Precision Medicine and Cancer

Robert B. Diasio M.D.

Director
Mayo Clinic Cancer Center

Precision Medicine and Cancer

on Medicine and Cancer

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 Diagnosis
- Screening
- Prognosis
- Therapy

Advances in Cancer Genomics

Timeline:

Advances in Cancer Genomics

We can sequence DNA (relatively inexpensively)
any given tumor within several weeks
Panel (50-400 genes)
Exome (transcribed portion of 20K genes)
Genome (Everything)
Other technologies (RNAseq, Flow sorting,
Comparative Genome Hybridization, Epigenomics)
Advances in Bioinformatics

Precision Medicine and Cancer

on Medicine and Cancer

National Cancer Institute (NCI)

New Initiatives

Funding

NCI Cancer Centers

Infrastructure

Multi-investigator teams

Mayo Clinic Cancer Center (MCCC)

NCI Genomic Initiatives

TCGA The Cancer Genome Atlas
Brain, Breast, GI, GYN, Head & Neck, Heme, Skin,
Thoracic, Urologic

CTD2 Cancer Target Discovery/Development

Data portal, Bioinformatics

TARGET Therapeutically Applicable Research

to Generate Effective Treatments
Pediatric tumors (ALL, AML, Neuroblastoma,
Osteosarcoma, Wilms Tumor)

MCCC Contributions to TCGA

Molecular Diagnosis

Chapman MA, Lawrence MS, Keats JJ, et al: Initial genome

sequencing and analysis of multiple myeloma. Nature. 2011;
471:467-472. (MCCC members from the Hematologic Malignancy
Program and Myeloma SPORE contributed to this manuscript.)
Cancer Genome Atlas Network. Integrated genomic analyses of
ovarian carcinoma. Nature. 2011; 474:609-615. (MCCC members
from the Womens Cancer Program and the Ovarian Cancer SPORE
contributed to this manuscript.)
Cancer Genome Atlas Network. Comprehensive molecular portraits
of human breast tumours. Nature. 2012; 490(7418):61-70. (MCCC
members from the Womens Cancer Program and the Breast
Cancer SPORE contributed to this manuscript.)

MCCC Contributions to TCGA

Molecular Diagnosis
Biankin AV, Waddell N, Kassahn KS, et al: Pancreatic cancer
genomes reveal aberrations in axon guidance pathway genes.
Nature. 2012; 491:399-405. (MCCC researchers from the GERA
and GI Cancer Programs and the Pancreatic Cancer SPORE
contributed to a pooled analysis of 142 patients that led to the novel
discovery of axon guidance pathway gene mutations in pancreatic
adenocarcinoma.)
The Esophageal Adenocarcinoma Genetics Consortium: Common
variants at the MHC locus and at chromosome 16q24.1 predispose
to Barrett's esophagus. Nat Genet. 2012; 44:1131-1136. (MCCC
investigators from the GI Cancer Program contributed samples from
a registry and tissue bank at Mayo Clinic).

Why is This Genomic Information

Important?
Cancer is genetically abnormal
Molecular Diagnosis, Screening, and Prognosis
Development of Therapies tailored for frequent
genetic events

BRAF (melanoma)
BCR-ABL (CML)
EGFR (Lung)
Her2 (Breast, gastric)

We know that these targetable lesions occur in

low frequencies in other tumor types

Cancer Genome Observations

One tumor type many different driver genes/mutations

Cancer Genome Observations

Many tumor types per gene, per pathway, per drug
e.g., Imatinib (Gleevec)

Argues for off-label use of drugs based on genomic typing

rather than histopathological typing

Cancer Genome Observations

Tumors are highly combinatoric for driver genes
Additional genetic combinatorics from
metastasis
treatment side effect allele
resistance
Estimated we need to learn from 105 107 cases
TCGA is only 500 cases of each histologic-type
Requires a different approach

NCI Precision Medicine Approaches

Exceptional Responders
Initiative

Phenotype to Genotype

Exceptional Responders Initiative: Pilot Study

1-10% of patients respond well to drugs that do not
go on to receive FDA approval for that indication
Molecular mutations or changes in gene expression
may explain these exceptional responses
Inactive drugs are sometimes active in a subset of
patients
Could lead to development of predictive assays
Improve biologic understanding for better
therapeutics/diagnostic development

Exceptional Responders
Complete response lasting at least 6 months
Drug did not go on to FDA approval in that
indication due to insufficient activity
Tissue
Prefer just before drug treatment; otherwise any
prior
50% tumor
FFPE, Frozen, core acceptable
Normal: blood or other

