressive

disease9PD:;

Chec3 !orAdditionalactiona#l

emutations

>

+oadditionalactiona#lemutations)or %ithdra%

consent

5?

study

; CR) PR) -D and PD as de@ned #y RECI-< -ta#le disease is assessed relative to tumor status at re8initiation o!study agent> Re#iopsy$ i! additional mutations) o?er ne% targeted therapy

COURSE1

COURSE

2

"C6/MA of MA#C6 #rial


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+CI87AC0 8evels o! Evidence, Drugs

• =e(el ?: 5DA appro(ed@ e(idence of tar!et inhibition4 or proof ofmechanism@ demonstration that patient selection with CDx are more

li*ely to respond

• =e(el 0: A!ent met a clinical endpoint 'obecti(e response4 P5"4 or 3")@

with e(idence of tar!et inhibition@ plausible e(idence of a predicti(e or

selection assay


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+CI87AC0 8evels o! Evidence, Genes

• 2ene (ariants N tar!et of an appro(ed dru!@ and robust clinical data arelac*in! re: efficacy in certain cancer subtypes harborin! that (ariant.

• Acti(atin! mutations in !enes upstream of the molecular tar!et of the a!ent

in the associated si!nalin! pathway's)

• 8nacti(atin! mutations in !enes that result in uni%ue susceptibility to a

specific molecular point of inter(ention 'e.!.4 BRCA? mutation and PARPinhibitors).

• 3ther !enes of interest that ha(e appropriate ustification for inclusion based

on scientific e(idence re!ardin! uni%ue susceptibility to a specific molecular

tar!eted therapy 'potential future dru! tar!ets4 potential biolo!ical


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+CI87AC0 8 Assays

• &2": 8on #orrent P2M with custom Amplise%

panel of 0--F-- actionable !enes

• Ealidation in networ* of C=8A certified labs.

• 86C4 58"6H

• Rule dri(en treatment assi!nment


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• Molecular Dia!nosis

• "creenin!• Pro!nosis

• #herapy


Examples from MCCC



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Colo!uard

+ A Precision Medicine Dia!nostic Methodfor "creenin! for Colon Cancer.

Da(id Ahl%uist4 M.D.


Examples from MCCC



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Cologuard


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Cologuard

• Noninvasive stool-based DNA test

• Targets Multiple Markers

+ 7ethylated BMP3 2 NDRG4

+ 7utant KRAS + β-actin 9human D+A:

+ 0emoglo#in

B;


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& /n!l > Med 0-?@ F-:?0

Cologuard


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CologuardNEM S!reening Stud"

• Cologuard = FI prior to screeningcolonoscopy• opline Cologuard data

-ensitivityCRCAll


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Screening for Other Gastrointestinal Cancers

•/sopha!eal Cancer

•2astric Cancer

•Pancreatic Cancer

•6epatobiliary Cancer


Examples from MCCC



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Screening for Gynecologic Cancers

Detection of endometrial cancer (ia molecular analysis of

D&A collected with (a!inal tampons.

>amie &. Ba**um2ame74 &icolas $ent7ensen4 Matthew >. Maurer4

1ieran M. 6awthorne4 et al


Examples from MCCC


$ynecologic Oncology ?F '0-?,) ?+00


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•2enes hypermethylated in primary endometrial cancer

tumors can be detected in endometrial brushin! and

tampon biospecimens.

•=ower !enital tract biospecimen collection (ia tampon was

wellaccepted by women in this study.

•Combinin! methylation analyses and a minimallyin(asi(ebiospecimen collection may yield a no(el screenin! test for

endometrial cancer.endometrial cancer


Examples from MCCC



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•cancer


Examples from MCCC


$ynecologic Oncology ?F '0-?,) ?+00


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Ne Method in Screening ! "i#$id %iopsy:

5ra!ments of tumor cell somatic D&A shed into the circulation

or released when cells die can now be detected and counted4 than*s

to ad(ances in !ene se%uencin!. #his circulatin! tumor D&A 'ctD&A)is deri(ed from somatic mutations that occur in the tumor durin! an

indi(idualGs life4 unli*e hereditary mutations that are present in e(ery

cell in the body4 so ctD&A is a specific cancer biomar*er that can be

detected4 measured4 and trac*ed.

Monitorin! ctD&A is expected to pro(ide clinicians with faster4 cheaper4less in(asi(e ways to assess cancer patientsG clinical status and

response to therapy. ctD&A assay for multiple !enes (ia next

!eneration se%uencin! '&2") mi!ht become a Qli%uid biopsyQ

alternati(e to in(asi(e tissue biopsy4


Examples from MCCC



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• "creenin!

• Pro!nosis

• #herapy




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• Prognosis & Molec$lar Mar'ers in Ne$ro!Onc




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• Prognosis & Molec$lar Mar'ers in Ne$ro!Onc

• >en*ins RB4 iao 94 "icotte 64 et al: A lowfre%uency

(ariant at %0.0? is stron!ly associated with ris* of

oli!odendro!lial tumors and astrocytomas with 8D6?or 8D60 mutation. -at $enet. 0-?0@ :??00??0,.

