Download The Development of Hereditary Cancer

Genetics 202: Clinical Cancer Genetics
James Ford, M.D., Associate Professor of Medicine (Oncology),
Pediatrics (Medical Genetics) and Genetics
Director, Stanford Program for Clinical Cancer Genetics and Genomics
Nicki Chun, M.S. Genetic Counselor, Stanford Cancer Genetics Clinic
Assistant Professor of Pediatrics - Genetic Counseling
Learning Goals
•
Understanding sporadic v. familial v. hereditary cancers
•
Patterns of inheritance of hereditary cancer risk
•
Characteristics of inherited cancer syndromes
•
Goals of genetic counseling and testing for cancer syndromes
•
Diagnosis and management of Hereditary GI cancer syndromes
• HNPCC – Lynch syndrome
• HBOC
• Gene Panels
•
Targeting BRCA mutant tumors for therapy with PARP inhibitors
•
DNA sequencing and rare genetic variants – going forward
•
Cancer Genomics – profiling tumors and personalized oncology
Opportunities to Increase Cancer Survival
Normal
tissue
Genetic Risk
Assessment
Malignant
tissue
Prevention
Distant
cancer
spread
Early detection
Early treatment
Death
Treatment
Somatic
Germline
 Genetic testing for cancer risk susceptibility
 Increased focus on early detection and prevention
 Tumor molecular profiling & targeted therapies
Personalized Medicine in Cancer:
Risk Assessment and Prevention
 Identification of germline and familial genetic alterations that
increase risk of cancer
 Development of targeted screening and early detection
techniques prevent development of advanced cancers
 Incorporation of moderate and low-penetrant, common
genetic variants in risk prediction and modification
Personalized Medicine in Cancer:
Tumor Profiling and Therapeutics
 Identification of genetic alterations that drive carcinogenesis
 Disease stratification for better prognostic/predictive
markers
 Development of drugs that can effectively inhibit the function
of these genetic alterations
 Molecularly targeted therapies to be used consistently and
effectively in patients with cancer
 Assessment and prediction of drug resistance mechanisms
Genetic Theory of Cancer
•
Cancer is a genetic disease
•
Most cancers have mutations in multiple genes
•
The underlying defect in cancers is Genomic Instability
•
Cancers require alterations in genes involved in
cellular proliferation, cell cycle, apoptosis, telomere
maintenance and DNA repair
•
Most inherited cancer syndromes are due to alterations
in genes required for genomic stability.
The Development of Hereditary Cancer
Nonhereditary
Mother
or
Father
Hereditary
1 damaged gene
1 normal gene
2 normal genes
1 damaged gene
1 normal gene
Loss of normal gene
1 damaged gene
1 normal gene
Loss of normal gene
Characteristics of Inherited Cancer Syndromes
Sporadic vs. Familial vs. Hereditary Cancer
Sporadic Cancers
account for the vast majority of tumors
occur without marked family history or early age
Familial Cancers
5 - 20% of most common tumors show familial clustering
may be due to chance, shared environmental factors or genes
Hereditary Cancers
account for 5 - 10% of cancers
recognizable inheritance pattern (usually autosomal dominant)
early age of onset, multiple primary cancers
identified germline genetic alterations
Cardinal Features of Hereditary Cancers
•
Early age of cancer onset
•
Multiple primary cancers showing specific combinations within
the patient’s family
•
Excess of multifocal, bilateral or multiple primary cancers
•
Physical stigmata
•
Distinctive pathological features
•
Occasional differences in survival and clinical severity
•
Dominant pattern of transmission, with marked variability in
phenotypic expressivity and gene penetrance
Autosomal Dominant Inheritance

Each child has 50%
chance of inheriting
the mutation

No “skipped
generations”

Equally transmitted by
men and women
Normal
Cancer
more typical . . .
Normal
Affected
Most Cancer Susceptibility Genes Are
Dominant With Incomplete Penetrance
Normal
Susceptible Carrier
Carrier, affected
with cancer
Sporadic
cancer



