what oncologists can learn from their genetics...

City of Hope Comprehensive Cancer Center and Beckman Research Institute

Jeffrey N. Weitzel, M.D.

Professor of Oncology and

Population Sciences

Director, Department of Clinical

Cancer Genetics

What Oncologists Can

Learn from Their

Genetics Colleagues:

Genomics and Cancer

Risk Assessment

Cancer Screening & Prevention Program

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CCG%20program%20overview/NCBC%20Weitzel%202007.ppt#19. Slide%2019

• I do not have any financial arrangements or

affiliations with any corporate organization

relating to the topic being presented

• I will not be discussing off label drug use

DISCLOSURES

Advancing

Age Genetics

Alcohol

Lack of

Exercise

Hormone

Replacement

Therapy

Overweight

Gender

???

Passive

SmokeLate

Menopause

Close

Relative

Age at

First Birth

Benign

Breast Disease

Early

Menarche

Risks Related to Cancer

Ionizing

Radiation

Chemicals

-Work

-Home

-Garden

-Recreation

Diet

Education & Income

Genetics

Kesselheim A and Mello M. N Engl J Med 2010;10.1056/NEJMp1004026

Timeline of Important Events in DNA Patenting (Top) and the Discovery and Use

of Genes Conferring Susceptibility to Breast and Ovarian Cancer (Bottom)

June 2013 - U.S. Supreme

Court rules that as nature,

genes cannot be patented

BRCA1- and BRCA2-Associated Cancers: Lifetime Risk

Breast cancer 50%-85% (often early age at onset)

Second primary breast cancer 40%-60%

Ovarian cancer 15%-45%

Absolute risk likely to be higher than 10%

- Prostate cancer

Absolute risk 10% or lower

- Male breast cancer

- Fallopian tube cancer

- Pancreatic cancer

BRCA1 mutations are

prevalent in patients with

triple negative breast

cancer (5-21%) and

medullary breast cancer

Contralateral Breast and Ovarian Cancer Risk in 491 BRCA Carriers

Contralateral breast cancer risk variables:

BRCA2 (v BRCA1): HR 0.73; 95% CI 0.47-1.15

Age 50 at diagnosis: HR 0.63; 95% CI 0.36-1.10

Tamoxifen use: HR 0.59; 95% CI 0.35-1.01

Oophorectomy: HR 0.44; 95% CI 0.21-0.91

10-year risk without Tamoxifen or Oophorectomy:

• 43.4% for BRCA1

• 34.6% for BRCA2

Ovarian cancer risk after breast cancer: 12.7% for BRCA1, 6.8% for BRCA2 (p=0.03)

Ovarian cancer was the cause of death in 25% of the Stage I breast cancer patients

Metcalfe et al. J Clin Oncol 2004, 22:2328-2335; Gyn Onc 2005; 96:222-226

Contralateral Breast and Ovarian Cancer Risk in Absence of Major Predisposition

Contralateral breast cancer risk:

On average for sporadic disease, 0.5% per year

Higher risk if young age (<35)

Modestly higher risk for lobular histology

Moderate risk genes (e.g., CHEK2) Ten year risk ~ 10-20%

Tamoxifen (or other adjuvant hormonal Rx) reduces risk

Ovarian cancer risk after breast cancer not measurably elevated if BRCA neg and no FHx

S. Narod. Bilateral Breast Cancers. Nature Reviews Vol 11:157-166, 2014

BRCA1 and BRCA2

On chromosomes 17 and 13, respectively

Autosomal dominant transmission

Proteins have a role in genomic stability

>2,000 different mutations, polymorphisms, and

variants distributed over both genes

Nonsense Missense Splice-site

BRCA1

Br-47

41

3123 33

Ov-3847

81

Br-45

Br-Pm

43

30

Br-49

28 25

45

21 2524 18261 99 11

Pr-50

71

Br-Pm

HEREDITARY BREAST AND OVARIAN CANCER

+ -+Negative =

Uninformative

Contribution of Known Genes to Explaining

Familial Aggregation of Breast Cancer

Other familial risk factors

(genes, environment)

