Transcript Hereditary pattern of breast and ovarian cancer

Genetic Testing for Hereditary
Cancer: Identifying Strategies
for Prevention and Treatment
Julie Culver, MS, LCGC, CCRP
Genetic Counselor
Cancer Genetics Program
USC Norris Comprehensive Cancer Center
University of Southern California
Disclosures
• No conflicts of interest
Most Cancer is Not Hereditary
Hereditary pattern of breast and ovarian
cancer
80
99
Br
81
Br-45
71
Br-47
Pr- 50
Br-50
41
45
47
Ov-38
Br-30
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BRCA1 and BRCA2 Lifetime Cancer Risk
Breast cancer 50%-85%
Second breast cancer 40%-60%
Ovarian cancer 15%-45%
Male breast cancer 2-8%
Prostate cancer 13-20%
Pancreatic cancer risk 13-20%, most notable in BRCA2
ASCO
5
Prevalence of BRCA mutations
• 1/400-500 individuals carries a BRCA
mutation, unselected for history
• Majority of mutations are unique however
recurrent mutations occur in specific ethnic
populations
• Most notable example is that of the Ashkenazi
Jewish population
• Three founder mutations
• Prevalence of 1/40 or 2.5%
BRCA1 and 2 Founder Mutations in the
Ashkenazi Jewish Population
1 in 40 Ashkenazi Jewish individuals
carries a BRCA1 or BRCA2 mutation
BRCA1
187delAG
5382insC
BRCA2
6174delT
These mutations are estimated to account for
95% of BRCA mutations in this population
Cancer Prevention
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Screening
Medications
Risk Reducing Surgery
BRCA1 and BRCA2 screening and prevention
recommendations (NCCN, 2015)
Increased breast surveillance
BSE training and education, begin at age 18
CBE, every 6-12 months, begin at age 25
Annual mammography and MRI, begin at age 25*
Consider risk-reducing mastectomy
>90% risk reduction
Consider chemoprevention (tamoxifen or Evista)
50-60% risk reduction
Risk-reducing bilateral salpingo-oophorectomy at age 35-40 and upon completion of child bearing
~96 % ovarian cancer risk reduction
>50 % breast cancer risk reduction
Ovarian screening, begin at 30, despite lack of evidence
Semiannual transvaginal ultrasound
Concurrent CA-125
Family-specific screening
Pancreatic cancer screening (MRCP alternating with EUS, with one test done annually)
Melanoma screening (dermatology)
*Individualized based on earliest age at diagnosis in the family
The Angelina Effect
• Actress Angelina Jolie revealed in an op-ed article to The New
York Times, My Medical Choice, published on May 14, 2013, her
choice to undergo a prophylactic bilateral mastectomy at age 37.
• Jolie’s mother died at age 56 from cancer, and she herself tested
positive for a mutation in BRCA1, which left her with a high risk of
developing breast and ovarian cancer.
• Note, on March 24, 2015, she announced her choice to undergo a
bilateral salpingo-oophorectomy for ovarian cancer risk reduction
at age 39.
• The following report illustrates the impact on NCI PDQ Cancer
Genetics digital resources after the high-profile actress brought
public attention to breast cancer and genetic risk.
PDQ® Cancer Genetics Summaries
Of the PDQ® Cancer Genetics summaries, the Genetics of Breast and
Ovarian Cancer summary received the largest increase in traffic, with a
more than 6-fold increase in page views on May 14 compared to the
previous Tuesday.
Source: Omniture
Molecular Origins of Cancer Inherited Susceptibility to Common Cancers William D. Foulkes, N Engl J Med 2008;359:2143-53.
