Download Breast cancer

Hereditary Breast Cancer –
Advances and Controversies
Dr. Ava Kwong
Chief, Breast Surgery Division,
Clinical Associate Professor and Assistant Dean, The University of Hong Kong;
Honorary Consultant, Department of Surgery, Hong Kong Sanatorium and Hospital;
Director, The Hong Kong Hereditary and High Risk Breast and Ovarian Cancer Programme;
Chairman, Hong Kong Hereditary Breast Cancer Family Registry;
Founding Member, Asian Hereditary Breast Cancer Consortium (ABRCA).
Hereditary Breast and Ovarian Cancer (HBOC)
• Inherited gene mutations account for about 5-10% of all breast cancers, and
about 15% of ovarian cancers. [National Cancer Institute, NIH]
• Most common breast cancer susceptibility genes: BRCA1 and BRCA2
• Over 1,700 BRCA1 and 2,000 BRCA2 distinct mutations have been reported
in Breast Cancer Information Core (BIC).
Elevated lifetime risk for BRCA1/BRCA2 mutation carriers
to develop breast/ ovarian cancer
100%
80%
General population
60%
BRCA1 carrier
40%
BRCA2 carrier
20%
0%
Breast cancer
Ovarian cancer
Antoniou et al, 2003; Chen et al., 2007
Genes Associated with HBC ++
33 (25-44)
The Genetic variants that predispose
to Breast Cancer
Couch FJ et al. Science 2014
HBOC genetic testing criteria
Breast cancer
Early onset, age ≤ 45 y
Male breast cancer
Triple negative breast cancer, age ≤ 60 y
Two breast cancer primaries, age ≤ 50 y
Family history
• with ≥ 1 close relative with breast cancer (≤ 50 y), male breast cancer, or
invasive ovarian cancer; or
• with ≥ 2 close relatives with breast cancer (any age), prostate cancer, and/or
pancreatic cancer; or
• ethnicity associated with higher mutation frequency.
Invasive ovarian cancer
Prostate cancer, with ≥ 1 close relative with breast (≤ 50 y), and/or
invasive ovarian, and/or pancreatic or prostate cancer.
Pancreatic cancer, with ≥ 1 close relative with breast (≤ 50 y), and/or
invasive ovarian, and/or pancreatic cancer.
NCCN Guidelines, Version 1.2015
Management Guidelines BRCA1/2 Carriers
Management Option
Screening Interval/Comments
SCREENING
• Clinical Breast Exam
• Breast MRI
• Mammogram
• Q6-12 mos beginning age 25
• Yearly age 25-75 (then individualize)
• Yearly age 30-75 (then individualize)
• Transvaginal ultrasound*
• CA-125*
• Q6 mos beginning age 30
• Q6 mos beginning age 30
PREVENTION
• Bilateral mastectomy
• Discuss option with patient
• Bilateral salpingo-oophorectomy • Recommend by age 35-40 and when
childbearing complete
• Consider oral contraceptive
• Consider tamoxifen
• Consider Raloxifene
* If no RRSO
Modified from NCCN guidelines – v1.2014
Annual MRI surveillance reduced incidence of advanced-stage
breast cancer in BRCA1/2 carriers
Cumulative incidence of early-/ late-stages of breast cancer
Stages 0 to I
Cumulative incidence at Year 6
• MRI screened cohort:
13.8% (95% CI, 9.1% - 18.5%)
• No MRI control group:
7.2% (95% CI, 4.5% - 9.9%)
Stages II to IV
Cumulative incidence at Year 6
• MRI screened cohort:
1.9% (95% CI, 0.2% - 3.7%)
• No MRI control group:
6.6% (95% CI, 3.8% - 9.3%)
Warner et al., 2011
Risk Reducing Salpingo-Oophorectomy (RRSO)
Mortality Reduction in BRCA Carriers
12
10
8
No RRSO
RRSO
6
%
RR 0.40*
4
RR 0.44*
2
RR 0.21*
* P < 0.05
0
All cause
Breast CA
Ovarian CA
RRSO associated with reduction in risk of
ovarian (~80%) and breast cancers (~ 50%)
Domchek S et al. JAMA 2010;304:967
Courtesy of Dr. JE Garber
Can we do breast conservation
surgery in BRCA mutation carriers?
