Inherited breast cancer

13.40-14.00 Inherited breast cancer
14.00-14.20 Inherited colon cancer
14.20-14.40 Other inherited cancer predispositions
Dr Anne De Leener
Centre de Génétique Humaine
1. INHERITED BREAST CANCER
Introduction
Breast cancer :
clinicopathological features
hormone receptor level (ER and PgR)
HER2
histological grade (1 to 3)
proliferation index (e.g. Ki67)
size (≤ 2cm, 2.1-5cm, >5cm)
peritumoral vascular invasion
axillary lymph node involvement
Ann Oncol. 2009 Aug;;20(8):1319-­29
Cliniques universitaires Saint-­Luc – Anne De Leener
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Introduction
Breast cancer : multidisciplinary team
surgeon / gynaecologist
medical oncologist
radiation oncologist
radiologist
pathologist
geneticist
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Cliniques universitaires Saint-­Luc – Anne De Leener
Breast cancer: risk factors
Sex
• 1 M / 100 F
Age
• the risk increases with age
• but 15-20% before the age of 50
Family history
Personal history
Environmental factors (geographic migration)
Prolonged exposure to oestrogens:
• Early menarche
• Late menopause
• Late first pregnancy, few pregnancies
• Lack of breast-feeding
Other breast lesions (in situ carcinoma, atypical hyperplasia, radial scar, ...)
Controversies: endocrine treatment for menopausal status, weight, alcohol,
tobacco, …
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Cliniques universitaires Saint-­Luc – Anne De Leener
Introduction
Familial cases
Breast cancer – genetic risk
Hereditary syndrome
15% of healthy women have at least one 1st degree relative with breast cancer
à risk x 2
Breast cancer risk increases with the number of 1st degree relatives with breast cancer
1: x 1.8
2: x 2.9
3: x 3.9
BRCA1 and BRCA2 germline mutations are responsible for 20-40% of familial breast
cancer cases, but < 5% of all breast cancers
> 50% of the genetic predisposition to familial breast cancer remains unexplained
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Risk of breast cancer predisposition
Robson & Offit, NEJM 2007
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Cliniques universitaires Saint-­Luc – Anne De Leener
Familial history:
? Genetic impact
Foulkes WD, NEJM 2008
¨
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Cliniques universitaires Saint-­Luc – Anne De Leener
Low-­‐risk breast cancer susceptibility genes/alleles
BRCA1, BRCA2, TP53, PTEN, STK11
Multiple risk alleles
Population frequency <0,1%
Relative risk 10–20 fold
Disease Risk
20x
ATM, BRIP1, CHEK2, PALB2
Multiple risk alleles in each gene
Population frequency <0,7%
Relative risk 2–4 fold
10x
rs2981582
rs3817198
5x
(FGFR2), rs3803662 (TNRC9), rs889312 (MAP3K1),
(LSP1), rs13281615 (8q), rs13387042 (2q), rs1045485
(CASP8)
Population frequency 10-50%
Relative risk 1,25-1,65 fold
0,1%
5%
Allele frequency
50%
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BRCA1 and BRCA2
Genes: Encode proteins that are mainly involved in DNA repair :
Loss of function
à genomic instability
à tumor development
BRCA1 :
chr 17q21
BRCA1
81 kbp
22 exons
BRCA2
84 kbp
26 exons
Proteins
BRCA2 :
chr 13q13
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BRCA1 and BRCA2
Exact pathophysiology remains unknown; tumor progression arises from different
cellular subtypes :
BRCA1 mainly triple negative (ER-, PgR-, HER2-)
“basal-like” subtype
BRCA2 mainly ER+
“luminal” subtype
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BRCA1 and BRCA2
Thousands of different sequence variants have been identified :
1) mutations that are known or likely to be deleterious and diseaseassociated: class 5 or 4
2) variants of unknown function : class 3
= UV : unclassified variants
3) genetic variants that are likely to be neutral and without clinical
importance: class 2 or 1
Help for interpretation of the variants:
Ø Databases: dbSNP, UMD,
Ø Look for conservation of the AA, functional site, etc
Ø Align: Grantham variation/grantham deviation: look for the impact
of AA changes
EMQN Best Practice Guidelines 2007
Ø Splice site prediction (Alamut, etc)
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BRCA1 and BRCA2:
High penetrance : high risk of disease if mutation is found
But risk also depends on:
Sex
• 1 M / 100 F
Age
• the risk increases with age
• but 15-20% before the age of 50
Personal history
Environmental factors (geographic migration)
Prolonged exposure to estrogens:
• Early menarche
• Late menopause
• Late first pregnancy, few pregnancies
• Lack of breast-feeding
Other breast lesions (in situ carcinoma, atypical hyperplasia, radial scar, ...)
