Cancer Risk Assessment Rebecca Johnson, MD - PowerPoint Presentation

Slide1

Cancer Risk Assessment

Rebecca Johnson, MD

March 4, 2016

Slide2

Objectives

Review

current recommendations for cancer screening for

average risk

patients

by age

Identify

high risk

patients who are

candidates for cancer risk assessment with a genetic counselor

Discuss screening tests available for that assessment

Slide3

Objectives

Cancer

screening for

average risk

patients

Identifying patients at

high risk

for cancer

Role of PCPs in cancer screening

Cancer predisposition syndromes: identifying high risk patients

Screening for high risk patients in your clinic

Genetic referral/testing

Slide4

Cancer in the US

Second leading cause of death

Lifetime risk: 1 in 3 for men,1 in 2 for women

Decreasing mortality since early 1990’s

D

own 22.9

% in men and 15.3% in

women) Mostly among common cancers (lung, breast, colorectal and prostate)Due to better therapies, reduction in smoking, and cancer screeningIn the last four decades, the number of cancer survivors has quadrupled; now >12 million> 30% of cancer deaths could be prevented by modifying risk factors alone e.g modifying obesity, physical activity; vaccinations, antibiotics for H. Pylori, tamoxifen and other preventive medsAt least half of all new cancer cases can be prevented or detected earlier by screening

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide5

Cancer screening for average risk patients

Death from cancer is the leading cause of death before the age of 85 years and the leading cause of premature

mortality

A person dying from cancer

loses on average15.5

years of life— 25% more

than with heart

disease (11.7 years).5 cancers breast, cervix, colon and rectum, lung, and prostate account for >50% of all new cancer diagnoses47% and 40% of the cancer deaths in men and women, respectivelyPCP recommendation is the most important predictor of whether or not a patient has a cancer screening test done

We will review screening recommendations for:

Breast

CervicalColorectal (CRC)Lung

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide6

Cancer screening-

considerations at the population level

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Important public health problem

Detectable preclinical phase of disease

Treatment benefit to early detection Data-driven consensus strategy for age to begin screening, screening interval Accurate, safe

Relatively easy to administer and inexpensive

Slide7

Breast Cancer Screening

Not a single disease- wide variation in tumor growth and spread

Treatment based on risk of recurrence; avoid overtreatment

Screening most beneficial for slow growing cancers

Aggressive cancers

May grow quickly

More common in young women

A negative mammogram should not deter full workup in a patient with a new lumpBenefit of early diagnosis of premalignant lesions is unclearless aggressive approaches need to be studiedMammogram every other year- likely to have the greatest screening benefitsHarmony with European guidelines

3% increase locally advanced cancers (NS)

Chance of biopsy in 10 year period decreased from 61% to 42%

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide8

Slide9

Screening for Gynecologic Malignancies

Of

gynecologic

malignancies, only cervical cancer has an evidence-based early detection screening program that has

led to reduced incidence

90% of HPV does not progress to precancerous state

Of cervical intraepithelial neoplasia grade 3 (CIN 3)

lesions:20% progress to invasive carcinoma within 5 years, 40% within 30 yearsCervical cancer screeningLiquid cytology=conventional cytology sensitivity for detecting CIN3- highest incidence in women aged 25-29 Start screening at 21 y.o., stop at age 65 3 year interval if cytology alone used; 5

years if

cytology+oncogenic

HPV contesting (3X increase in cost; 4X false negative rate)HPV vaccination may decrease abnormal cytology screens and need for colposcopy/excisional procedures

Gardasil

 protection for

>

5

years

HPV-6

and -11, the major causes of genital

warts

Cervarix

 protection for > 9.4 years against seven oncogenic cervical and 5 vulvar/vaginal HPV types; 100% effective in one dose

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide10

US Cervical Cancer Screening Guidelines

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide11

CRC Screening Recommendations

Have an office screening policy that has at least two options for patients— colonoscopy and a sensitive fecal occult blood test/ fecal immunochemical test (FOBT/

FIT)

FIT preferable: unaffected by diet or meds

Clearly

recommend screening for all eligible

patients

Use office systems and technology to track screening results, identify care gaps, and issue remindersDevelop an “open access” colonoscopy system with your colonoscopist partnersMonitor practice-wide screening rates  strive for 80%Decreasing death rates largely due to screeningRose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide12

