1. 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

2. 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

3. Opportunities to Increase Cancer Survival
Normal tissue
Distant cancer spread
Malignant tissue
Death
Early detection Early treatment
Prevention
Treatment
Somatic
Genetic Risk Assessment
Germline
Genetic testing for cancer risk susceptibility
Increased focus on early detection and prevention
Tumor molecular profiling & targeted therapies 3

4. 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

5. 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

6. 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.

7. The Development of Hereditary Cancer
Nonhereditary
2 normal genes
Hereditary
Mother or Father
1 damaged gene
1 normal gene
1 damaged gene
1 normal gene
1 damaged gene
1 normal gene
Loss of normal gene
Loss of normal gene

8. Sporadic vs. Familial vs. Hereditary Cancer
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 % of cancers
recognizable inheritance pattern (usually autosomal dominant)
early age of onset, multiple primary cancers
identified germline genetic alterations

9. 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

10. Autosomal Dominant Inheritance
Each child has 50% chance of inheriting the mutation
No “skipped generations”
Equally transmitted by men and women
Cancer
Normal

11. more typical . . .
Affected
Normal

12. 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

13. Age-Specific Penetrance
Percentage of individuals with an altered disease gene who develop the disease 20 40 60 80
100
Affected with colorectal cancer (%)
HNPCC mutation carriers
General population

14. Inherited Cancer Syndromes
Autosomal Dominant
Inherited Cancer Syndromes
• Breast and Ovarian Cancer BRCA1&2
• Colon Cancer and Polyposis
HNPCC MMR
FAP APC
Polyposis MYH
Cowdens PTEN
Peutz-Jehgers STK11
Juvenile Polyposis SMAD4
BMPR1A
• Other GI Cancers
Gastric CDH1
Pancreas p16
• MEN1 Menin
• MEN2/MTC RET
• VHL VHL
• Li-Fraumeni p53

15. 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?

16. Genetics of Colorectal Cancer
Syndrome
Gene(s)
Lynch syndrome
MLH1, MSH2, MSH6, PMS2, EPCAM
Adenomatous polyposis
Familial Adenomatous Polyposis(FAP)
APC
Attenuated FAP
MYH-associated polyposis
MYH (biallelic)
Hamartomatous polyposis
Peutz-Jeghers Syndrome
STK11
Juvenile Polyposis Syndrome
SMAD4/BMPR1A
Cowden Syndrome
PTEN

18. Categories of colorectal cancer (CRC)
Sporadic (~65%)
Familial
Unknown gene (~30%)
Rare CRC syndromes (<0.1%)
Hereditary Nonpolyposis Colorectal Cancer (Lynch) (5%)
Familial Adenomatous Polyposis (FAP) (1%)

19. 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

20. Contribution of Gene Mutations to HNPCC Families
Sporadic
Familial
Unknown ~30%
MSH2 ~30%
HNPCC
Rare CRC syndromes
FAP
MLH1
~30%
MSH6 (rare)
PMS2 (rare)

21. Cancer Risks in HNPCC 100 % with cancer 80 60 40 20 20 40 60 80
Colorectal 78% 60
Endometrial 43% 40
Stomach 10% 20
Urinary tract 10%
Biliary tract 15%
Ovarian 9% 20 40 60 80
Age (years)

22. 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 , repeat every 2 – 3 years
Renal/Ureteral
Urine cytology
Annually, starting at age 30

23. Colonoscopy Improves Survival of Genetically-Confirmed HNPCC
92.2%
Surveillance
73.9%
100 80
No surveillance 60 40 5 10 15
Follow-up time (years)

24. Familial Risk for Common Cancers

25. New Paradigm in Cancer Treatment: Targeted Therapy
Cancer Patient
Robust Clinical Tumor
Genotyping Assays
Clinical Information
Routine Pathology
Molecular Pathology
Targeted Therapy

26. Cancer Genomic Profiling and Treatment: A New Paradigm
Words
More words d
Use repeat liquid biopsies
To monitor response and assess
Mechanisms of resistance

27. Genomic Profiling: What to Expect
Vogelstein et al.
Cancer Genome Landscapes. Science (2013)

28. Slide 4

29. Miller et al, Foundation Medicine, ASCO 2013. Abstract 11020

30. Stanford Molecular Tumor Board Workflow
CLIA Lab
Research Lab
Referral to Cancer Genomics Service
Molecular analysis (NGS)
Research Consent
Coordinator
Analytics & Informatics
Genetic Counseling
Tumor Biopsy
Molecular Tumor Board
Identify Drug
Drug Approval
Pathology
Tissue Bank
Treatment
Clinical f/u
Sample Prep
Results and Treatment

31. Genomic testing for patients: example report

32. 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

33. [TITLE]

34. 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

35. Tumor Heterogeneity

36. Tumor Heterogeneity

37. Tumor Heterogeneity

38. Liquid Biopsies

39. CAPP-Seq Liquid Biopsy Applications: Target Biomarkers

40. Slide 29

41. 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

42. 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)

43. 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

44. Clinical Outcomes: Intermountain Cohort Study
Standard Treatment
Cohort
Genomic Treatment
Cohort
Matched
Age
Gender
Diagnosis
#Previous trx
- No Sequence
- Chemo
- Sequence
- Targeted Trx
Compare Outcomes:
1° Progression Free Survival
2° Cost of Care
Adverse Events
Quality of Life

45. Cost of Care: Traditional: 12.0 weeks Targeted: 23.9 weeks
Progression Free Survival:
Traditional: weeks
Targeted: weeks
Cost of Care:
HR: 0.53, p<0.002
Traditional: $3,473/wk
Targeted: $3,023/wk
p= 0.22
Nadauld (IMH), Ford (Stanford) et al. ASCO 2015

46. 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!

47. Patient Case: Colon Cancer

48. 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

49. 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

50. 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