genetics and risk of breast cancer what is the evidence
TRANSCRIPT
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Genetics and Risk of Breast Cancer
What is the Evidence
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Questions
• What is the role of mutation testing
• What is the risk to mutation carriers
• What is the evidence for intervention
• How does family history predict risk
• What lines of future research are required
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What is the likelihood of finding a mutation ?
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BRCA1 and BRCA2
• Mutations confer an autosomal dominant susceptibility to Breast and Ovarian cancer with high penetrance
• In some populations there are common mutations
• These are not the only genes involved
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BRCA1 and BRCA2
• Population frequency (British Cases)
BRCA1 0.11%
BRCA2 0.12% (Peto et.al. 1999)
• Estimate 16% of hereditary breast cancer susceptibility is caused by these genes in UK.
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Determining Probability of Being a Gene Carrier
• Empirical data
• Logistic Regression Analysis
• Bayes calculation
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Ford et.al. 1997, Narod et.al. 1995
• 84% of BCLC families showed evidence of linkage to BRCA1 or BRCA2. (4 affected members).
• 76% of breast-ovarian families linked to BRCA1 (3 affected members, one ovarian).
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Peto et.al. 1999• BRCA1 and BRCA2 Mutation Analysis
Status Mutation detected
BRCA1 BRCA2
Affected < 35 9/254 6/254
Affected 36-45 7/363 8/363
Affected <45, mother breast cancer 2/54 1/54
Affected <45, 1o with breast CA<60 3/52 1/52
*Affected <45, 1o with ovarian CA 3/5 0/5
*Affected 36-45, 2X 1o with breast <60 1/8 3/8
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Schattuck Eidens et.al. 1997• BRCA1 and BRCA2 Mutation Analysis
Status Mutation detected
BRCA1 BRCA2
Affected < 35 ~5%
Affected 36 - 45 1-2%
Affected <45, mother breast cancer ~2%
Affected <45, 1o with breast CA<60 ~2%
Affected <45, 1o with ovarian CA ~6%
Affected 35, 1o relative with breast + ovarian 20%
Affected 35, Bilateral Breast Cancer 20%
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Parmigiani et.al.1998
• Bayes Risk Calculation
– Uses population frequency of mutation– Uses penetrance data for gene mutation– Takes family structure into account– Assumes all non BRCA1/BRCA2 cancer is sporadic– Has been computerised
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CASH data Ford data
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Likelihood of identifying a mutation
BRCA1 and BRCA2 Mutation Detection
Status Cyrillic Peto
(BRCAPro)
BRCA1 BRCA2 BRCA1BRCA2
Affected < 35 2% 0.3% 4% 2%
Affected <45, 1o with breast CA<60 4% 2% 6% 2%
Affected <45, 1o with ovarian CA 22% 1.6% 60% 0%
Affected <45 2X1o relative with breast <60 21% 10% 13% 38%
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Population Specific Mutations
Ashkenazi Jewish Population Over 2% of population
BRCA1 185delAG
5382insC
BRCA2 6174delT
Icelandic population 0.6% of population
BRCA2 999del5
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Mutation Detection with Askenazi Jewish descent
• Lalloo et.al. 1998– Breast cancer <60 1/4– 2 X Breast cancer <70 3/10– BCLC criteria 5/5–
• Schattuck-Eidens et.al. 1997– Affected age 40 ~12%– Affected at 40 + 1o relative breast ~20%– Affected at 40 + 1o relative ovarian ~35%
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Male Breast Cancer
Friedman et.al. 1997 (Californian Male Cases)
• 2/54 cases of male breast cancer had BRCA2 mutations• 17% had a 1o family history of breast cancer
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Conclusions
In a small proportion of cases, mutation testing for BRCA1 and BRCA2 would be expected to have a high pickup rate.
Eg.
4 family members with breast cancer
Breast cancer <age 45 with 1o ovarian cancer
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Conclusions
• Different systems exist to predict likelihood of detecting a mutation.– BRCApro– Logistic regression curves
• Not all of these have been validated in clinical practice.
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Conclusions
• Testing for the common Ashkenazi Jewish mutations may be relevant,
– In the presence of modest family history. – with isolated young onset disease.
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What is the Risk to Mutation Carriers ?
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Risk to Mutation Carriers
• Derived from Linkage– Easton et.al. 1993
– Ford et.al. 1994,1998
• Empirical data from common mutations– Struewing et.al. 1997
– Steinumn et.al. 1998
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Risk To Mutation Carriers (%)
Easton et.al. Ford et.al. Struewing Steinum ISD
BRCA1 BRCA2 BRCA1+2 BRCA2 (Population)
Br Ov Br Ov Br Ov Br Ov Br O v
By age 40 19 0.6 12 0.0 - - - - - -
By age 5050 22 28 0.4 33 7 15 - - -
By age 6054 30 48 7.4 - - - - - -
By age 65 - - - - - - - - 5.5 0.9
By age 7085 63 84 27 56 16 35 - - -
By age 75 - - - - - - - - 7.9 1.5
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Conclusions
• BRCA1 and BRCA2 mutations confer a high risk of breast and ovarian cancer.