• ';sin! next!eneration se%uencin!4 Robert >en*ins4

MD4 PhD4 and collaborators from &euro3ncolo!y

Pro!ram and Brain "P3R/ identified a !enomic(ariant that carries a sixfold hi!her ris* for de(elopin!

certain brain tumorsSa disco(ery that could lead to

better dia!nosis and treatment.)




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Prognosis & Molec$lar Mar'ers in (ematologic!Onc

Easmat7is 24 >ohnson "64 1nudson RA4 1etterlin! RP4

Bra!!io /4 5onseca R4Eiswanatha D"4 =aw M/4 1ip &"4

37san &4 2rebe "14 5rederic* =A4 /c*loff B$4 #hompson/A4 1adin M/4 Milose(ic D4 Porcher >C4 Asmann 9$4 "mith

D84 1o(tun 8E4 Ansell "M4 Do!an A4 5eldman A=. 2enome

wide analysis re(eals recurrent structural abnormalities of

#PF and other p,Frelated !enes in peripheral #celllymphomas. #lood. 0-?0 "ep ?F@ ?0-'??):00-. 0-?0



# cell =ymphoma: 2enomic Disco(ery


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#cell =ymphoma: 2enomic Disco(ery

;&1&3$&

I

/SP

I

0P12

I

%34 ?-I

#umor

D&A

"e%uencin!

Disco(ered by Mayo #eam '5eldman =ab)

Ealidation in

?F Mayo Patients

# ll = h 2 ti Ri *


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0P12

/SP

%34

;&1&3$& 2enetics

Months from dia!nosis

3 ( e r a l l "

u r ( i ( a l

Abnormality Median "ur(.

0P12 ? mos.

;&1&3$& 0F mos.

/SP 0 mos.

%34 ? mos.

pN.--?? 'lo!ran*)

8mmediate needs:

?. 8dentify !enetics in I of

patients currently ;&1&3$&

0. 8ndi(iduali7e therapy based

on !enetic ris*

#cell =ymphoma: 2enetic Ris*


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• "creenin!

• Pro!nosis

• #herapy




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Mayo )ision for Genomic!%ased Therapy

• 8ndi(iduali7ed cancer therapy based on !enomese%uence 'host and the tumor)

• 8dentification of !enomic alterations associated with

chemotherapy response to be used as a templatefor dru! de(elopment

• 8ndi(iduali7ed !enome se%uence !uided adapti(e

therapy could be extended to many other cancers


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*#s+ Matt,e (oet./ ud" 0oug,e"ab *#+ ieei ang

ab tea3+ Eri! ieben/ Di!k eins,ilbou3/ a3es #ngle/ ia 4u/ Minetta iu

*at,olog" tea3+ Dan 5iss!,er/ Ann Mo"erRadiolog" tea3+ A3" Conners/ 6atie ones

(eneti! !ounselor+ Marissa EllingsonStats tea3+ 5era Su3an/ Travis Do!kter/ 6ris,na 6alari/ Steve 'art/

'ugues Si!ottes/ ason Sinnell/ *eter 5edell/ 7iao8ia Tang and 6evinT,o3pson

Ari.ona tea3+ Don Nort,9elt/ Ri!k (ra"

:lorida tea3+ Alvaro Moreno/ Sara, M!aug,lin

BEAUTY - Breast Cancer GenomeGuided Therapy Study


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Breast Cancer 2enome 2uided

#herapy study 'B/A;#9)

130 !o%en !ith

in.asi.e -reast

cancer

Ma$netic esonance I%a$in$

4MI

Molecular 6reast I%a$in$

4M6I

Tumor biopsy

Mouse “a.atars” 4eno$rats

Geno%ic sequencin$

Blood sample

*"+

*"+,

#aclitael Trastuu%a- /,#ertuu%a-

#aclitael 4" and/, Car-oplatin 4triplene$ati.e

AC or "C or("C

AC or "C or("C

Ma$netic esonance

I%a$in$ 4MI

Molecular 6reast

I%a$in$ 4M6I

Tumor biopsy

Geno%ic sequencin$

Blood sample

'ur$er:

MI

M6I

Tumor tissue

Mouse “a.atars”

4eno$rats

Geno%ic sequencin$Blood sample

5 :earo-ser.ationChe%otherap: 1 Che%otherap: +


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Tar$et

identiied dru$a.aila-le;


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Other T$mor Types

P*OMOTE St$dy ! +PROstate CancerMedically Optimized Genome Enhanced

ThErapy)

This is second Genome-Guided Stud at

!CCC

A


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ouse Aatars

519B

317B

+72B

173B

•3pportunity to test indi(idual or combinations ofdru!s a!ainst human tumors implanted inimmunocompromised mice.

• Ealuable for precisionbased dru!s

• Many examples usin! this approach at MCCC.


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Tuestions


precision medicine and cancer

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