Study
Yr
No. of
BRCA1/2
mutation
carriers
No. of
Controlsa/
noncarriers
b
Median
followup (yr)
IBTR
CBC
Carriers (%)
Controlsa/
noncarriers
b (%)
P
valuec
Carrier
s (%)
Controls
P
a/noncar
valuec
riersb (%)
Robson
99
28
277b
10
22
7
0.25
27
9
0.002
Pierce
00
71
213a
5
2
4
0.8
20
2
<0.000
1
Haffty
02
22
105b
12
49
21
0.007
42
9
0.001
Seynaev
04
26
174a
6
30
16
0.005
14
6
0.06
Robson
05
87
_
6
14
_
_
38
_
_
Kirova
05
27
261a
104b
9
24
19a
22b
0.47
0.96
37
7a
18b
0.0003
0.02
Pierce
06
160
104d
445a
435d
8
24
NM
17
NM
0.19
0.04d
39
7
<0.000
1
GarciaEtienne
09
54
162a
4
27
4
0.03
25
1
0.03
IBTR ipsilateral-breast tumor recurrence; CBC contralateral breast cancer; NM not mentioned
a Untested controls with negative family history
b Tested non-carriers
c Carriers vs. controls or carriers vs. noncarriers accordingly
d Only patients without oophorectomy (multivariate analyses)
Three important factors have been
identified
• Prophylactic oopherectomy
• Tamoxifen
• Use of chemotherapy
• IBTR after BCS in BRCA mutation carriers compared
with sporadics is significantly increased without
these factors whereas with these the IBTR is similar
to sporadics
OCP and breast cancer risk
• Oncological (medication)
– Oral contraceptive pills
• >6 years decrease risk by 60%
• Moderate increase in breast cancer risk
– Mainly in those using OCP before 1975
– Brohet et al- increase risk of breast cancer among mutation
carriers but this is same as general population (HR1.47, 95% CI,
1.16-1.87)
– Moorman et al 2013: meta-analysis 6 studies
» Reduced ovarian cancer risk (0.58, 95% CI0.46-0.73)
» Trend towards iincreased breast cancer risk (OR1.21, 95% CI
0.93-1.58)
» Both BRCA mutation carriers or non carriers
Newer approach – therapeutic
Gepar-Sexto: Results in TNBC by BRCA/Family Hx
•
•
•
•
Blood on 295 of 315 patients in TNBC trial cohort
35 gBRCA1+ and 3 gBRCA2+
78 patients have family history of breast cancer
179 neither BRCA1/2 nor family history
Overall pCR
Carbo
No Risk
Family Hx
gBRCA+
40.2%
44.9%
57.9%
54%
64.9%
82.9%
• gBRCA mutation and family history are predictors of higher pCR
rates after neoadjuvant Anthracycline/Taxane in TNBC.
• Carboplatin effects are additive, most prominently in gBRCA
carriers
Von Minckwitz et al. 2014: ASCO #2005
Single Agent Olaparib in Metastatic Breast and
Ovarian Cancer +/- BRCA
TNBC: No responses if BRCA1/2 –
Ovarian: Responses in BRCA1/2+ and WT
Gelmon KA et al. Lancet Oncol 2011;12:852-61
Conventional ways to detect BRCA1/2 mutations
Sanger Sequencing
• DNA sequencing by chain termination method.
• Utilize di-deoxy-nucleotides to terminate DNA
chain elongation, followed by capillary
electrophoresis, and detection of fluorescentlabelled terminators.
• The Gold Standard in mutation testing.
Genotyping
 High resolution melting
•
Scan mutations by monitoring the melting
temperatures of PCR products.
 Sequenom mass spectrometry
•
Detecting the different masses of nucleotides.
 SNaPshot
•
Detecting the different fluorescent-labelled
nucleotides.