Penetrance is often incomplete
May appear to “skip” generations
Individuals inherit altered cancer susceptibility gene,
not cancer
Age-Specific Penetrance
Percentage of individuals with an altered
disease gene who develop the disease
100
Affected
with
colorectal
cancer (%)
80
HNPCC
mutation
carriers
60
40
General
population
20
0
0
20
40
60
80
Autosomal Dominant
Inherited Cancer Syndromes
• Breast and Ovarian Cancer
• Colon Cancer and Polyposis
HNPCC
FAP
Polyposis
Cowdens
Peutz-Jehgers
Juvenile Polyposis
• Other GI Cancers
Gastric
Pancreas
BRCA1&2
MMR
APC
MYH
PTEN
STK11
SMAD4
BMPR1A
CDH1
p16
• MEN1
Menin
• MEN2/MTC
RET
• VHL
VHL
• Li-Fraumeni
p53
Hereditary Susceptibility to Cancer
• Who to test for genetic susceptibility?
• What are the risks of cancer associated with known
genetic mutations?
• What can be done to prevent cancer in unaffected
carriers?
Genetics of Colorectal Cancer
Syndrome
Gene(s)
Lynch syndrome
MLH1, MSH2, MSH6,
PMS2, EPCAM
Adenomatous polyposis
Familial Adenomatous Polyposis(FAP)
APC
Attenuated FAP
APC
MYH-associated polyposis
MYH (biallelic)
Hamartomatous polyposis
Peutz-Jeghers Syndrome
STK11
Juvenile Polyposis Syndrome
SMAD4/BMPR1A
Cowden Syndrome
PTEN
Colorectal Multistep Carcinogenesis
Chromosomal Instability
APC
Normal
Colorectal
Epithelium
K-ras
Early
Adenoma
hMSH2
hMLH1
MMR
DCC
p53
Intermediate
Adenoma
Advanced
Adenoma
??
Colorectal
Carcinoma
??
Invasive
Carcinoma
TGFBRII MSH3
APC
IGFIIR
MSH6
BAX
PTEN
Microsatellite Instability
??
??
Metastatic
Carcinoma
Categories of colorectal cancer (CRC)
Sporadic
(~65%)
Rare CRC
syndromes
(<0.1%)
Familial Adenomatous
Polyposis (FAP) (1%)
Familial
Unknown gene
(~30%)
Hereditary
Nonpolyposis
Colorectal Cancer
(Lynch) (5%)
Clinical Features of Lynch Syndrome
 Early but variable age at CRC
diagnosis (~45 years)
 Tumor site in proximal colon
predominates (2/3rds)
 Extracolonic cancers: endometrium,
ovary, stomach, urinary tract, small
bowel, bile ducts, brain, sebaceous
skin tumors
 Autosomal pattern of inheritance
Contribution of Gene Mutations to HNPCC Families
Sporadic
Familial
Unknown
~30%
MSH2
~30%
HNPCC
Rare CRC
syndromes
FAP
MSH6
(rare)
PMS2 (rare)
MLH1
~30%
Cancer Risks in HNPCC
100
80
%
with
cancer 60
Colorectal 78%
Endometrial 43%
40
Stomach 10%
Urinary tract 10%
Biliary tract 15%
Ovarian 9%
20
0
0
20
40
60
Age (years)
80
Surveillance Options for LS Mutation Carriers
Malignancy
Intervention
Recommendation
Colorectal Cancer
Colonoscopy
Begin at age 20 – 25,
repeat every 1 – 2 years
Endometrial Cancer
Transvaginal ultrasound
Endometrial aspirate
Annually, starting at age 35
Gastric Cancer
EGD
Begin at age 30 - 35,
repeat every 2 – 3 years
Renal/Ureteral
Urine cytology
Annually, starting at age 30
Colonoscopy Improves Survival of
Genetically-Confirmed HNPCC
Surveillance
100
92.2%
80
No surveillance
73.9%
60
40
0
5
10
Follow-up time (years)
15
Familial Risk for Common Cancers
New Paradigm in Cancer Treatment:
Targeted Therapy
Robust Clinical Tumor
Genotyping Assays
Cancer Genomic Profiling and Treatment:
A New Paradigm
 Words
–More words
 Words
–More words
d
Use repeat liquid biopsies
To monitor response and assess
Mechanisms of resistance
Genomic Profiling: What to Expect
Vogelstein et al.
Cancer Genome Landscapes. Science (2013)
Slide 4
Miller et al, Foundation Medicine, ASCO 2013. Abstract 11020
Stanford Molecular Tumor Board Workflow
Referral to
Cancer
Genomics
Service
Tumor Biopsy
Pathology
Sample
Prep
Research
Consent
Coordinator
Tissue Bank
Molecular
analysis
(NGS)
Analytics &
Informatics
Molecular
Tumor Board
Results and
Treatment
CLIA Lab
Research Lab
Genetic
Counseling
Identify Drug
Drug Approval
Treatment
Clinical f/u
Genomic testing for patients: example report
Challenges: Cancer Genomic Medicine
 Genomic targets are rare
 Need for common, cost-effective NGS diagnostics / databases
 Effective targeted therapies; predictive biomarkers
 Small sample sizes; alternative endpoints
 Tumor Heterogeneity
 Drug Resistance
 Incidentalome
[TITLE]
Challenges: Cancer Targets
 ER Pathway (GATA3, FOXA1, RUNX1)
 PI3K Pathway (PIK3CA, AKT, mTOR, PTEN)
 MAP3K, JNK, ERK
 Cyclin D, CDK4/6
 Epigenetic Pathways
 MDM2/p53
 DNA Repair Pathways
 FGFR
 Notch
 HER2
Tumor Heterogeneity
Tumor Heterogeneity
Tumor Heterogeneity
Liquid Biopsies
CAPP-Seq Liquid Biopsy Applications: Target Biomarkers
Slide 29
Molecularly-guided Trials
 Trials in Progress
–Lung MAP – lung squamous cell carcinoma
–FOCUS4 – First-line metastatic colorectal
–MODUL - First-line metastatic colorectal
–SIGNATURE – not disease-specific
–MyPathway – not disease-specific
 Evolving Trials
–MATCH – Any line –not selected by primary site
–ASSIGN – 2nd line colorectal – Phase II/III
Barriers to Personalized CA Therapy Trials