Controversies: endocrine treatment for menopausal status, weight, alcohol,
Cliniques universitaires Saint-­Luc – Anne De Leener
tobacco, …
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BRCA1 and BRCA2
High penetrance :
BRCA1 :
breast (women) : young age, 82% cumulative risk at
age 80 years
ovary : 54% cumulative risk at age 80 years
colon
prostate
BRCA2 :
breast (women) : cumulative risk same as BRCA1
ovary : lower cumulative risk than BRCA1 (23% at age
80 years)
breast (men) : increased risk (10% of breast cancers in
males have a BRCA2 mutation)
pancreas
colon
prostate
larynx
BJMO 2008 – 2(4), pp. 198-­204
Am. J. Hum. Genet. 72:1117–1130, 2003
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Aims of the genetics consultation
Provide answers to an individual who is looking for the origin of their personal and
family history of cancer
Establish whether tumor risk is higher or similar to the risk of the general
population
Recommend how patients should be taken care of
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Br. T, 54
Br. T, 42
Br. T, 45
Br. T, 56
?
Br. T, 36
Br. T, 34
aged 39
Br. T, 40
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Cliniques universitaires Saint-­Luc – Anne De Leener
BRCA1 and BRCA2: who should be tested?
BRCA1 and BRCA2 analyses: expensive in terms of manpower and material
à define a sub-population in which the mutations are frequent
à improvement of the cost / benefit ratio
Criteria to take into account :
family history (family tree – up to 3rd generation)
age at onset
triple negative breast cancer
male case in the family
Ashkenazi Jewish origin
other types of cancer
in the same patient
or in the family
Define the risk of having a mutation
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Indication of genetic analysis
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Cliniques universitaires Saint-­Luc – Anne De Leener
Indication to perform a genetic analysis (KCE 2015):
Ø High risk woman.
Ø Risk to find a mutation > 5%
Ø BeSHG criterias
Woman with breast cancer + one or more of the following : Ø diagnosed ≤ 35 yrs, Ø diagnosed < 50 yrs and one relative with bilateral, or ovarian, or breast < 50, or male breast
cancer Ø bilateral breast cancer and both diagnosed < 50 yrs
Ø ovarian cancer, any age
Ø triple negative breast cancer < 50 yrs
Ø three individuals with breast cancer, one is a first degree relative (FDR) of the other two
(excluding male transmitters) and one diagnosed < 50 years
Ø individual of ethnicity associated with higher frequency of specific mutations (eg, Ashkenazi Jewish): eligible for founder mutation testing
Ø other family situations (eg multiple pancreatic cancer) with a priori chance of mutation >10% according to BRCAPRO or Evans criteria or Manchester score Ø test more than one affected relative if criteria remain positive after excluding the negative
Ø case as a phenocopy
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Ø Woman with high grade serous or papillary epithelial ovarian cancer at any age
(excludes borderline, low grade and mucinous ovarian cancer) Ø Male with breast cancer
Ø Individual with pancreatic cancer at any age with ≥ 2 FDR excluding male transmitters
with breast where one diagnosed <50 or bilateral ,or ovarian, or 2 more pancreatic cancer at any age
Family history
•First degree unaffected relative of any of the above on a case by case basis •Testing of unaffected family members should only be considered when no affected family member is
available and then the unaffected family member with the highest probability of mutation should be
tested
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BRCA1 and BRCA2: How to interpret the results?
