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CHRISTOBEL SAUNDERS
Managing women at high risk of breast cancer –
how to assess risk and what to do
The Global Burden of breast cancer
1.8 million women diagnosed this year (and around 10,000 men)
Australian breast cancer statistics
2019
19,000 women and 160 men
2005
11,500 women
2007
13,000 women
2010
14,000 women 2014
15,000 women
Incidence by age
Incidence of breast cancer, by age of diagnosis, females, Australia, 2011
AIHW, Cancer in Australia, 2014
0
50
100
150
200
250
300
350
400
0–4
5–9
10–14
15–19
20–24
25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
80–84 A
ge-s
pecif
ic r
ate
(p
er 1
00
,00
0)
Age group
Mortality
Mortality from breast cancer, by year of death, females, Australia, 1982 to 2016
AIHW, Cancer in Australia, 2014
0
5
10
15
20
25
30
351982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
Ag
e-s
tan
dard
ised
rate
(p
er 1
00
,00
0)
Year
Breast Cancer Survival
Stage 1-3
5-year survival rates
1982-86 72.2%
1987-91 74.7%
1992-96 80.6%
1997-01 85.4%
2001-06 88.1%
2007-11 89.6%
2031-36 99% ??
2018 - 93%
Survival - single institution results Survival of SurvFFStage:Survival proportions
0 12 24 36 48 600
10
20
30
40
50
60
70
80
90
100Stage 0
Stage I
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Time (months)
Percen
t su
rviv
al
What puts a woman at increased risk?
• Age - a woman aged 30 has 1 in 3000 chance over next 10 years
• a woman of 50 has a 1 in 50 (2%) chance over the next 10 years
• OCP – extra 3 cancers/10,000 women over a decade during use only
• HRT – 1.4 RR mostly longer term and combined
• Endogenous hormonal factors
• Alcohol
• Obesity and sedentary lifestyle
• Breast density
Risk factors
Lifestyle Factors Environmental factors
Biomedical factors
Alcohol consumption Radiation Age
Overweight and obesity
?Occupation Family History of breast cancer
Physical inactivity Previous diagnosis of breast cancer or DCIS
Breast density
Hormonal factors
Family history
• Family history of
• Multiple relatives with young onset breast cancer and/or ovarian cancer or bilateral
• Male BC in the family
• Other cancers
• A known mutation in the family
• Ashkenazi Jewish heritage
• Only about 5% of women with breast cancer will carry a known genetic mutation
14
‘Angelina Jolie effect’ sees increase in double mastectomy rates among high-risk women at UK centre 83 procedures were performed during the 2014-2015 period, compared to 29 between January 2011 and June 2012. There was also an increase in new referrals. A total of 388 referrals were recorded from January to June 2014, up from 201 in the same period in 2012
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In the six weeks before Ms Jolie's announcement, Victorian clinics at the PeterMac and Royal Melbourne Hospital saw 10 low-risk, 101 medium-risk and 229 high-risk referrals. In the six weeks afterwards, they saw 42 low-risk, 235 medium-risk and 483 high-risk referrals
The size of the problem
• Over 100,000 Australian women have a strong family history of BC and/or OC and are at potentially high-risk ( >3 times the population risk).
• 450,000 women are at moderate risk (1.5-3 times the population risk).
• 30% of families with multiple cases of BC and/or OC have germline mutations in major cancer predisposition genes.
What are these high risk genes?