CRC screening

A

verage-risk

men and women aged

50+

C

olonoscopy

every 10 years or a sensitive stool blood test every yearProven value: Annual FOBT  33% reduction in mortalityColonoscopy <age 70, ~1/1000 have complications within 30 days, more if polyps removed Five key points to maintaining a high-quality screening program:Rose MG, DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide13

CRC screening

Slide14

Lung Cancer Screening

Do not screen for lung

cancer

with

chest

radiography

Screening with annual

low-dose computed tomography reduces mortality from lung cancer by 20%Follow National Lung Screening Trial (NLST) screening protocol Ideally, care from an experienced multidisciplinary teamPCPs should inform patients eligible for screening of the benefits, limitations, and potential harms before screening is initiated

All

screening discussions should be accompanied by a discussion of smoking cessation

Rose MG, DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide15

No screening

Slide16

Slide17

Summary:

S

creening and Risk Reduction Options for Average

R

isk

P

atients

Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide18

Objectives

Cancer

screening for

average risk

patients

Identifying patients at

high risk for cancerRole of PCPs in cancer screeningCancer predisposition syndromes: identifying high risk patientsScreening for high risk patients in your clinicGenetic referral/testing

Slide19

Role of Primary Care Provider (PCP) in Cancer Prevention and Treatment

T

ake

d

etailed family history

K

now risk factors

Refer appropriately for genetic counselingFollow up with surveillance, risk reduction recommendationsUse national screening guidellinesRose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Risk Assessment

Slide20

Inherited cancer predisposition

Goal:

Identify people

with elevated risk and then appropriately manage the risk

New cancer diagnoses

90% caused by de novo somatic mutations

10

% due to inherited genetic traitsCancer predisposition syndromesIncreased risk for cancerYounger average age of onset Cancer genetics screening Identifies individuals at high risk of cancer May help target therapies Patients with a 5-10% chance of a genetic condition warrant genetic evaluation

Offer testing only if the results beneficially influence the medical management of the patient and/or family members

Saletta

F et al. (2015)

Transl

Pediatr

4:67-75

J

Clin

Oncol

1996; 14:1730-1736

Strahm

B and

Malkin D (2006) Int. J. Cancer 119: 2001–2006

Slide21

Myths about cancer genetic counseling

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Psychological, insurance concerns

are

less

of a risk than wrong genetic test being ordered and/ or results misinterpreted

Slide22

Most Cancer Susceptibility Genes Are Dominant With Incomplete

Penetrance

Mutation present in all cells of the body, including germ cells

 transmitted to offspring

Individuals inherit cancer susceptibility genes, NOT CANCER

Incomplete

penetrance



May

appear to “skip” generations

Start by testing a family member with cancer

Normal

Carrier, affected Ca

Sporadic Ca

Susceptible Carrier

Slide23

Potential pitfalls in family history assessment

Lack of awareness of cancer types associated with predisposition syndromes

Importance of ancestry

F

actors

that can falsely lower

risk assessment

Small family Little knowledge of family history Artificial alteration of cancer risk (e.g., total hysterectomy at young age, reducing risk for ovarian, uterine, and breast cancers)Changes in family history over time- update at each visit!

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide24

Physician barriers

to collecting/using family history data

Personal/family history data not collected

nor used effectively in either

oncology primary

care

Lack

of time, reimbursement, and confidence Clinical guidelines valuable but increasingly detailed, rapidly changing50–90 % of patients with increased cancer risk are not recognized and are potentially mismanaged Two studies:Only 19 % of PCPs consistently recognized patients appropriate for a genetics evaluation for Hereditary Breast and Ovarian Cancer (HBOC) syndrome O

nly

31

% of Canadian Oncologists appropriately referred their patients for (free) genetic counseling

Baumgart

LA et al. (2015) Familial Cancer

Slide25

Cancer Risk Assessment:

PCP practice patterns

83%- take detailed family cancer history

33%- obtain three generation pedigree

8%- get details necessary for accurate risk assessment

Key questions: which family member, cancer type, age at diagnosis

S

ome clinicians can devote only 2 to 3 minutes to a family history discussion Most not confident in taking a detailed family history. Consider screening for strong cancer histories by having all patients complete a family history worksheet at each visit.Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide26