Escalating regulatory burden
Access to approved drugs off label
Access to investigational agents
Tracking patient outcomes
Need for new clinical trial paradigms
–Prospective randomized vs. observational
–Retrospective observational (exceptional responders)
Indirect Results: Tumor Whole-Genomes
Coming soon . . . .
 Tumor and germline DNA sequence mostly identical
 Medical significance of Incidental Genomic Findings
often unclear – non-syndromic, penetrance?
 Germline Variants that will be found in tumors:
Disease genes, Disease risk, drug response, VUS
 Guidelines for “Actionable”
 Ethics – obligation to inform
 Consent – opt-in versus opt-out
Clinical Outcomes: Intermountain Cohort Study
Standard
Treatment
Cohort
Matched
Age
Gender
Diagnosis
#Previous trx
- No
Sequence
- Chemo
Genomic
Treatment
Cohort
- Sequence
- Targeted
Trx
Compare Outcomes:
1° Progression Free
Survival
2°
Cost of Care
Adverse Events
Quality of Life
Progression Free Survival:
Traditional: 12.0 weeks Targeted: 23.9 weeks
Cost of Care:
Traditional: $3,473/wk
HR: 0.53, p<0.002
Targeted: $3,023/wk
p= 0.22
Nadauld (IMH), Ford (Stanford) et al. ASCO 2015
Cancer Genomics Tumor Board Case
 49 yo male with widely metastatic CRC – lungs, liver, colon.
Progressed through Xelox/Bev, Xeliri, Irinotecan/Cetuximab.
 Liver biopsy sent for sequencing
–HER2 amplification
–APC mutation
–P53 splice site alteration
 Trial of Herceptin – no effect
 Trial of TDM-1 -> Responding!
Patient Case: Colon Cancer
Future Directions: Germline
 Genotyping carriers for more accurate risk assessment
 Multigene panels / NGS for diagnosis
 Exome / WGS for “mystery” families
 Identification of novel moderate penetrant genes
 Calculating risk of multiple low-penetrant alleles
 VUS: ethnic/racial groups, functional studie
Future Directions: Germline
 Genotyping carriers for more accurate risk assessment
 Multigene panels / NGS for diagnosis
 Exome / WGS for “mystery” families
 Identification of novel moderate penetrant genes
 Calculating risk of multiple low-penetrant alleles
 VUS: ethnic/racial groups, functional studie
Future Directions: Somatic Tumors
 Tumor profiling and genotyping will identify more targets
 Gene panels vs. exomes vs. WGS
 Targeting multiple alterations simultaneously
 Clinical trials to assess outcomes
–genomic v. empiric; exceptional responders; bucket-trials
 Non-invasive DNA sampling
 New technologies and informatics
 Clinically oriented genomics programs