• BRCA 1 and 2 – they are genes which control repair of our DNA – around 1 in 800 men and women in Australia will have an inheritable defect in one area of these genes
• 40–80% risk of breast cancer
• 10–60% risk of ovarian cancer
• increased risk of breast cancer and prostate cancer in men
• potential slightly increased risk of other cancers such as melanoma and pancreatic cancer
Cumulative breast cancer risk in BRCA1 carriers
to 30y 3.2%
31-40y 19.1%
41-50y 50.8%
51-60y 54.2%
61-70y 85%
NB: A male BRCA2 carrier at 70 has about the
same risk as a normal female at 70
Other genes involved in breast/ ovarian cancer susceptibility
• Mutations in TP53, PALB2 and PTEN are associated with a high risk of breast cancer
• Mutations in CHEK2 are associated with moderate risk of breast cancer
• Common single nucleotide polymorphisms (known as SNPs) may (in combination) slightly increase or decrease a woman's risk of breast cancer
• Other undiscovered gene mutations may be associated with a high risk of breast and ovarian cancer
Abe Lincoln
Cowden’s Syndrome - PTEN
Identification : Gene Carrier
Risk assessment - identifying potential gene carriers
Identification potential gene carriers
FRA-BOC https://canceraustralia.gov.au/clinical-best-
practice/gynaecological-cancers/familial-risk-assessment-fra-boc
• Familial risk assessment
• Potentially high risk of breast and ovarian cancer (category 3) – advise referral to family cancer clinic, discuss risk reduction and surveillance, discuss trials, modifiable risk factors and self awareness
• Moderately increased risk (category 2) – possible referral to family cancer clinic, advise on surveillance, risk reduction and trials
• At or slightly above average risk – reassure, BreastScreen, modifiable risk factors
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https://www.petermac.org/iprevent
Who to refer and where to refer to
• Who to refer
• Known gene carriers and their relatives
• Those at high risk
• Selected individuals at medium risk
• What to do with the “worried well”
• Those with prior breast cancer who may be carriers
• Where to refer
• Familial cancer service KEMH
• Private genetic counselling
• High risk surveillance clinics
• Public RPH, FSH and SCGH
• SJOG Subiaco
• Private breast surgeons
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Potential gene carriers
10-15% mutation found
No mutation found
Predictive testing in at-risk relatives
Inconclusive
Positive Negative
Genetic counselling
Small % - mutation search (usually an affected
relative)
Women at high risk of breast cancer – what can we do? Screening
• Monthly BSE
• 6 monthly CBE
• Annual mammogram from 30 or 5 years younger than youngest affected relative
• Annual MRI from about 25 or 5 years
younger than youngest affected relative until 50y
• Ovarian surveillance useless
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BREAST MAGNETIC RESONANCE IMAGING performed under the professional supervision of an eligible provider at an eligible location where the patient is referred by a specialist, consultant physician or BreastScreen service clinical coordinator; and (i) a dedicated breast coil is used; and (ii) the request for scan identifies that the person is asymptomatic; and (iii) the patient is aged 50 (60) years or less; and (iv) that the patient is at high risk of developing breast cancer, due to one of the following:
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(A) three or more first or second degree relatives on the same side of the family diagnosed with breast or ovarian cancer; (B) two or more first or second degree relatives on the same side of the family diagnosed with breast or ovarian cancer, if any of the following applies to at least one of the relatives: - has been diagnosed with bilateral breast cancer; - had onset of breast cancer before the age of 40 years; - had onset of ovarian cancer before the age of 50 years; - has been diagnosed with breast and ovarian cancer, at the same time or at different times; - has Ashkenazi Jewish ancestry; - is a male relative who has been diagnosed with breast cancer; (C) one first or second degree relative diagnosed with breast cancer at age 45 years or younger, plus another first or second degree relative on the same side of the family with bone or soft tissue sarcoma at age 45 years or younger; or (ii) that genetic testing has identified the presence of a high risk breast cancer gene mutation.
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(A) genetic testing has identified the presence of a high risk breast cancer gene mutation either in them or in their first degree relative; or (B) has a first or second degree relative diagnosed with breast cancer before age 45 years, plus another first or second degree relative on the same side of the family with bone or soft tissue sarcoma at age 45 years or younger; or (C) has a personal history of breast cancer prior to age 50 years; or (D) has a personal history of mantle radiation therapy; (E) has a lifetime risk estimation of > 30% or a 10-year absolute risk estimation > 5% using the Tyrer-Cuzick (IBIS Risk Evaluator) algorithm version 8 or later
CESM images: standard mmg and subtraction view
Std (low energy) mmg Subtraction image shows areas of
iodine uptake
Non enhancing cyst
Mass
Mass
Enhancing IDC
Mammographic density is a strong predictor of breast cancer risk
•Women with extensive mammographic density are 4-6 times more likely to develop breast cancer than women of the same age with little or no mammographic density
Examples of mammographic density
Source: McCormack et al Cancer Epi Biomarkers & Prev 2006
Women at high risk of breast cancer – what can we do? Prevention
•Healthy lifestyle advice
• Tamoxifen
• Chemoprevention with other drugs (Arimidex)
• Prophylactic surgery (breast and ovaries)
Prevention
• Tamoxifen is the first PBS listed cancer prevention drug
• April 2016 the PBAC recommended a Restricted Benefit listing of tamoxifen for the reduction of breast cancer risk in patients at moderate to high risk of breast cancer.
• The evidence based on 4 placebo controlled trials • for every 1,000 patients treated with tamoxifen over a 10 y 14 fewer patients
would develop breast cancer
• 3 additional patients would develop endometrial cancer, 4 additional patients would develop deep vein thrombosis or pulmonary embolism, 7 additional patients would develop cataract
• same number of patients would die of all causes and breast cancer.
BRCA-P trial
• Denosumab to prevent breast cancer in BRCA carriers
41
Who at high risk takes up prevention?