Many mutations, different from one family to another
A clearly deleterious mutation cannot be identified in all cases
à 2-step process :
Index case (usually a family member treated for cancer at a young age)
then analyze the relatives, if appropriate (usually asymptomatic)
If no mutation could be identified after the analysis of the index case, the test should be
considered as non informative, because the presence of a deleterious mutation cannot be
excluded, and no presymptomatic test can be offered to the relatives
If a mutation is identified, a predisposition test can be offered to the relatives : if it is
negative, it can be concluded that the relative has not inherited the familial predisposition
factor
Minors : no indication to test
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BRCA1 and BRCA2
Software for risk assessment
e.g. BOADICEA
http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_intro.html
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Cliniques universitaires Saint-­Luc – Anne De Leener
Br. T, 54
Br. T, 42
Br. T, 45
Br. T, 56
?
Br. T, 36
Br. T, 34
aged 39
Br. T, 40
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Cliniques universitaires Saint-­Luc – Anne De Leener
Br. T, 54
Br. T, 42
Br. T, 45
Br. T, 56
?
Br. T, 36
Br. T, 34
aged 39
Br. T, 40
INDEX
CASE
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Hypothesis 1
Br. T, 54
Br. T, 42
Br. T, 45
Br. T, 56
?
Br. T, 36
Br. T, 34
aged 39
INDEX
CASE:
BRCA1 mt
Br. T, 40
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Hypothesis 1-a
Br. T, 54
Br. T, 42
Br. T, 45
Br. T, 56
?
Br. T, 36
Br. T, 34
aged 39
INDEX
CASE:
BRCA1 mt
BRCA1
mt
Br. T, 40
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Hypothesis 1-b
Br. T, 54
Br. T, 42
Br. T, 45
Br. T, 56
?
Br. T, 36
Br. T, 34
aged 39
INDEX
CASE:
BRCA1 mt
BRCA1
wt
Br. T, 40
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Hypothesis 2
Br. T, 54
Br. T, 42
Br. T, 45
Br. T, 56
?
Br. T, 36
Br. T, 34
aged 39
INDEX
CASE:
BRCA1 wt
Br. T, 40
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Cliniques universitaires Saint-­Luc – Anne De Leener
BRCA1 and BRCA2
Software for risk assessment
e.g. BOADICEA
http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_intro.html
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In case of BRCA1 / BRCA2 mutation
Breast cancer screening:
From 20 y.o.:
‒ Physical examination every 6 months
From 25 y.o. if BRCA1 (or 30 y.o. if BRCA2):
‒ Physical examination every 6 months
‒ MRI 1x/year
‒ Ultrasound (+/- mammogram at 35 – 40y) 1x/year
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In case of BRCA1 / BRCA2 mutation
Alternative to breast cancer screening
Prophylactic mastectomy
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Cliniques universitaires Saint-­Luc – Anne De Leener
In case of BRCA1 / BRCA2 mutation
Ovarian cancer prevention
No screening technique is effective
Preventive removal of the ovaries
‒ never if childbearing wish
‒ not before 35 y.o.
‒ ideally at the latest
§ at 40 y.o. if BRCA1
§ at 50 y.o. if BRCA2
‒ indication validated by a multidisciplinary team
‒ consultation with the team’s psychologist
‒ clinical and psychological follow-up
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The benefics of prophylactic salpyngo-oophorectomy
Kauff et al, NEJM 2002
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Treatment of breast cancer in case of BRCA1 or BRCA2 mutation
Adjuvant treatment:
Same as if no mutation
Often younger age of onset and thus more chemotherapy
Endocrine therapy if ER+
Herceptin if HER2+
Metastatic treatment:
Same as if no mutation
Sensitivity to platins
The future: PARP inhibitors?