Solicitation of Exceptional Responders Cases

Solicit Tissue Samples and Clinical Data Letters

to CTEP investigators for identified ER cases
Pharma
Cooperative Groups, U01 and N01 grants
Cancer Centers

Sites will be reimbursed for effort

Sample Submission and

Preparation
Central Biorepository: Nationwide Childrens
Hospital
Site
Receives
Samples

DNA transferred to
sequencing center
RNA & additional
tissue banked

Sequencing and Analysis of

Samples
Contract Existing TCGA Sequencing Center
Site
Receives
Samples

Sequenci
ng

Analysis

Data
submitted
to
database

Screening of Potential ER
Cases
Sites submit data through the CTSUs OPEN
Eligibility Stage
Synopsis:
Response
Treatment
info
Copy of
consent
form
Pathology
reports
Submitted
through
CTSU OPEN

Internal
NCI
review

Case is
not
exceptio
nal
Case is
exceptio
nal

Response
letter to
submittin
g
investigat
or
Request
sample
and data

NCI Precision Medicine

Approaches
Molecular Analysis for Therapy Choice
(NCI-MATCH)
Genotype to Phenotype

NCI-MATCH
Umbrella protocol for multiple, single-arm phase II
trials
Each molecular subgroup matched to a targeted agent

IND for protocol template arms could be added or

deleted without affecting other arms
Initially focused on single-agents (commercial or
experimental) Combinations will be considered for
targets that have validated combination targeted therapy
Need minimum dose/safety established in phase 1 trials

Study will be reviewed by the CIRB

NCI-MATCH
Identify mutations/amplifications/translocations
in patient tumor sample - eligibility determination
Assign patient to relevant agent/regimen
Tumor biopsies & sequencing at progression to
illuminate resistance mechanisms
De-identified samples submitted to central labs
Whole-exome sequencing (research purposes) to
detect non-ambiguous germline variants

NCI-MATCH - Eligibility
Solid tumors and lymphomas that have progressed
following at least one line of standard therapy
Exclude histologies from a given arm if already FDA
approved for that indication or lack of efficacy documented

Tumor accessible for biopsy and patient willing to

undergo biopsy
At least 18 years of age
Performance status ECOG 0-2
Adequate organ function

NCI-MATCH Patient population considerations

Target: at least 25% of total enrollment to be
patients who have rare tumors
Common defined as breast, NSCLC, colon,
prostate
Terminate enrollment to an arm if accrual on pace
to require > 5 years to accrue

SCHEMA of MATCH Trial

COURS
E
2

COURS
E
1

Genetic
sequencin
g

Actionabl
e
mutation
detected

Study
agent

Stable
Disease
(SD)1 for
6
months

Drug
holida
y

PD

Study
agent

Stable
diseas
e or
better
2

Complete
or partial
response
(CR+PR)1

Progressiv
e
disease
(PD)1

Continue
on
study
agent
until
progressi
on

Continue
on study
agent until
progressio
n

PD

Check for
Additional
actionabl
e
mutations
3

CR, PR, SD and PD as defined by RECIST

Stable disease is assessed relative to tumor status at re-initiation of
study agent
3
Rebiopsy; if additional mutations, ofer new targeted therapy
1
2

No
additional
actionable
mutations,
or withdraw
consent
Of
study

NCI-MATCH Levels of Evidence: Drugs

Level 1: FDA approved; evidence of target inhibition, or proof of
mechanism; demonstration that patient selection with CDx are more
likely to respond
Level 2: Agent met a clinical endpoint (objective response, PFS, or OS);
with evidence of target inhibition; plausible evidence of a predictive or
selection assay/analyte
Level 3: Agent demonstrated evidence of clinical activity with evidence of
target inhibition; some evidence of a predictive or selection assay/analyte
Level 4: Preclinical evidence of anti-tumor activity and evidence of target
inhibition; hypothesis for a predictive or selective assay/analyte

NCI-MATCH Levels of Evidence: Genes

Gene variants = target of an approved drug; and robust clinical data are
lacking re: efficacy in certain cancer subtypes harboring that variant.
Activating mutations in genes upstream of the molecular target of the agent
in the associated signaling pathway(s)
Inactivating mutations in genes that result in unique susceptibility to a
specific molecular point of intervention (e.g., BRCA1 mutation and PARP
inhibitors).
Other genes of interest that have appropriate justification for inclusion based
on scientific evidence regarding unique susceptibility to a specific molecular
targeted therapy (potential future drug targets, potential biological/clinical
interest).