•Uptake of risk-reducing medication in Australian mutation carriers <1%
• BSO - only 26% of Australian BRCA1 and 66% BRCA2 mutation carriers have had BSO by age 40/50 years
Surgery - mastectomy +/- reconstruction
Who could consider prophylactic mastectomy
• Known gene carriers
• Strong family history – role for testing unaffected women
• Age of FH cases
• Previous cancer
• Previous high risk benign lesions
•Dense breasts on mammography
• Ashkenazi ancestry
•Unclassified variants
• SNPs
Implant based
Implant reconstruction +/- “internal bra”
LD flap
Scarless Latissimus Dorsi Flap
Scarless LD Vs Traditional Myocutaneous Flap
• Shorter operating time (1hr)
• Shorter hospital stay (1.5 days)
• 25% less complication rate
• Outcomes equal to or better
Bilateral DIEP
Correcting defects - lipofilling
Nipple preservation or reconstruction?
•Risk of keeping nipple
•Different techniques to create a nipple • Local flap
• Skin graft
• Tattoo
Bilateral implant reconstruction with tattooed nipples
When should a patient consider surgery?
• Age of youngest affected in family
• Test results
• Newly diagnosed family members
• Childbearing
• Work and home life
• Increasing numbers of very young….
Who at high risk takes up prevention?
• Mastectomy: decreases risk>90% and reduces mortality. Australian data suggest only 21% mutation carriers have BPM.
• Associated with age, parity, FH, being mutation +, risk perception, fear of surgery, family obligations, doctor (inc GP) recommendation and possibly public wait times
Treatment Focused Genetic Testing – women DIAGNOSED with breast cancer
•Should women newly diagnosed with breast cancer all get a genetic test?
•Young (ie under 40 years) women diagnosed with breast cancer, even without a family history, may have up to 25% chance of having a mutation.
•Especially if cancer is of a special type called “triple negative”
•Or if they are of Ashkenazi Jewish (or a few other) origins
Health Insurance (Section 3C Pathology Services – BRCA Gene Testing No.2) Determination 2017. Effective
1st November 20172
2Australian Government Department of Health. Medicare Benefits Schedule Book, Operating from 01 November 2017 http://www.mbsonline.gov.au/internet/mbsonline/publishing.nsf/Content/1BC94358D4F276D3CA257CCF0000AA73/$File/201711-MBS.pdf (accessed 22 October 2017)
58
3https://www.eviq.org.au/cancer-genetics/genetic-testing-for-heritable-mutations/620-genetic-testing-for-heritable-mutations-in-the#65563 (accessed 17 November 2017) This Disclaimer is subject to copyright and may not be reproduced in any form without the express permission of the Cancer Institute NSW.
Current EviQ Guidelines: Genetic Testing for heritable mutations in the BRCA1 and BRCA2 genes (ID: 620 v.5)3a
59
3bhttps://www.eviq.org.au/WWW_eviQ/CmsPages/Protocols/PDF.aspx?uid=1620&format=Standard&print=print&pdf=pdf&pOpt= (accessed 17 November 2017) This Disclaimer is subject to copyright and may not be reproduced in any form without the express permission of the Cancer Institute NSW.
Referral guidelines for breast cancer risk assessment and consideration of genetic testing (ID: 1620 v.2)3b
3
Take Patient’s personal and family history of cancer
Manchester Scoring System Process4
4Adapted from: Evans DG, Harkness EF, Plaskocinska I, et al., Pathology update to the Manchester Scoring System based on testing in over 4000 families. Journal of Medical Genetics 2017;54:674-681.
Assign score based on Manchester Scoring system table
Manchester Scoring System table
(with pathology adjustment)4
Patient’s total score ≥15
This equates to >10% probability of BRCA1/2
gene mutation
Patient qualifies for MBS funded
BRCA1/2 genetic testing
Patient’s total score <15
Patient does not qualify for MBS funded BRCA1/2
genetic testing
(However, depending on personal and family history,
these patients may warrant a referral to genetics services
for further genetic investigation).
Consent patient for and order
BRCA1/2 genetic testing
Why breast cancer in gene carriers (or those with a strong FH) is managed differently
• Implications for
• Family
• Fertility
• Ovarian management
• Systemic treatments
• Radiotherapy
• Surgical management
• Surveillance
Support for high risk women
• High risk surveillance clinics
• Side effect management
• Support services
• State wide breast cancer clinical psychology service/ cancer psychology service
• Solaris Care
• Cancer Council WA
• Sex counseling (Women’s Centre, Subiaco)
• Breast Cancer Care WA
• Peer support
Take home messages
• Estimating risk of breast cancer in those with a family history and/or a known mutation
• Who to refer to familial cancer service or high risk clinic
• Understanding how to minimise risk
• Prevention strategies
• Screening in high risk women
• For women who have had breast cancer knowing how “gene status” can affect treatment decisions
• Support available