BRCA1

BRCA2

TP53

PTEN

ATM

CHEK2,BRIP1,PALB2

8 WGA SNPs

CASP8

Results of a

combined analysis

of 154 families:

• good estimate of

BC risk (greater

with + family Hx)

• Inadequate data

to determine

magnitude of

increased OC

risk

Li-Fraumeni Syndrome (LFS)

Bilateral Breast, 40

Leukemia, 33

Brain tumor, 32

Breast, 38Osteosarcoma, 42

Breast, 25

Soft tissue sarcoma, 7

Leukemia, 6

Affected with cancerOften triple positive BC

TP53-mutation carrier

50

LFS Core Cancers:

Brain tumors (choroid plexus)

Sarcoma (rhabdoid, lipo)

Adrenal cortical carcinoma

Breast cancer (young onset)

She has breast cancer – Why the mouth?

Cowden Syndrome Pedigree

Multinodular goiter,

dx 25

Follicular thyroid

cancer, dx 35

Trichilemmomas, dx 21

Breast cancer, dx 35

Macrocephaly

Papillomatous papules

Multinodular goiter, dx 22

Affected

Noncarrier

Eng C. J Med Genet. 2000;37:828-830

Risk for uterine,

but not ovarian

cancer in CS

Major criteria:

• Breast cancer

• Thyroid cancer, usually follicular

• Macrocephaly

• Pathognomonic mucocutaneous lesions: facial trichilemmomas,

papillomas of tongue, oral mucosa

• Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma)

• Endometrial cancer

Clinical Management of Mutation-Positive Patient

Positive high penetrance

gene test result

Possible testing for

other adult relatives

Increased

surveillance

Prophylactic

surgery

Targeted

Therapy

Chemo-

prevention

“Angelina Jolie’s

double mastectomy

puts genetic testing

in the spotlight”

Study of 483 BRCA

carriers: >90% risk

reductionRebbeck, T.R., et al. JCO

22:1055, 2004

An effective intervention:

Warner et al. JCO 19:3524-3531, 2001

Cumulative incidence of early-stage (stages 0 to I) breast cancer in magnetic resonance imaging

(MRI) –screened cohort and comparison group (competing risk model).

Warner E et al. JCO 2011;29:1664-1669

Diagnosis stage 0-I

Oophorectomy Reduces

Ovarian Cancer, Breast Cancer,

and all cause mortality

Greatest breast cancer risk

reduction among BRCA1

mutation carriers without a prior

dx of breast cancer who had

their oophorectomy < age 50

HR: 0.15 (95% CI 0.04-0.63)

Fanconi Pathway and Contribution of Genomic Stability

Genes to Hereditary Breast and Ovarian Cancer

Synthetic Lethality, BRCA Status and PARP Inhibition

McLornan DP et al. N Engl J Med 2014;371:1725-1735.

Genetic Cancer

Risk Assessment

PreventionTreatment

Oncologic

Consultation

Decisions, decisions…

Somatic/Tumor Genomics – Precision Rx and Germline implications

Homologous Recombination (HR) Gene Mutations in

Ovarian Cancers and Association with Platinum Sensitivity

Pennington K P et al. Clin Cancer Res 2014;20:764-775

• Overall response rate of 33% (16/49)

• Next-generation sequencing identified loss

of function mutations in DNA-repair genes

(n=16); BRCA2 (n=4)

• The response rate was 88% (14/16) among

patients with tumors with defects in DNA

repair genes (P < .001)J. Mateo, et al. NEJM 2015

Schema of Personalized Oncologic Medicine

MacConaill L E , Garraway L A JCO 2010;28:5219-5228

Frequent somatic and

germline gene mutations in:

(A) colorectal,

(B) gastric

(C) pancreatic cancers

Elena M. Stoffel JCO doi:10.1200/JCO.2014.60.6764

MacConaill L E JCO 2013;31:1815-1824

Advances in Massively Parallel Technologies Have

Dramatically Reduced the Cost of Sequencing

How Much Breast and Ovarian Cancer Is Hereditary? It Is a Different Answer with Multiplex Testing