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Conclusion I:
Refer to genetic counseling
KCE 2012
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2. Other inherited cancer predisposition (breast cancer risk)
TP53
Li-Fraumeni syndrome :
prevalence : 1-9/100,000
due to TP53 germline mutation
association :
breast cancer
Sarcoma: osteosarcoma, soft tissue sarcoma,
Adrenocortical carcinoma
leukemia
brain tumor
Others (lung, colon, genitourinary, skin, prostate etc)
occurrence at a young age, multiple cancers
Incomplete penetrance has been described
Avoid radiation
Accumulation of defective protein in the cell:
Loss of transcriptional activity
Eur J Hum Genet. 2009 Jun;;17(6):722-­31
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Li-Fraumeni syndrome:
heterozygous TP53 mutation
Brain T, 35
Sarcoma, 39
28 y.o.
Br. T, 38
Br. T, 39
Sarcoma, 15
Br T, 41
Lung T, 44
21 y.o.
Brain T, 6
Brain T, 9
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Cliniques universitaires Saint-­Luc – Anne De Leener
Rare syndromes
Peutz – Jeghers syndrome :
frequency : 1-9/100,000
heterozygous germline mutations of STK11 (tumor suppressor gene)
association :
gastro-intestinal polyps (hamartomas) IG (jéjunum proximal) > Colon > Rectum >
Estomac
abnormal pigmentation of the skin and mucosa
increased risk of various cancers
‒ including breast cancer (ductal carcinoma) :
§ 45% risk at age 70 years
‒ Gynecologic cancer
‒ Ovarian cancer
§ Sex cord tumors with annular tubules (SCTAT)
Eur J Hum Genet. 2009 Jun;;17(6):722-­31
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Rare syndromes
Cowden syndrome
frequency : 1-9/1,000,000
germline mutations of PTEN (tumor suppressor gene)
association :
Macrocephaly
multiple hamartomas (skin, breast, thyroid, gastro-intestinal tract, endometrium, brain)
increased risk of various cancers:
‒ including breast cancer : 30-50% at age 70 years
‒ Thyroid: carcinoma
trichilemmome
Eur J Hum Genet. 2009 Jun;;17(6):722-­31
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Rare syndromes
CDH1 mutations (tumor suppressor gene) : Epithelial
cadherin
Somatic alteration: loss of E-Cadherin expression
association :
diffuse gastric cancer
lobular breast cancer (risk 60% at 80y), bilateral
Fitzgerald, R. C., R. Hardwick, et al. (2010). "Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research." J Med Genet 47(7): 436-­444. Cliniques universitaires Saint-­Luc – Anne De Leener
Eur J Hum Genet. 2009 Jun;;17(6):722-­31
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Rare syndromes
Type 1 neurofibromatosis :
von Recklinghausen disease
frequency : 1-5/10,000
autosomal dominant transmission
NF1 germline mutations (tumor suppressor gene)
association :
cafe au lait spots
neurofibromas
lentigines
Lisch nodules (=hamartomas of the iris)
bone problems
increased risk of breast cancer
‒ standardized incidence ratio : 3.5
Eur J Hum Genet. 2009 Jun;;17(6):722-­31
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Conclusions II
Breast cancer is frequent
Genetic predisposition is only partially explained by BRCA1/2
mutations
+/- 10% of breast cancers are due to a genetic predisposition
< 5% are due to BRCA1 or BRCA2 germline mutations
BRCA1 and BRCA2 mutations are rare in the general population
(<1/800)
‒ But they have a high penetrance
Multiple different mutations exist
Only patients with a real probability of mutation should be tested
Other, rare genetic anomalies exist
Future breast cancer treatments will take into account constitutional
and somatic GENETIC alterations
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