PCPs and family risk assessment

Despite high

levels of confidence in assessing breast cancer

risk

48%

incorrectly

categorized a

high-risk breast cancer scenario as low-risk breast cancer 19% identified all increased risk and no low-risk scenarios for BRCA1 and 2 testingUse of genetic risk calculators is complicated91% PCCs agree with national recommendations for pre-test genetic counseling but one study showed that 30% of PCCs had ordered their own genetic testing in the past year. Genetic testing companies market directly to PCPs- and medical and legal liability lies solely with the PCC.Patients do not expect their PCCs

genetics experts but want them to play

a key role in referring them for genetic

servicesPCPs should: know the risk factors that increase hereditary cancer risk

ask

these

questions

r

efer

patients who appear to be at increased risk to a qualified cancer genetic

counselor

Referrals historically more likely if genetic counselor is within a 10 mile radius- remote services now available

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide27

Risk factors that warrant cancer genetics counseling

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide28

Genetic Testing: myths and facts

Oncology in Primary Care (2013) Rose MG et al. eds.

Lippencott

, Williams and Wilkins.

Slide29

Genetic testing: myths and facts (2)

Slide30

Objectives

Cancer

screening for

average risk

patients

Identifying patients at

high risk for cancerRole of PCPs in cancer screeningCancer predisposition syndromes: identifying high risk patientsScreening for high risk patients in your clinicGenetic referral/testing

Slide31

Hereditary breast-ovarian cancer syndrome

Germline mutations

in the BRCA1

or BRCA2

tumor suppressor

gene

Autosomal dominant

Penetrance varies considerably between mutationsIncreased risk: Women- breast and ovarian cancerMen- prostate cancer Cumulative cancer risk by age 70 in females with:BRCA1breast 65%, ovarian 39%BRCA2

 breast

45%, ovarian11%

Relative risk BRCA1: highest at 30-39 years of age, ovarian cancer when older

BRCA2: relative risk for breast cancer does not vary with age.

Other

rare

loss-of-function

variants

confer

moderate

increased risk: PALB2, ATM, BRIP1, CHEK2

and

RAD51C,

and the p53 inducible protein phosphatase PPM1D in a mosaic

form

Saletta F et al. (2015) Transl Pediatr 4:67-75

Slide32

BRCA1

-Associated Cancers: Lifetime Risk

In men: Increased

risk

for prostate cancer

Breast cancer 60%-80% (often early age at onset)

Second primary breast cancer 64%

Ovarian cancer 20%-40%

Slide33

BRCA2

-Associated Cancers: Lifetime Risk

pancreatic cancer (3

%)

breast cancer

(50%-80%)

ovarian cancer

(10-30%)

male breast cancer

(7%)

contralateral breast

(50%)

Prostate cancer

(10-20%)

Slide34

Slide35

Slide36

G

enetic referral is indicated…

…when there is

>

20% chance of finding a BRCA mutation

Asymptomatic patients

Slide37

Cancer patients

Slide38

Case

Study:

Ruth

Ruth

, a 35 year old Ashkenazi Jewish woman, comes because she is anxious about her family history of cancer. You inquire about family health history and find out the following information:

Family

history

:

Paternal grandmother diagnosed with ovarian cancer at age 63

Paternal aunt diagnosed with breast cancer age 42

Ruth

has no other risk factors

or pertinent family history

Slide39

Case

Study

- Ruth, a 35 year old Ashkenazi Jewish woman, presents because she is anxious about her family history of cancer.

- Ruth has no other risk factors

or pertinent family history

Key

-Ov Ca

-

Br CA

Dx 63

82 yrs

Ruth

35

Russian Jewish

Polish Jewish

41

38

60

58

Dx 42

64yrs

Slide40

Assessment

Ruth

is in “Moderate risk” category

Ethnicity

is important as she is of Ashkenazi Jewish descent

Refer to genetics clinic

Moderate

risk screening for breast cancer arranged

Genetic

testing for 3 common ‘Jewish Mutations’

Slide41

Slide42

Identifying Patients at High Risk for CRC

Slide43

Hereditary non-polyposis colon cancer,

(Lynch syndrome)

Increased risk for early onset colorectal, stomach and pancreatic cancer

2-4% of all colorectal

cancers

Autosomal dominant, high penetrance

Germline mutations

in DNA mismatch repair genes (such as MLH1, MSH2, MSH6 and PMS2)Age-specific cumulative risk varies with specific mutationDefective mismatch repair  microsatellite instability and frame-shift mutationsLifetime risk for colorectal cancer for mutation carriers: 38-100% (men) 24-54% (women)

Typical

age of cancer onset is 40-50

yrsPolyps

may be

present (onset in teens),

multiple primaries common

Saletta

F et al. (2015)

Transl

Pediatr

4:67-75

Slide44

HNPCC, lifetime cancer risks:

Colorectal 80%

Endometrial 20-60%

Gastric 13-19%

Ovarian 9-12%

Biliary

tract 2%

Urinary tract 4%

Small bowel 1-4%

Brain/CNS

1-3

%

Slide45

High risk for CRC: who needs screening?