Sporadic

Family clusters

Hereditary

Ovarian CancerBreast Cancer

~5% 15-24%

15% -20%

Proportions Ovarian, Fallopian Tube, or Peritoneal Cancer

Patients with Respective Germ-Line Loss-of-Function Mutations

Walsh T et al. PNAS 2011;108:18032-18037

Cancer Risks in Lynch Syndrome

ASCOAarnio M et al. Int J Cancer 64:430, 1995

% with

cancer

100

80

60

40

20

020 40 60 800

Age (years)

Colorectal 78%

Endometrial 43%

Stomach 19%Biliary tract 18%

Ovarian 9%

Genetic Heterogeneity and Overlapping

Phenotypes = Expanded Differential Diagnoses

Pancreatic

Breast

MelanomaColon

CDKN2A

BRCA2

PALB2

PRSS1

ATM

CHEK2

MMR

Ovarian

Uterine

Breast

BRCA1

BRCA2

PALB2

RAD50

RAD51D

BRIP1

MRE11A

BARD1

RAD51C

PTEN

TP53

STK11

ATM

CHEK2

CDH1MMR

• Could be either

parental lineage

• Magnitude of

ovarian cancer

risk not yet clear

• Need to think

about pancreatic

cancer risk too

Cancer Panel Genes, Stratified by Relative Risk

Cancer

Site

High Relative

Risk (≥5.0)

Moderate

(≥1.5 and <5.0)

Low Relative Risk

(≥1.01 and <1.5)

Breast

TP53, PTEN,

STK11, CDH1,

BRCA1,

BRCA2

CHEK2, ATM,

PALB2, BRIP1

AXIN2, BAP1, BARD1, MRE11A,

NBN, RAD50, RAD51C,

XRCC2, RAD51D

Colon

rectum

APC, MLH1,

MSH2, MSH6,

PMS2

CHEK2

AXIN2, BMPR1A, CDH1, DCC,

EPCAM, EXO1, MUTYH,

PDGFRA, PMS1, PTEN,

SMAD4, STK11, TP53

Ovary

RAD51D,

RAD51C,

BRCA1,

BRCA2

MLH1, MSH2,

MSH6, PALB2

BRIP1

ATM, AXIN2, BARD1, BRIP1,

EPCAM, MRE11A, MUTYH,

NBN, PALB2, PMS2, RAD50, ,

STK11, TP53

Weitzel et al. Genetics, Genomics, and Cancer Risk Assessment: State of the Art and

Future Directions in the Era of Personalized Medicine. CA Cancer J Clin 2011;61:327–359

Suggested Guidance, Pending Real Data

• ASCO affirms that it is sufficient for cancer risk assessment to

evaluate genes of established clinical utility that are suggested by

the patient’s personal and/or family history.

• Because of the current uncertainties and knowledge gaps,

providers with particular expertise in cancer risk assessment should

be involved in the ordering and interpretation of multigene panels

Clinical Management of High-Risk Breast Cancer Susceptibility Gene Mutation-Negative Patients

Negative BRCA and/or multigene panel test

Member of family w/ known high penetrance mutation?

YESNO

Emphasize empirically increased risk of breast and/or ovarian cancer

(moderate risk gene overlap)

Provide individualizedrisk-management plan

Encourage adherence to population screening

guidelines

Emphasize risk of sporadic cancer

• There is clearly a potential to benefit carefully

selected and counseled families, with ever

broader arrays of genetic tools and precision Rx

• PALB2 is among the first rare variant genes to

acquire adequate data for absolute risk estimation

• Genetic technologic advances are changing diagnostic approaches; discerning germline and somatic mutations is an emerging challenge

• Surveillance and prevention can improve survival in at-risk individuals

• Protocols will need to be adapted to lower risk

Cancer Screening & Prevention Program

Hereditary Cancer Risk Assessment and Management

City of Hope Clinical Cancer Genetics Team

Lung Cancer Screening

Dan J. Raz, M.D.Co-Director, Lung Cancer Screening Program

Co-Director, Lung Cancer and Thoracic Oncology ProgramAssistant Professor, Thoracic Surgery

