1. No category

Cancer Genetic
Counseling Services:
What is it? Is it for
me?
You can’t help those who are at risk
unless you find them!
WHY IT MATTERS FOR THOSE WITH
and without CANCER and for their
families.
BE AWARE…..
Familial cancer risk assessment
DOES NOT ALWAYS EQUAL GENE TESTING**
The Goal of Testing is not to test as many people as
possible it is to test the right people
**you can be high risk with a normal gene test
AND IT’S NOT JUST ABOUT BRCA1/2
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Cancer Risk: It is not just about Genes
Personal
Risk
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Family
Risk
Identify
High
Risk
Multi-step Process of Tumorigenesis
• Multiple “hits” needed in
single cell for
tumorigenesis
• General population
cancers have all somatic
mutations
• Hereditary cancers have
inherited “head start”
followed by somatic
mutations
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Sporadic vs Hereditary Cancer
Tumor
Develops
In hereditary cancer, one damaged gene is inherited.
Tumor
Develops
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CANCER IS IN THE GENES
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Hereditary Cancer is Rare
Sporadic Cancer
Hereditary Cancer
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HOW MUCH CANCER IS DUE TO
MAJOR HERITABLE RISK:
• 5-10% OF ALL BREAST CANCER( 1/3 OCCUR IN
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11
CLUSTERS)
5-10% OF ALL COLON CANCER (20-30% OCCUR IN
CLUSTERS)
UPTO 15% OF OVARIAN CANCER( ALL WITH EPITHELIAL
CANCERS,ESP HIGH GRADE PAP-SEROUS SHOULD HAVE
GC)
2-3% OF UTERINE CANCER IS DUE TO LYNCH
SYNDROME
ETC…………..
Why is it Important to Identify Families with Hereditary
Cancer Syndromes?( ONLY ~10% of All Cancers)
• High risk for cancer
• Multiple organ systems may be involved
• Increased risk for second primary cancer
• Increased risk of cancer to relatives
• Possible treatment(targeted therapy-
PARPinhibitors for BRCA; need for CT, surgery;
avoid RT withTP53; ?mTor inhibitors for
PTEN,STK11)
• The ultimate goal is treatment or prevention or
early detection of cancer- for patient and FAMILY
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Why is this important?
It’s the right thing to do for our pts!!
• The USPSTF(2005&2013) recognizes benefits of and
recommends ID of BRCA carriers(B)—data suggest
that 3 in 4 women with relevant family hx who
might benefit from genetic counseling for HBOC
have not used these services
• 6+% of all screening mammo pts qualify for BRCA
assessment
• AmAssoc for Ca Research(2013): only 53% of newly
d’d BC pts who met criteria for genetic testing were
referred by their MDs
• Healthy People 2020: ID BRCA carriers and Lynch
families—most affected are unaware
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Legal: “a woman in CT sued her MD for failing to
warn her that her...fhx of breast ca… suggested
risk of ov.ca.. The CT supreme court upheld a
$4million jury verdict after her dx of ov.ca..”
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Screening for “Familial Cancer”
• Help your doctor collect appropriate
Family History Details:
- Type of primary cancer(s) in each relative(not mets)
- PATHOLOGY
- Age of disease onset in each relative
- Cancer status in 1st ,2nd and 3rd degree relatives-minimum
- Cancer/precursors in both sides of the family
- Ethnic background on both sides
- Other medical/environmental findings – benign tumors, congenital
abnormalities, preventive surgery etc.
- Update often: hx dynamic
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Confounders
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Incomplete penetrance
Hx incomplete/inaccurate
False paternity
Adoption
Sporadic Ca’s among familial ones
Early non-CA death of informative relative
Those w/ PM/PSO - mask susceptibility
Absence of medical records
Pedigree too small
Who to Refer?