Patient

or first

degree relative

with:

CRC <50yrs

2 or more

primary CRCs any

age

Colorectal cancer and a related cancer* any age.

2 first degree relatives

with CRC or

related cancer* at any age

3

relatives affected with

CRC or

related cancer* at any age, one of which must be a first degree relative

.

History

of

p

olyposis

(e.g. Familial

adenomatous

Polyposis

)

*

related cancers- endometrial, ovarian, small bowel,

ureter

, renal pelvis and stomach

Slide46

Slide47

Familial Adenomatous Polyposis (FAP)

Caused by mutations in APC gene

Thousands of colon polyps

Early onset colon cancer

Hepatoblastoma

-

APC mutation in 15%Desmoid tumors-

APC mutation in 15%

Slide48

MAP (MYH associated

polyposis

)

Autosomal

recessive

Median number of polyps = 55

Mean age of polyp diagnosis = 30-50 years

Polyps mainly small, mildly dysplastic tubular

adenomas

30% of individuals with 15-100 polyps have homozygous mutations in the MYH gene

Genetic testing should be offered if >10-15 polyps (and APC gene testing negative)

Slide49

Many possibilities

Slide50

Other

Cancer Predisposition Syndromes

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide51

Li-

Fraumeni

Syndrome

Associated Tumors:

Adrenocortical

carcinoma

Sarcomas of soft tissue and boneBrain tumors LeukemiaGerm cell tumors, MelanomaBreast cancer- 42% risk of developing cancer by age 16

-

Frameshift

mutations worse than missense

D’Orazio

JA (2010) J

Pediatr

Oncol

32: 195-228

Slide52

Criteria for

P53

testing:

Chompret’s

Criteria:

Proband

with tumor in LFS spectrum <age 46

AND at least 1 first or second degree relative with LFS-type tumor < age 56Proband with multiple tumors <age 46Adrenocortical carcinoma or choroid plexus carcinoma at any age, irresepctive of family historyEeles' definition of LFL:Two first- or second- degree relatives with LFS-related malignancies at any age

Slide53

Cancer risk in

P53

mutation

carriers

Female

carriers are at high risk for early breast cancer

Avg. age of diagnosis 34 yearsScreening should begin in early 20’s- MRIAffected patient has 15% risk of developing a second primary malignancyCarriers need annual screening

Slide54

Objectives

Cancer

screening for

average risk

patients

Identifying patients at

high risk for cancerRole of PCPs in cancer screeningCancer predisposition syndromesScreening for high risk patients in your clinicGenetic referral/testing

Slide55

Considerations prior to testing

Careful

family history

and

physical exam

Pretest Counseling

-

implications of testing for the patient and relativesWritten consent (documentation now usually from provider)Consider predictive testing in children only when it will immediately affect their clinical careIt takes time

Slide56

Risk screening tools

in the primary care setting

Population-based cancer screening programs may cause harm (over-diagnosis, false positive)

Risk-stratified screening

M

ay

reduce harm and identify patients at higher risk

Used in many countries to assess cancer risk:Breast CRCCervicalGuide primary preventive measures or chemoprevention (breast, CRC)Tools identify an individual’s risk of developing cancer, carrying a cancer predisposition syndrome or both Newer risk models incorporate genomic profiles and environmental, behavioral risk factorsUse in UK Increased appropriate

referrals

Led to improvements in diet and physical activity

Walker et al. (2015) Ann Fam Med 13: 480-489

Slide57

Systematic review of

cancer risk assessment tools

11 published

randomized controlled trials (RCTs)

using 7 tools

Use by patients was

greater

when:Initiated by patientsUsed by a dedicated clinicianCombined with decision support

Improved patient

R

isk perceptionKnowledgeScreening intentions, (not necessarily screening behavior)