• All studies have potential sources of bias, the true risk will depend on the population and mutation type.
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Modifying Risk to Gene Carriers
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Modifying Risk
Screening Breast examination
Mammography
Ovarian Ultrasound
Hormonal Manipulation Tamoxifen
Surgical Intervention Mastectomy
Oophorectomy
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Screening / Mammography
• Proven benefit when age > 50 in individuals at population risk– Meta-analysis, Kerlikowske JAMA 1995
• Conflicting Evidence for population screening ages 40 to 49– Some studies for, some against
• High Risk Screening– Uncontrolled longitudinal follow up of high risk cohort
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Screening / Mammography
• Chart et.al. 1997 - Canadian High Risk Programme– 1044 women categorised as high, moderate or low risk
– 6 year follow up, mammography and breast examination
– in high risk group 7/381 had tumours at presentation
– 5/381 high risk developed tumours on follow up
• Lalloo et.al. 1998 - Manchester high risk breast clinic– 1259 women with a lifetime risk of breast cancer > 1 in 6
– 7 tumours prevalent (4 were in situ), 9 tumours incident
– 2 tumours were detected by self examination between screens
– 6 of incident tumours were palpable
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Tamoxifen prevention Studies
The Breast Cancer Prevention Trial (P1)– Women at “increased Risk”, 13388 cases, 5 year follow up
– Tamoxifen reduced breast cancer risk (RR 0.5)
– Increased endometrial cancer and pulmonary embolus + cataract
– Overall mortality not significantly lower
Royal Marsden Chemoprevention Trial– 8 year follow up of 2471 women, power 90% for 50% effect
– No detectable effect on breast cancer
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Hormone Replacement Therapy
• No study has looked at HRT in BRCA mutation carriers
• Generally, HRT confers a small increased risk of breast cancer.
• HRT decreases cardiovascular and osteoporotic events.
• In one large meta-analysis (anonymous 1997) positive family history did not show a significantly increased risk of breast cancer in HRT users as opposed to non-users. Numbers analysed were small.
• Breast cancer in BRCA1 carriers is often oestrogen receptor negative.
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Prophylactic Surgery• Mastectomy
– Various modelling approaches looking at cost/benefit– Hartmann et.al. 1999 Retrospective study
• Estimated 90% reduction in breast cancer incidence• Did not take other post-operative morbidity into account
• Oophorectomy– Rebbeck et.al. 1998 (ASHG abstract)
• reduction in breast cancer in BRCA1 mutation carriers– Papillary serous carcinoma of peritoneum may arise in BRCA1 carriers after
oophorectomy. (Schorge et.al.1998, Piver et.al. 1993.)
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Conclusions
• The benefits of prophylactic tamoxifen remain unproven.
• Family history of breast cancer is not necessarily a contraindication for HRT.
• More studies are needed
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Conclusions
• Prophylactic mastectomy can have a role in patients at high risk of breast cancer.
• Prophylactic oophorectomy may reduce risk of ovarian cancer and breast cancer. Peritoneal tumours may still arise.
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Conclusions
• Screening of high risk patients can be effective in detecting breast cancer.
• Overall benefit of screening remains to be demonstrated.
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Presenting Risk
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Lifetime Absolute Risk
• Your lifetime risk of dying is 100%
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Relative Risk
• Your Risk of dying is 1X that of the population
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Absolute Risk over Time
• Your risk of dying over the next 10 years is
2%
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Presenting Risk
• Absolute Risk over a given time is – Easy to understand– Easy to base decisions upon
• Relative Risk can be converted to absolute risk– Assuming relative risk is constant over time– Assuming individual belongs to the population studied
• (Dupont and Plumber 1996)
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How Can Risk be Estimated from Family History ?