Minimum criteria for Breast Cancer
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•
BC dx ≤ 45y
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Two breast primaries with first dx ≤ 50y
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BC Dx ≤ 60y with triple negative breast cancer
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Male with BC
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Ethnicity associated with higher mutation frequency i.e Any Ash. Jewish woman with
breast cancer
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BC with family history of ovarian cancer(epithelial)any age
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Consider also with family hx of multiple breast cancers, pancreatic cancers or other
cancers(sarcomas, brain tumors etc); consider measuring OFC
•
Always if patient is concerned about cancer risk to self/family
“Evaluation of a breast/ovarian cancer genetics referral
screening tool in a mammography population”
Bellcross, 2009
-2464 unselected women undergoing
mammogram filled out referral
screening tool (RST)
-Of those, 300 randomly selected
for phone 4-gen pedigree
-”Positive screen” from RST
compared to likelihood of “high
risk” created by models
-Overall, 89% sensitivity, 91% spec
-Online updated version of
Bellcross tool (includes bilateral
breast and br/ov ca)
www.brcagenscreen.org
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Simple Mammo Screen
• IF you answer ‘yes’ to any of the following, you may benefit
from additional cancer risk assessment and specialized
screening:
Do any of the following apply to you or a close family
member (parent, brother, sister, child, aunt, uncle, niece,
nephew, grandparent or first cousin):
• three or more relatives on the same side of your family
(either your mom’s side or your dad’s side) with breast
cancer at any age
• ovarian cancer at any age
• male breast cancer
• breast cancer at 45 or younger
• breast cancer at any age with Jewish ancestry.
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10 yr risk of CBC
AGE@DX
Graeser-JCO
2009
30.7%
HooningSABC-2009
54%
31-40
30.7%
39%
41-50
10.6%
26%
>50
7.9%
17%
20.7%
28%
41-50
12.8%
19%
>50
9.2%
10%
BRCA 1 <30
BRCA 2 ≤40
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Don’t forget the other BRCA cancers
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Pancreatic
Melanoma: cutaneous and ocular
Prostate: high grade; excess <65. IMPACT study
?stomach and other GI
?colon
?some head and neck
? HGPSU cancer( embryonic rests vs mets from FT)
BRCA
• ~20-23% of high grade pap serous OC due to BRCA
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( ~1/3 are in women with no other family hx)
?~70% are actually from the fimbria( native tissue is serous)
Risk for breast cancer ranges from ~37%-70+% but could be
further stratified by gene modifiers and density
Risk for ovarian cancer by age 30 with BRCA 1 is 1% or
less(~2/1000 for BRCA 2)BUT 1.6-3.4% between 30 and 40
for BRCA 1
PROSE study: HRT not contraindicated in those without
cancer, at least until natural menopause. Decrease in BC
risk with BSO> for nat. menopause and postmenopausal
BSO also protects against BC (AACRfor cancer Research
may7,2012;Kotsopoulos etal)
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Testing Results:
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BREAST CANCER GENES
>10
TP53 STK11
PTEN CDH1
RR
6-7
Don’t exist
BRCA 1/2
2-4
1.5
1
Too rare
0
0.10%
Chek2
ATM
PALPB2
CAPS8
BR1P1
NBS1
RAD
1-5% Carry
1%
FGFR2
LSP1
RR 1.2
TNRC9 TGFB1
per allele
MAP3K1 Etc.
10%
Allele Frequency
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30-40%
Other Breast Cancer Genes besides BRCA 1 and
2( only 13 of 43 researched & published
extensively)
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Next-gen Panels:
(Breast, ovarian, colon, renal focused OR full cancer
panels—eventually WES and WGS)
-Cheaper(low cost)
-Moderate accuracy (techniques may
-Many Genes(mutations in any one of a add coverage but some genes more
comprehensively covered than others)
number of genes can meaningfully
elevate risk).
-Not hypothesis driven
-Lack of clinical utility proven for some
genes esp moderate risk ones( no good
data on outcome, specific risks)
-Good when more than one dx possible
OR multiple unrelated cancer i.e .when -Only some of the genes have proven
phenotype of pt or family is unable to interventions available(may not have
specific recommendations &/or may
clearly direct testing
not be covered by ins.)
-May learn more broad phenotypes:
-Some ins. Consider these
(for moderate penetrance genes =
investigational
opportunity&challenge)
-Most associated with at least mod risk -High rate of VUS
for other cancers.