City of Hope

Disclosures

Consultant, Cireca LLC

Outline

–Update on lung cancer screening

–Challenges with lung cancer screening

–Surgery for early stage lung cancer

–High risk patients

Annual U.S. Lung Cancer Deaths

Stage of Lung Cancer at Diagnosis

Stage IV 40%Stage I 20%

Stage II 10%

Stage IIIa 15%Stage IIIb 15%


Early Lung Cancer Action Program (ELCAP)

– Low dose CT scan of the chest

– 80% of lung cancers detected stage I

– 85% of stage I patients treated cured

– Decrease lung cancer deaths by about 60%• Save 82,000 lives/year

• 224 lives every day

• Mammography: 15% reduction in breast cancer deaths


RCT, n= 53,454 : LD CT vs CXR x 3 years

NLST criteria:Age 55-74>30py smoker or former smokerQuit <15 yrs ago if former smokerNo symptoms of lung cancer

NLST: Lung Cancer CT Screening

– Baseline + 2 yearly screens

– 20% relative reduction in lung cancer mortality

– 7% all cause mortality reduction

– 367/1060 lung cancers detected diagnosed after screening phase

NLST: Lung Cancer CT Screening

Other Benefits of LDCT

• Tobacco cessation

• Coronary calcification

• Emphysema

• Aortic aneurysm

Potential Harms

• Cost

• False positives

– Unnecessary invasive testing

– Anxiety

• Radiation

• ‘Overdiagnosis’

• License to smoke

NLST: Costs

– 24% “positive” (4mm nodule cutoff) 16% with 5mm• 96% false positive

• Definition of positive vs indeterminate

• Invasive testing among positives:– 2% needle biopsy

– 4% bronchoscopy

– 4% surgical procedure

– Adverse events• 16 patients died with 90d of invasive procedure (<0.1%)

• 10 had lung cancer (of 1060 lung cancers)

• Radiation related deaths or morbidity

Henschke, Ann Intern Med 2013

ELCAP:False positives reduced by raising nodule threshold.

No cancers missed by raising from 4mm to 6mm.

ACR Lung RADS


IS COST EFFECTIVE

Milliman 2012, Health Affairs:

Cost per year of life saved =$19,000

Cost for mammography=$30-50,000

Cost for screening population=$0.76 per member/month

Cost for mammography=$3.16 per member/month

Cost Analysis: NLST

• Included cost of treating ‘radiation induced lung cancer’

Black et al. NEJM 2014

Effective Radiation Dose

• Chest xray 0.1 mSv

• Mammogram 0.7 mSv

• Low-dose CT 1 mSv

• IV Contrast CT 8 mSv

• CTA (PE) 15 mSv

• PET/CT 25 mSv

3 mSv= background x1yr

FBP VeoASiR

Courtesy of Dr. A. Rotter, COH RadiologyCXR effective dose is about 0.06 mSv.”

Imas courtesy of Pr De Mey,

Universitair Ziekenhuis Brussels, Belgium

Source: Health Physics Society.http://www.hps.org/publicinformation/ate/q2372.html

*Obtained by ICRP using a chest factor of 0.014DLP

100 kVp, 10 mA, 0.4 rotDLP 6.3, 0.09 mSv*

0.625mmRoutine chest CT at nearly chest X-ray dose - 0.09 mSv

False Positives: Anxiety

• NLST: No difference in anxiety/HRQOL at 1 or 6 months in positive vs negative

• NELSON: Anxiety in both groups, higher at 2 months in those with positives

• No information on diverse populations, sex differences, mental illness

COH LCS Video Education Pilot

• Patients randomized in blocks of 5 to video/written education or standard counseling

• What is a nodule?

• What happens if you have a nodule detected?

• What are the odds of needing additional testing?