× Do not identify the exact sequence
alteration;
New approach to detect BRCA1/2 mutations
Next-Generation Sequencing (NGS)
• Also known as massively parallel sequencing;
• DNA sequencing by synthesis; detects signals (can be fluorescent, chemoluminescent, pH changes, depending on platforms) as DNA chains extend.
• Employing nano-technologies, the sequencing reactions are highly
minimized and multiplexed, allowing simultaneous sequencing of millions
of DNA chains (Massive and Parallel).
Different platforms developed:
 Roche 454
 Illumina
 Ion Torrent
 ABI SOLiD
 Pacific Biosciences RS
Illumina, Inc.
Benefits of NGS technologies
Decreasing cost for
DNA sequencing and
genetic testing
Next generation sequencing and VUS
Introducing Next-generation sequencing into Breast/ Ovarian cancer
genetic testing:
• Lower full genetic testing costs, providing more genetic and clinical
data for VUS interpretation.
• Allow simultaneous testing of multiple genes, including less penetrance
genes:
High penetrance genes:
• BRCA1; BRCA2; PTEN; TP53 …….
Moderate/low penetrance genes:
• ATM; CHEK2; PALB2; BRIP1 ……
• Co-occurrence of BRCA1/BRCA2
VUS with deleterious mutations in
other genes associated with the same
syndrome increases VUS neutrality.
Variants of Unknown Significance (VUS)
• With ambiguous effects on protein functions, and hence having uncertain
clinical significance.
• Over 800 (>45%) BRCA1 and 1,000 (>50%) BRCA2 distinct mutations in BIC
Database were classified as unknown importance.
• VUS rates for BRCA1/BRCA2 genetic testing: 5-20%; varied by ethnicity.
Mutations in
BRCA1 and BRCA2
Protein truncation,
Loss of functional
domains
Pathogenic /
Deleterious
not enough
evidence for
classification
?
Unknown
significance
No clinical significance,
polymorphism
?
Neutral /
Benign
VUS: Difficulties in risk managements, surveillance, and clinical options.
Multi-gene panels
• Helpful in some cases and has rapidly become the norm.
• Turnover time and even cost for panel testing is no longer a
barrier
• However --- Setting patient expectations about testing, Which
Panel to use?
• Already into thorny issues with panels
Incidental findings
Variants and Interpretive challenges
• Currently there are not strict management guidelines for lesser-
known breast/ovarian cancer susceptibility genes.
Specific issues management of Hereditary
breast cancer Asia
• Risk Assessment
• Cost
– Genetic test
– Surveillance, surgery, chemoprevention
– NGS is however reducing cost- more people can be tested
• Counselling availability
• Interpretation and clinical use of data from multigene panels
• Which panel is more accurate?
• Cultural and ethnic differences
– Mutation spectrums and Novel mutations
• Can be an advantage in studying BRCA2 mutation carriers
– Acceptance of surgical prevention strategies and
chemoprevention
– Psychological impact
Specific issues management of BRCA
mutation carriers in Asia
• Interpretation of Variants
• Unknown Penetrance
– Should we be doing prophylactic mastectomies
– Cost effectiveness of screening modalities such as MRI
breast screening due to possible differences in prevalence
• Mutation guided treatment- applicable worldwide
– Advances in development of new therapeutic agents
• Parp Inhbitors, Carboplatin based chemotherapeutics
– Biomarkers
Conclusion and Future perspectives
• Still , a large unexplored area for research here in
Asia and world wide
– Clinical outcome and relevance in screening and
prevention options
– Penetrance
– The Non BRCA mutation carriers
• Gene panels/NGS/Advanced Bioinformatics
• Interpretation and clinical use of data generated
from advances in Sequencing techniques!
Special thanks to all members of ABRCA who
contributed
My own team in University of Hong Kong, Hong
Kong Sanatorium and Hospital and Hong Kong
Hereditary Breast Cancer Family
Patients and families who have contributed to
research in the area of hereditary breast
cancers
Thank you
Ava Kwong
Contact:
[email protected]
[email protected]