NCI-MATCH - Assays
NGS: Ion Torrent PGM with custom Ampliseq
panel of 200-300 actionable genes
Validation in network of CLIA certified labs.
IHC, FISH?
Rule driven treatment assignment

Precision Medicine and Cancer

Examples from MCCC
on Medicine and Cancer

Molecular Diagnosis
Screening
Prognosis
Therapy

Precision Medicine and Cancer

Examples from MCCC
on Medicine and Cancer

Cologuard
A Precision Medicine Diagnostic Method
for Screening for Colon Cancer.

David Ahlquist, M.D.

Cologuard

Cologuard
Noninvasive stool-based DNA test
Targets Multiple Markers
Methylated BMP3 & NDRG4
Mutant KRAS
-actin (human DNA)
Hemoglobin

2010 MFMER | slide-31

N Engl J Med 2014; 370:1287-97

Cologuard
NEJM Screening Study
Cologuard + FIT prior to screening
colonoscopy
Topline Cologuard data
CRC
All

Sensitivity*

92%
Stage I-II
94%
Adv Precancer
All**
42%
>2 cm
66%
HGD
69%

Superiority over
FIT, all categories

*At specificity 90% (subset with normal colonoscopy) **Adv adenoma + serrated polyp >1cm

Precision Medicine and Cancer

Examples from MCCC
on Medicine and Cancer

Screening for Other Gastrointestinal Cancers

Esophageal Cancer
Gastric Cancer
Pancreatic Cancer
Hepatobiliary Cancer

Precision Medicine and Cancer

Examples from MCCC
on Medicine and Cancer

Screening for Gynecologic Cancers

Detection of endometrial cancer via molecular analysis of
DNA collected with vaginal tampons.
Jamie N. Bakkum-Gamez, Nicolas Wentzensen, Matthew J. Maurer,
Kieran M. Hawthorne, et al

Gynecologic Oncology 137 (2015) 1422

Precision Medicine and Cancer

Examples from MCCC
on Medicine and Cancer

Screening for Gynecologic Cancers

Genes hypermethylated in primary endometrial cancer
tumors can be detected in endometrial brushing and
tampon biospecimens.
Lower genital tract biospecimen collection via tampon was
well-accepted by women in this study.
Combining methylation analyses and a minimally-invasive
biospecimen collection may yield a novel screening test for
endometrial cancer.endometrial cancer

Precision Medicine and Cancer

Examples from MCCC
on Medicine and Cancer

Screening for Gynecologic Cancers

cancer

Gynecologic Oncology 137 (2015) 1422

Precision Medicine and Cancer

Examples from MCCC
on Medicine and Cancer

New Method in Screening - Liquid Biopsy:

Fragments of tumor cell somatic DNA shed into the circulation
or released when cells die can now be detected and counted, thanks
to advances in gene sequencing. This circulating tumor DNA (ctDNA)
is derived from somatic mutations that occur in the tumor during an
individual's life, unlike hereditary mutations that are present in every
cell in the body, so ctDNA is a specific cancer biomarker that can be
detected, measured, and tracked.
Monitoring ctDNA is expected to provide clinicians with faster, cheaper,
less invasive ways to assess cancer patients' clinical status and
response to therapy. ctDNA assay for multiple genes via nextgeneration sequencing (NGS) might become a "liquid biopsy"
alternative to invasive tissue biopsy,

Precision Medicine and Cancer

on Medicine and Cancer

Molecular Diagnosis
Screening
Prognosis
Therapy

Precision Medicine and Cancer

on Medicine and Cancer

Prognosis Molecular Markers in Neuro-Onc

Precision Medicine and Cancer

on Medicine and Cancer

Prognosis Molecular Markers in Neuro-Onc

Jenkins RB, Xiao Y, Sicotte H, et al: A low-frequency

variant at 8q24.21 is strongly associated with risk of
oligodendroglial tumors and astrocytomas with IDH1
or IDH2 mutation. Nat Genet. 2012; 44:1122-1125.

(Using next-generation sequencing, Robert Jenkins,

MD, PhD, and collaborators from Neuro-Oncology
Program and Brain SPORE identified a genomic
variant that carries a six-fold higher risk for developing
certain brain tumorsa discovery that could lead to
better diagnosis and treatment.)

Biomarkers
More robust biomarker
capability

SR: GA, BS
Grant: P50 CA108961

Increased Survival of Patients with Combined IDH and 1p/19q Co-deletion

Interactions with GERA Program

and UCSF
rs55705857 associated with
gliomas with IDH1/2 mutations
rs55705857 G Allele Increases Therapeutic Response

1p/19q co-deletion and IDH

mutation a better prognostic and
predictive factor 1, 2
First time a germline SNP has been
associated with response to therapy
in gliomas.