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Marked Genotypic and Phenotypic Heterogeneity
in Hereditary Colorectal Syndromes
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Colorectal Cancer Patients:
Universal Tumor Testing
Allina’s Model
• IHC (on all CRC and EC):
- IHC normal  GC only if dx <50 OR significant history OR
>10polyps
- IHC absent MLH1/PMS2—reflex to BRAF& hypermethylation
- IHC absent MSH6, MSH2 or PMS2 only---refer for GC
• MSI-stable and/or IHC normal--- GC only if dx <50 OR significant
history OR >10polyps
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Lynch Syndrome Cancer Risks
• Risk Depends on Gene!
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Other Colon Cancer Genes
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Who to refer?
Minimum for colon cancer:
• Abnormal IHC suggestive of Lynch syndrome (universal
screening done at Allina)
• Negative Lynch screen BUT dx < 50
• >10 adenomas
• Consider IF family hx of colon cancer, other cancers,
multiple polyps
• Always if patient is concerned about cancer risk to self or
family
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Who to refer:
Other GI
• Pancreatic cancer pt with 2 relatives with PC(FPC)
- Consider if also FHX breast, ovarian, colon,
melanoma/dysplastic moles and/or cancer
• Diffuse gastric cancer dx <40
- Consider also if fhx DGC or lobular breast cancer
• Adenocarcinoma of stomach:
- Consider with fhx of colon, uterine
• Always if patient is concerned about cancer risk to
self/family
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Who to refer?
Minimum for GYN
• All ovarian, non-mucinous, non-borderline epithelial
ovarian cancers(~14%w/BRCA; upto 23% with high
grade pap serous)
• Endometrial: positive Lynch screen(also UPS, MMMT)2-3%
- If none done arrange(universal screen at Allina)
• Leiomyosarcoma+cutaneous leiomyomas-HLRCC
• Uterine ca + breast+thyroid;macroceph-PTEN(<1%)
• Always if patient is concerned about cancer risk to
self/family OR if family hx of rare tumors
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Who to refer?
Minimum for GU
• Renal Papillary type 2(HLRCC)
• collecting duct cancers-Lynch syndrome
• Multifocal/bilateral clear cell tumors/other OR dx <40
even w/o family hx
• Consider with significant family hx/consider derm exam
for suspicious derm lesions and/or if renal/panc
cysts(?? Pt re:pheo, skin findings, colon ca etc)
• Always if patient is concerned about cancer risk to
self/family
• Prostate cancer: consider with positive hx, Jewish
ancestry, fhx of early onset breast, ovarian cancer-esp
with high Gleason
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Who to refer?
Other(minimum)
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ACC <45
Choroid plexus tumor
Pheochromocytoma
Hemangioblastoma(cerebral/retinal/spinal)
Medullary thyroid cancer
Consider with multiple primaries, multiple early onset
cancers; always if pt is concerned.
• ALWAYS IF A PATIENT IS CONCERNED!!
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Why is it Important to Identify Families with Hereditary
Cancer Syndromes?( ONLY ~10% of All Cancers)
• High risk for cancer
• Multiple organ systems may be involved
• Increased risk for second primary cancer
• Increased risk of cancer to relatives
• Possible treatment(targeted therapy, surgery)
• The ultimate goal is treatment or prevention
or early detection of cancer- for patient and
FAMILY
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HBOC Family History
Cancer
Ovarian dx 60
d. age 66
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Breast
ca
dx 38
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Breast ca
dx 47
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30
32
28
60
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39
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Other “At-Risk” Relatives
Cancer
Ovarian ca dx 60
d. age 66
At risk?