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Risk Analysis - Situation A
• Mother and Sister Affected with Breast Cancer
60
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Risk Analysis - Situation B
• Three Relatives Affected with Breast Cancer
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Risk Analysis - Situation C
• Mother Affected with Ovarian Cancer and Sister with Breast Cancer
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Risk Analysis - Situation D
• Mother affected with bilateral breast cancer
40/55
40
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Risk Analysis - Situation E
• Two second degree relatives with breast cancer < age 60
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Risk Analysis - Situation F
• Mother affected with breast cancer age 45 and ovarian age 65
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Estimation of Risk
• Empirical Data Studies– OPCS data set 3295 cases of breast cancer– CASH data set 4730 cases of breast cancer– Meta-analysis - Pharoah et.al.74 published studies
• Modelling of Data– CASH data– Gail Model 2,852 cases of breast cancer
• Linkage/Computer Analysis– Cyrillic (Uses CASH data)
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Empirical Estimation of Risk
Advantages
– No model is assumed
– Information is directly applicable
Disadvantages
– Data is population specific
– Data only covers a small range of situations
– Large studies are needed for meaningful data
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CASH data (Claus et.al. 1990)
• Kaplan-Meier estimates of cumulative risk– By age of onset of breast cancer in 1o relative
• Hazard ratios for other family histories
– Sister and mother affected RR 5.9 (3.9-8.9)
– Two sisters affected RR 3.6 (2.1-6.1)
– One mother, 2 sisters RR 17 (9.4-31)
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Meta-AnalysisPharoah et.al.1997
• Applicable to limited situations
– Affected 1o relative RR 2.1 (2.0-2.2)– Mother and sister RR 3.6 (2.5-5.0)– Sister affected <50 RR 2.7 (2.4-3.2)– Mother affected <50 RR 2.0 (1.7-2.4)
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Estimation of Risk Using Models
Advantages
– Data can be widened to a greater range of situations
Disadvantages
– Can generalise to situations where data is not applicable
– Risks are often based on a small number of data points
– Risks calculated are population specific
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Modelling of Breast Cancer Risk
“Gail” Model (BCDDP data)– Incorporates age at menarche, parity, and affected 1o relatives
– Curves given to estimate 10, 20 and 30 year risk
– No mode of inheritance assumed
CASH data model– Using age of onset and first degree relative data only
– Segregation analysis suggests dominant major locus
– Give cumulative risk curves based on relatives and age of onset
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Linkage/Computer Analysis
Likelihood of developing breast cancer
=
Likelihood of dominant mutation in family
+ Likelihood of carrying mutation
+ Likelihood of developing cancer if mutation carrier(Mendel to determine LOD score, CASH data
penetrance figures/ current age)
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Linkage/Computer Risk Analysis
• Advantages– Generates a risk for a complex situation
• Uses age of onset• Uses unaffected individuals
– Easy to apply– Removes subjective element
• Disadvantages– Assumes single dominantly inherited gene– Assumes one set of penetrance values for a single gene– Prone to “rubbish in, rubbish out” phenomena– Essentially unvalidated
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So Which is Best ?
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20 Year Risk ComparisonRelative Risk
(Absrisk)CASH
(Empirical)GRAIL Cyrillic 3
SituationA (M+S)
13.7% 11%/21%* 8.5% 7.4%
SituationB (3 relatives)
(12.6%) (5.3%) (4%) 8.1%
SituationC (ov +Br)
- 14.4% - 6.3%
SituationD (Bilat. Br.)
9.7%/16.5 10%* 8.5% 10.3%
SituationE (2X2o Br.)
6.7% - - 5.1%
SituationF (Br/Ov)
- 14.4% - 7.4%
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Conclusions
• Different systems for risk estimation can give different results.
• Empirical risk calculation systems can only apply to well defined situations.
• Computerised risk assessment is based on assumptions that are not necessarily valid.
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Where do we start screening ?
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Current Guidelines
• SIGN Guideline - 3 times population risk
– 1o relative with bilateral breast cancer*– 1o relative with breast cancer <40– 1o male relative with breast cancer– 1o relative with breast and ovarian– 2 first or second degree relatives with breast cancer < 60– 3 first or second degree relatives with breast cancer
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Bilateral breast cancer in 1o relative
• 2-5% of breast cancer is bilateral• CASH data (USA families)
– risk same as if unilaterally affected relative
• Tulinius et.al. 1992 (Icelandic families)– RR 4.4* (3.39-6.49), RR 9 if first onset <45
• Houlston (British families, OPCS data)– RR 4.78 (0.12 to 26.62) postmenopausal onset– RR 7.78 (0.94 to 28.08) premenopausal onset
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10 Year Risk Estimates
Relative RiskAge
1 2 3 5 10
20 0.1 0.1 0.2 0.3 0.6
30 0.5 0.9 1.4 2.3 4.6
40 1.5 3.0 4.5 7.4 14
50 2.5 5.0 7.4 12 23
60 2.5 4.9 7.3 12 22
70 2.4 4.7 7.0 11 21
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Conclusions
• Setting the criteria for screening should depend on
– Estimation of absolute risk (age dependant)
– Effectiveness of screening (may be age specific)
– Resources available
– A sensible risk estimation system
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Future Research
• Validation of risk estimation
– Detailed comparison of methods of risk analysis– Application to pedigrees with known outcome
• (A retrospective-prospective study !)
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Future Research
• Validation of screening protocols for high risk individuals.
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Future Research(Long term)
• Audit of effectiveness of screening protocols and accuracy of risks calculated.
• This will be greatly facilitated by an effective computerised database.