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BRCA2 family
• Human genetic variation dec issue
Panel Testing
• Next-generation sequencing technology has
reduced the cost of genetic testing
• Many genes conferring cancer risk have been
discovered and have become clinically relevant
• Hereditary cancer panels offering simultaneous
testing for dozens of genes since 2012-2013
• The implications for clinical care are still under
investigation
USC Pilot study of Panels
Among 189 breast cancer patients ,
12 (6%) had mutation in BRCA1 or BRCA2;
15 (8%) had mutation in BARD1, CDH1, CHEK2,
MUTYH, PALB2, RAD50, RAD51D, or TP53
JO Culver, CN Ricker, K Lowstuter, DY Sturgeon, CR Chanock, WJ Gauderman, K McDonnell, GE Idos, SB Gruber.
Multiplex panel testing improves the yield of mutation detection in cancer genetics clinics. 2014.
Presented at the 2014 American Society of Human Genetics annual education conference.
PALB2 family
BRCA mutations and treatment options
• Platinum based chemotherapy known to be more
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effective in BRCA+ breast and ovarian cancers
Group of pharmacological inhibitors of the enzyme
poly ADP ribose (PARP)
PARP 1 helps to repair single strand breaks in DNA
BRCA2, BRCA2 and PALB2 are involved in repair of
double-strand DNA breaks
Clinical Trails underway
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PARP inhibitor for BRCA+ breast cancer
Hereditary colon cancer
Heterogeneity in Lynch syndrome
The Mismatch Repair Genes
MSH6
MSH2
MLH1
PMS2
EPCAM
Chr 7
Chr 2
Chr 3
• ~ 80-90% caused by mutations in MSH2 and MLH1
• 7-10% caused by mutations in MSH6
• < 5% caused by mutations in PMS2
Mismatch repair
Lynch syndrome
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Most common form of hereditary colon cancer
Uterine cancer second most common cancer
Polyps can be present – tend to be flat adenomas
History (family and personal) along with tumor analysis by
MSI/IHC can help identify families
Colonoscopic surveillance can improve survival in at-risk
individuals (recommended annual screening starting age 20)
Benefits of surveillance for most extracolonic cancers are still
unknown
Noncarriers can be spared anxiety and the need for increased
surveillance
General Population 5-10 years
Lynch Syndrome
1-3 years
Cancer Risk in Individuals with Lynch syndrome to Age
70 Compared to General Population
Cancer
General
Population Risk
Lynch syndrome
Risk
Lynch Mean Age
of Onset
Colon
7%
80%
45 years
Endometrium
2.7%
20-60%
46 years
Stomach
<1%
11-19%
56 years
Ovary
1.5%
9-12%
42.5 years
Hepatobiliary tract
<1%
2-7%
54 years
Urinary tract
<1%
4-5%
~55 years
Small Bowel
<1%
1-4%
49 years
Brain / CNS
<1%
1-3%
50 years
from: http://www.genetests.org
Tumor analysis - MSI
Microsatellite Instability (MSI)
• Microsatellites are repeating sequences found in genes
• Instability occur when these repeats are different lengths compared to normal
tissue
• Seen in 90-95% of HNPCC colorectal tumors
• Seen in 15-20% of sporadic colorectal cancers
• Requires access to paraffin-embedded colorectal tumors
• Most informative in colon cancer, but can be performed in other Lynch related
tumors, specifically uterine and to a lesser degree gastric and ovarian
• Can be performed in polyps, most informative in adenomas with high-grade
dysplasia
Normal
Microsatellite instability
Tumor analysis - IHC
Red flags for colon or endometrial
cancer patients
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Diagnosis before 50
Abnormal MSI or IHC
Two or more Lynch cancers at any age
Lynch syndrome cancer with a relative with a
Lynch syndrome cancer
Colorectal cancer treatment decisions
• 15% of all colon cancers are MSI high.
• MSI high colon cancer shows better prognosis than
microsatelite stable (MSS).
• MSI high colon cancers do not seem to benefit from
adjuvant fluorouracil (FU) -based chemotherapy.