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Breast
ca
dx 38
36
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Breast ca
dx 47
32 30
32
28
60
27
39
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Other “At-Risk” Relatives
(impacted by genetic testing)
Cancer
Ovarian dx 60
d. age 66
At risk
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+
Breast
ca
dx 38
neg
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+
+
Breast ca
dx 47
neg
neg
32 30
32
neg
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28
60
27
39
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Interpreting a Negative Result
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D-CRC
@ 40
neg hx
80
UTCA
@ 67
CRC
@ 38
neg hx
D-70
D-glioblastima
@ 50
BC @ 55
D-36
BC @ 48
60
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Pre-Consult
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• 37 y/o concerned re: breast cancer
risk
• Desires PM
• Wants “gene test”
BE AWARE…..
Familial cancer risk assessment
DOES NOT ALWAYS EQUAL GENE TESTING**
The Goal of Testing is not to test as many people as
possible it is to test the right people
**you can be high risk with a normal gene test
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Highest Risk
• BRCA+: 11-15X
• TP53,PTEN: >10x
• Extremely dense breast (75-100%)-4-5X (Lowest
density 1% over 3 yrs vs. 2.4% with highest density)
Some data suggest RR 6—also informs BRCA related
risks
• LCIS—6-10X
• RT<20
• ADH/ALH-4-5X
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RR
Gail
Claus
BRCAPro
IBIS
BOADICEA
Age
30
x
x
x
x
x
Body Mass Index
2
Etoh intake
1.24
Age menarche
2
x
x
Age 1st livebirth
3
X
X
Age menopause
4
X
HRT use
2
X
OCP use
1.24
Breast feeding
0.8
Plasma estrogen
5
Breast biopsies
2
X
X
ADH
3(4-5)
X
X
LCIS
4-?10
Breast density
6
1st degree relative
3
2d degree relative
http://www.halls.md/breast/risk.htm
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x
X
X
X
X
X
X
1.5
X
X
X
X
Age of breast ca
3
X
X
x
X
Bilateral breast ca
3
x
X
X
Ovarian ca
1.5
X
X
X
RISK MODELS
• All have limits
• Use a tool/model that includes the risk factor of
concern AND know the limits of each model or risk
evaluation may be in error and result in wrong
management decisions i.e. over screening some and
under screening others.
• often may need to use > 1
• Those with ALH, LCIS, significant density, prev. BC may
face significant risks BUT ACS— “can’t argue for or
against..MRI”-meets PBC guidelines (20%)
• Remember—pedigree analysis!!
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Case 1
all 3 from Aug 2009; Oncology Genetics; Community Oncology
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Case 2
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Case 3
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What Goes on during Cancer Genetic
Counseling
Before Consult:
• Gather three-four generation family tree
- Confirm diagnoses through medical records
During Consult:
• Assess hereditary cancer risk
• Provide management options in light of personal risks(
refer to appropriate resources).
• Discuss possible genetic syndromes IF indicated.
• Address the option of genetic tests
- If indicated and choose best to test
- Help informed decision making
- All risks, concerns, limits, benefits
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Genetic Counseling
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After Testing if done:
Interpret test result for patient and family
Discuss continuing care with screening/surgeries/prevention
Encourage conversation with family members
Address psychosocial issues for both patient and family
• Goals:
• Eliminate the burden of cancer in our patient and their family
members
• Limit psychosocial stress throughout process
• YOU CAN’T HELP THOSE WHO ARE HIGH RISK UNLESS YOU CAN
FIND THEM!
•
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http://www.cancer.net/patient/All+About+Cancer/Genetics/What+to+Expect+When+
Meeting+With+a+Genetic+Counselor
Common Myths
• Hereditary cancer is common – most cancers
“run” in families
• If my mother had breast cancer, I am
automatically at an increased risk for breast
cancer
• I cannot inherit breast cancer risk from my
father’s side of the family
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Common Myths
• There is nothing I can do about it if I am at high
risk for cancer, so why find out?
• If I go see a genetic counselor, they will pressure
me into genetic testing and/or make medical
decisions that I am not comfortable with
• I have already had cancer, so genetic testing is
not appropriate for me – it is only appropriate
for my family members
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Common Myths
• A negative test result means I do not have an
increased risk for breast cancer or other cancers
• Insurance won’t cover the cost of genetic
counseling or genetic testing
• If I have a genetic test, my health insurance
company will drop my coverage or raise my rates
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