No

increase in cancer

worry

Walker et al. (2015) Ann Fam Med 13: 480-489

Slide58

Success of recruitment strategies

Low- Phone contact

High- (

>

93%) Approach by dedicated

research assistant or practice nurse

in waiting room before primary care appointment

When intervention was delivered by a practice nurse, 75% of patients completed a risk assessmentOnly 12% of general practitioners attended trainingWalker et al. (2015) Ann Fam Med 13: 480-489

Slide59

Sample family cancer history checklist

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide60

Health Heritage,

a patient-facing tool for personal and family history collection and cancer risk assessment

Clinically validated tool to:

I

dentify

patients appropriate for further genetic evaluation

A

ccurately stratify cancer riskInstrument developmentRetrospective chart review on 100 patients who presented to adult genetics clinic with concern for an inherited predisposition to cancerRelevant personal and family history collated, algorithm developed Concordance between Health Heritage and :National eligibility guidelines for genetic

evaluation

Agreement was

97 % (sensitivity 98 % and specificity 88 %) overall Risk stratification by geneticist: 90 , 93, and 75 % agreement for breast, ovarian and colorectal cancer

Baumgart

LA et al. (2015) Familial Cancer

Slide61

Cancers and hereditary cancer syndromes evaluated by Health Heritage

Breast cancer

Attenuated

Familial Adenomatous Polyposis (AFAP)

Colorectal

cancer

Classic

Familial Adenomatous Polyposis (FAP) Melanoma Cowden syndrome Ovarian cancer Familial Atypical Multiple Mole Melanoma syndrome (FAMMM) Pancreatic cancer Hereditary Breast and Ovarian Cancer syndrome (HBOC) Prostate cancer Hereditary Diffuse Gastric Cancer syndrome Uterine cancer

Hereditary Pancreatitis

Juvenile

Polyposis syndrome Li-Fraumeni syndrome Lynch syndrome

Peutz

–

Jeghers

syndrome

Serrated

Polyposis syndrome

Slide62

Objectives

Cancer

screening for

average risk

patients

Identifying patients at

high risk for cancerRole of PCPs in cancer screeningCancer predisposition syndromesScreening for high risk patients in your clinicGenetic referral/testing

Slide63

How to find a genetic counselor for your patient

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide64

Sequencing Panels

Screens simultaneously for many potential cancer predisposition genes

H

ereditary breast cancer genes: BRCA1/2, p53

, CHEK2, PALB2, and PTEN,

etc.

Colon

cancer: MSH2, MLH1, MSH6, EpCAM, PMS2, MYH, APC, and SMAD4, etc.Simplifies workup of cancers/traits seen in multiple cancer syndromesCancers: thyroid, sarcoma, pancreatic, adrenal cortical carcinomaNoncancerous findings: autism, benign skin findings, speckled genitaliaRose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide65

Gene Panels-

UW BROCA and

ColoSeq

BROCA



suspected

hereditary cancer

predispositionFocus on syndromes that include breast or ovarian cancer; may co-occur with other cancer types (such as colorectal, endometrial, pancreatic, endocrine, or melanoma)Next-generation sequencing for 51 (and counting) genesAssay completely sequences all exons, non repeating introns, and select promoter regions of these genes AND detects large deletions, duplications, and mosaicismLab can also do single gene testing for any gene on the panel, as well as BRCA1/2 founder mutation testing for Ashkenazi Jewish patients

ColoSeq

 suspected

hereditary colon cancer

syndrome

http://

tests.labmed.washington.edu/BROCA

accessed 2/28/16

Slide66

Test results- potential gray areas

1

. Deleterious mutation.

C

ancer risk for patient is within published range

test

both parents— whenever

possible2. True negativepatient tests negative for the familial mutation, which segregates with the cancer family history. Risk = general population3. Negative. Mutation not detected4. Uninformative negative

Patient tests negative,

but no mutation has been identified in the family.

Families with significant personal and family history may still be

high risk

5. Variant of uncertain significance

Genetic change found, but unclear if deleterious or benign. Interpretation based on personal and family history.

Don’t test unaffected family members for VUS

Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.

Slide67

When the test results come back…

Next steps for asymptomatic carrier and their PCP

Patient

T

ake time to consider options

Review information from genetic

counselor

onSupport options Cancer risksPCPConsider referrals to psych, reproductive counseling, gynecology (if considering BSO)Follow up (along with support person) in 4-6 weeks to discuss Plan for the next yearPatient contacting family members who may be at risk Periodic

tumor surveillance

(See NCCN guidelines) or consider referral Rose MG,

DeVita

VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.