• In stage 2 colon cancer, testing of MSI is
commonplace for chemotherapy decisions
Ribic et al, NEJM, 2003 ; Sargent et al, JCO, 2010
Colorectal cancer treatment decisions
Testing an Affected
Colon CA
dx. 46
Colon CA
dx. 42
Colon CA
dx. 45
This man wants to be
tested, but ideally, his
father should be first
Testing affected person first allows for
accurate interpretation of test results on
relatives
Negative result on an unaffected person
can never be a true negative
Consider DNA banking if affected
individual has terminal cancer
Informative Testing Strategy
Family history of cancer? Who is the best
person to do genetic testing?
New
yellow
apple
Red apple tree growing red apples
Red apple tree growing one yellow apple
Genetic Counseling – Pre-testing
Assess
• Personal and family medical history
• Risk perception and motivation for testing
Educate
• Cancer genetics and risk
• Risks, benefits, limitations to genetic testing
• Management options
Informed Consent
• Possible results, including positive, negative,
uncertain variants
Genetics Counseling – Post-testing
Results disclosure
• Interpretation of results, including positive
tests and uncertain variants
• Genetic testing recommendations for family
Risk assessment
• Risk calculation
• Screening recommendations
• Family member screening recommendations
Psychosocial Issues in Testing
Common emotions:
• Anxiety
• Guilt
• Grief, and or anticipatory loss
• Altered self-esteem
• Changes in family dynamics
Genetic counseling can help patients work
through these emotions
Incidental findings of cancer gene
mutations in exome testing
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Several hereditary cancer genes are included in ACMG guidelines for reporting
incidental findings (BRCA1, BRCA2, TP53, STK11, MLH1, MSH2, MSH6, PMS2, APC,
MUTYH, VHL, MEN1, RET, PTEN, SDHB, SDHC, SDHD, SDHAF2, TSC1, TSC2, WT1,
NF2) (Green RC et al, Genet in Med, 2013)
Clinseq study reported on whole exome sequencing (WES) on 572 healthy adults;
seven participants had a BRCA1 or BRCA2 mutation (four were of Ashkenazi
Jewish; one met family history criteria; two were neither Jewish nor met family
history criteria); one had a deleterious SDHC mutation, which causes
paragangliomas. (Johnston JJ et al, Am J Hum Genet 2012)
DICER3 study at Baylor performed WES in 110 pediatric cancer cases and found 10
patients with dominant pathogenic mutations, including 4 that were suggested at
study entry (TP53, MSH2, DICER1, VHL), 6 that were not (BRCA1x2, BRCA2, CHEK2,
APC, mosaic WT1) (Plon SE et al, 2014 ASHG meeting)
Precision Medicine in Cancer Treatment
• Discovering unique therapies that treat an
individual’s cancer based on the specific
abnormalities of that person’s tumor
• Identify the mutation that is the driver of cancer
growth
• Match mutations to known drugs or trials that
can offer better response
• Examples include HER2+ breast cancer, use of
KRAS mutation to determine treatment for colon
cancer
Pancreas Cancer Case:
66 year old man
with pancreatic cancer,
metastatic to liver.
Ashkenazi Jewish ancestry
Pancreas case, continued
• Somatic tumor analysis identified BRCA2
S1982fs*22 (known as BRCA2 6174delT)
• Germline BRCA1 and BRCA2 testing identified
the same BRCA2 mutation
• Patient referred to UCLA for PARP trial
• Brother recommended to undergo genetic
testing
Ovarian Cancer Case:
65 year old woman
with ovarian cancer,
metastatic to liver.
Ovary case, continued
• Somatic tumor analysis identified BRCA2
mutation, BRCA2 Q2157fs
• Germline BRCA1 and BRCA2 testing identified
that she did not have a germline mutation
• However, potential benefit from somatic
mutation was identified
Conclusions
• Cancer genetic testing offers the promise of improved
prevention and lower cancer risk
• Genetics is not destiny
• Genetic testing is changing rapidly with the availability of
multi-gene panels and whole genome testing
• Treatment for BRCA1 and BRCA2 mutation carriers and Lynch
syndrome mutation carriers may be altered due to genetic
status.
• Precision medicine can offer treatment options and may also
reveal germline mutation carriers.