J Clin Oncol 20121; J Clin Oncol 2013, NEJM (in press)

Precision Medicine and Cancer

on Medicine and Cancer

Prognosis Molecular Markers in Hematologic-Onc

Vasmatzis G, Johnson SH, Knudson RA, Ketterling RP,
Braggio E, Fonseca R,Viswanatha DS, Law ME, Kip NS,
Ozsan N, Grebe SK, Frederick LA, Eckloff BW, Thompson
EA, Kadin ME, Milosevic D, Porcher JC, Asmann YW, Smith
DI, Kovtun IV, Ansell SM, Dogan A, Feldman AL. Genomewide analysis reveals recurrent structural abnormalities of
TP63 and other p53-related genes in peripheral T-cell
lymphomas. Blood. 2012 Sep 13; 120(11):2280-9. 2012

T-cell Lymphoma: Genomic Discovery

Validation in
163 Mayo Patients

Tumor

UNKNOWN
76%

DNA

Sequencing

ALK
10%
DUSP22
8%

TP63
6%

Discovered by Mayo Team (Feldman Lab)

T-cell Lymphoma: Genetic Risk

Overall Survival

ALK

DUSP22

Abnormality

Median Surv.

TP63
UNKNOWN
DUSP22
ALK

16 mos.
23 mos.
92 mos.
176 mos.

p=.0011 (log-rank)
Immediate needs:

UNKNOWN Genetics
TP63
Months from diagnosis

1. Identify genetics in 76% of

patients currently UNKNOWN
2. Individualize therapy based
on genetic risk

Precision Medicine and Cancer

on Medicine and Cancer

Molecular Diagnosis
Screening
Prognosis
Therapy

Mayo Vision for Genomic-Based Therapy

Individualized cancer therapy based on genome
sequence (host and the tumor)
Identification of genomic alterations associated with
chemotherapy response to be used as a template
for drug development
Individualized genome sequence guided adaptive
therapy could be extended to many other cancers

BEAUTY - Breast Cancer Genome

Guided Therapy Study

PIs: Matthew Goetz, Judy Boughey

Lab PI: Liewei Wang
Lab team: Eric Wieben, Dick Weinshilboum, James Ingle,
Jia Yu, Minetta Liu
Pathology team: Dan Visscher, Ann Moyer
Radiology team: Amy Conners, Katie Jones
Genetic counselor: Marissa Ellingson
Stats team: Vera Suman, Travis Dockter, Krishna Kalari, Steve Hart,
Hugues Sicottes, Jason Sinnwell, Peter Vedell, Xiaojia Tang and Kevin
Thompson
Arizona team: Don Northfelt, Rick Gray
Florida team: Alvaro Moreno, Sarah McLaughlin

Breast Cancer Genome Guided

Therapy study (BEAUTY)
Paclitaxel +
Trastuzumab +/Pertuzumab

HER2+
140 women with
invasive breast
cancer

AC or EC or
FEC

Chemotherapy 1
Paclitaxel (ER+) and
HER2- +/- Carboplatin (triple
negative)

AC or EC or
FEC

Magnetic Resonance Imaging

(MRI)

Magnetic Resonance
Imaging (MRI)

Molecular Breast Imaging

(MBI)

Molecular Breast
Imaging (MBI)

Tumor biopsy

Tumor biopsy

Mouse avatars (xenografts)

Genomic sequencing

Genomic sequencing

Blood sample

Blood sample

Surgery

Chemotherapy 2

MRI
MBI

5 year
observation

Tumor tissue
Mouse avatars
(xenografts)
Genomic sequencing
Blood sample

Breast Cancer Genome Guided Therapy (II)

High-risk
invasive breast
cancer
considered for
neoadjuvant
chemotherapy

Paclitaxel +
trastuzumab
+/pertuzumab
Paclitaxel +/carboplatin

AC
cycles
1+2

Tumor
biopsy,
ptDNA and
imaging to
identify nonresponders

Identify
actionable
alterations

Target
identified, drug
available:

Nonresponder

No target or no
drug

Responder

Tumor biopsy
Xenografts
Genomic sequencing

Novel agent
window
study

Sequencing complete and

identification of target and
drug: 2-3 weeks

complete 3rd
and 4th cycle
of AC

S
U
R
G
E
R
Y

Other Tumor Types

PROMOTE Study - (PROstate Cancer
Medically Optimized Genome Enhanced
ThErapy)
This is second Genome-Guided Study at
MCCC

Mouse Avatars
Opportunity to test individual or combinations of
drugs51.9%
against human tumors implanted in
41.7%
immunocompromised
mice.
drugs
Valuable for precision-based
27.3%

this approach at MCCC.

Many examples using17.4%

Precision Medicine and Cancer

Questions