• Survey tools

Overdiagnosis: Natural History of Stage I NSCLC

Raz DJ, et al. Chest 2008


• LDCT SCREENING SAVES LIVES

• CXR screening does not save lives

– Mayo lung, PLCO

• USPSTF draft: Recommended (B)

• CMS approved

• ELCAP, DANTE (Italy), NELSON, Danish

LCS Criteria

LCS criteria for screening USPSTF1 CMS2

NCCN3

Organizations4-6 using NLST

derived criteria

AATS7

Primary Secondary Primary Secondary

Age (years) 55-80 55-77 55-74 ≥50 55-74 55-79 50-79

Smoking History (pack year) ≥30 ≥30 ≥30 ≥20 ≥30 ≥30 ≥20

Quit time (years) 15 15 15 - 15 none none

Other criteria - - - Additional risk factor -

Additional risk factor

or

Lung cancer survivors

USPSTF = US preventative Services Task Force; CMS = Center for Medicare and Medicaid Services; NCCN = National Comprehensive Cancer Network; NLST = National Lung Screening Trial; AATS = American Association for Thoracic Surgery[1] Organizations including the American Cancer Society (ACS), American College of Chest Physicians (ACCP), American Society of Clinical Oncology (ASCO), American Lung Association (ALA)[1] History of personal cancer, lung disease, family member with lung cancer, radon exposure, occupational exposure, COPD or pulmonary fibrosis. [1] Resulting in cumulative lung cancer risk ≥5% in 5 years (ie. COPD with FEV1<70%, environmental/occupational exposure, prior cancer/radiation therapy, genetic/family history)[1] After 4 yrs negative surveillance

CMS Requirements

• Written order during a “LCS counseling and shared decision meeting.”

– Eligibility

– Shared decision meeting using decision aid to include benefits, harms, follow-up diagnostic testing, overdiagnosis, false positive rate, and radiation exposure

• Tobacco cessation counseling

• Nodule management protocol

• Participated in LCS trial or ACR certified

• Dose <1.5mSv

• Collect and submit data to CMS-approved registry of LCS– ACR

What Makes a Quality LCS Program?

CHEST and ATS (Chest 2015)

• Adhere to USPSTF guidelines

• LDCT based on ACR-STR technical recommendations



• Nodule management protocol and structured reporting (LungRADS)

• Expertise in multidisciplinary management of nodules, including non-surgical biopsy and minimally invasive surgery



• Nodule management tracking system/database of procedures and outcomes

• Reporting of data annually



• Integrated tobacco cessation program with database

• Strategy for educating providers and patients on benefits and harms of LCS

How to Find an LCS Center

ACR Accredited Facility Search

http://www.acr.org/Quality-Safety/Accreditation/Accredited-Facility-Search

Lung Cancer Alliance Screening Centers of Excellence

http://www.lungcanceralliance.org/

http://www.acr.org/Quality-Safety/Accreditation/Accredited-Facility-Search

LCS Program at COH

•NP run

•Program Coordinator

(Sophia Yeung)

•Multidisciplinary:

•Pulmonology, Thoracic

Surgery, Radiology

•Integrated tobacco

cessation

Barriers to Lung Cancer Screening• Primary Care

– Time

– Incentive

– Understanding of guidelines

– Understanding risk/benefit/cost

• Patient

– Awareness

– Fear

– Availability

• System– Identification of eligible patients

– Availability

Physician Barriers

• COH Primary Care Physician Study

– Lung Cancer Research Foundation

• Surveyed PCPs in LA County on utilization and perception of lung cancer screening

– Analysis beginning

• Goal is to develop educational and system interventions to improve utilization

Patient Barriers

• Plan ‘pilot’ survey of perceptions of LCS among current and former smokers

• Data on lung cancer risk perception

• Integration with tobacco cessation efforts

– California Quit Line

• Tailor educational intervention

– Diverse populations

System Barriers

LCS in Never Smokers

• IELCAP-FAMRI (Flight attendant medical research institute)

• Never smokers exposed to ‘significant’ second-hand smoke

• Age >40

• Target accrual 7000

• Goal: prevalence of nodules, cancer, emphysema, CAC in never smokers

• COH is the Southern California site

Criteria for LCS

What We Find on LCS

Non-solid= Adenocarcinoma

in situ (AIS) or minimally

invasive adenocarcinoma

(MIA)

Part-solid

Solid

Conclusions

• Lung cancer screening saves lives

• All patients with early stage lung cancer should be evaluated for treatment

• Minimally invasive surgery is the standard of care for clinical stage I lung cancer

what oncologists can learn from their genetics...

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