Inherited mutations in BRCA1 and BRCA2 in an unselectedmulti‐ethnic cohort of Asian breast cancer patients and
healthy controls from Malaysia
Wei Xiong Wen, Kah Nyin Lai, Jamie Allen, Craig Luccarini, Joanna Lim, Min Min Tan, Shivaani Mariapun, Cheng Har Yip, Nur AishahMohd Taib, Alison Dunning, Douglas Easton, Soo Hwang Teo
Country Cohort Sample size BRCA1 carriers
BRCA2Carriers
BRCA1/2carriers
China1 High‐risk 99 7(7.1%)
11(11.1%)
18(18.2%)
China2 High risk 133 13(9.8%)
10(7.5%)
23(17.3%)
India3 High risk 91 11(12.1%)
4(4.4%)
15(16.5%)
Korea4 High risk 2,403 157(6.5%)
224(9.3%)
378(15.7%)
Malaysia5 Moderate‐to‐high risk 108 6(5.5%)
6(5.5%)
11(11%)
China6 High risk 1,576 68(4.3%)
80(5.1%)
146(9.3%)
Singapore7 High risk 359 14(3.9%)
18(5.0%)
31(8.6%)
Majority of BRCA1 and BRCA2 prevalence studies in Asians are conducted among high‐risk cohorts
1Yang, PLoS One, 2015, 2Cao, BMC Cancer, 2016, 3Rajkumar, APJCP, 2015, 4Kang, BCRT, 2015, 5Ng, Clin Genet,2016, 6Zhang, BCRT, 2016, 7Wong, PLoS One, 2015
Current risk models underestimate number of BRCA1 and BRCA2 carriers in Asian cohorts
Lower sensitivity, specificity, and positively‐predictive value compared to that of Caucasian populationsPossible reasons:• Lower population‐specific breast cancer incidence in Asians• Potential differences in lifestyle and genetic modifiers of risk
3
Thirthagiri, Breast Cancer Res 2008; Kurian et al., JCO 2008
BRCAPROAsians White
Observed Predicted Observed Predicted
BRCA1 11.5% 10.1% 7.5% 9.0%
BRCA2 13%* 2.2% 5.5%* 2.9%
Combined BRCA1/2 24.5%* 12.3% 12.5% 11.8%
Objective
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• To determine the prevalence of BRCA1 and BRCA2mutation in an unselected cohort of Asian breast cancer patients and unaffected control subjects• Determine odds ratio of breast cancer risk• Determine variables associated with carrier status• Enable calibration of risk prediction models
Methodology
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2592 Cases[incident & prevalent]Jan 2003‐Apr 2015
Invasive, female, CMI
2815 Controls[opportunistic screening]
Jan 2011‐Apr 2015No personal history of cancer, CMI
Amplicon‐based targeted sequencing[31 breast cancer associated genes]
Variant calling[GATK Recommended Best Practices]
Fluidigm Access ArrayIllumina HiSeq 2000
Variant reconfirmation[Sanger sequencing]
Current study
Number of genes 31
# confirmed variant 371 out of 419
Sensitivity 89% [86‐92%]
Cohort Description
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Category Cases (2,592) Controls (2,815)
Age (year)*Age distribution (%)*
<3030‐3940‐4950‐59≥60
Ethnicity (%)*ChineseMalayIndian
Family history (%)1o relatives with breast ca*1o /2o relatives with breast ca*
50.0 ± 10.8
2.613.832.531.719.4
66.919.113.9
13.621.3
52.6 ± 8.2
‐0.439.238.821.6
60.119.420.5
7.115.0
*p < 0.05
ClassCases
(N = 2,592)Controls(N = 2,815)
OR (95% Cl)
Non‐carriers
BRCA1DeleteriousNon‐C0 rareMS
BRCA2DeleteriousNon‐C0 rareMS
2,425
57 (2.2%)15 (0.6%)
66 (2.5%)32 (1.2%)
2,758
5 (0.2%)6 (0.2%)
6 (0.2%)40 (1.4%)
(reference)
13.0 (5.2‐32.4)2.8 (1.1‐7.3)
12.5 (5.4‐28.9)0.9 (0.6‐1.5)
Prevalence of BRCA1 and BRCA2 mutations
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BRCA1 and BRCA2 prevalence is similar to other Asian populations
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1Zhang, BCRT, 2016; 2This study; 3Zhong, PLoS One, 2016; 4Newman, JAMA, 1998; 5Kim, JMG, 2005; 6Hoberg‐Vetti,EJHG, 2016; 7Tung, JCO, 2016; 8Winter, Ann Oncol, 2016; 9Fackenthal, IJC, 2012; 10Lyce, BCRT, 2015; 11Koumpis, HCCP,2011; 12Abugattas, Clin Genet, 2015
Population Country Patients Mean age
BRCA1 BRCA2 Either %
Asian
China1 5,931 NOS 110 (1.9%)
122 (2.1%)
232 3.9%
Malaysia2 2,592 50.0 57 (2.2%) 66 (2.5%) 123 4.7%
China3 507 51 18 (3.6%) 22 (4.3%) 40 7.9%
Caucasian
USA4 211 56 3 (1.4%) ‐ 3 1.4%
USA5 400 57 ‐ 1 (0.3%) 1 0.3%
Norway6 405 57 6 (1.5%) 1 (0.2%) 7 1.7%
German7 488 50 18 (3.7%) 12 (2.5%) 30 6.1%
Sweden8 273 62 10 (3.6%) 10 (3.6%) 20 7.3%
African‐American
USA9 434 46.5 31 (7.1%) 17 (3.9%) 48 11.1%
USA10 149 47 11 (7.4%) 9 (6.0%) 20 13.4%
HispanicColumbia11 244 42 2 (0.8%) 1 (0.4%) 3 1.2%
Peru12 266 49 11 (4.1%) 2 (0.8%) 13 4.9%
4‐8%
0.3‐11%
11‐13%
1‐5%
% of BRCA1/2 carriers expressed as a function of overall carriers a Included 38 Ashkenazi Jewish
Population; Age Other studies Present study P
N BRCA1/2 N BRCA1/2
AsianZhang, BCRT, 2016≤40>40Missing
CaucasianTung, JCO, 2016 ≤4546‐60>60Missing
5,9311,144 (19%)4,787 (81%)
‐
488 a180 (37%)199 (41%)109 (22%)
‐
23284 (36%)148 (64%)
‐
2318 (78%)5 (22%)
‐‐
2,592483 (19%)2,063 (81%)
46
2,592861(34%)1,242 (48%)495 (19%)
46
12353 (44%)67 (56%)
3
12373 (61%)38 (32%)9 (8%)
3
0.15
0.19
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Age‐distribution of BRCA1 and BRCA2 carriers: More similar than expected
Population; Age Other studies Present study P
N BRCA1/2 a N BRCA1/2 a
Ashkenazi JewishWarner, JNCI, 1999
<3030‐3940‐4950‐59≥60Missing
African‐AmericanFackenthal, IJC, 2011
<50≥50Missing
4123 (0.7%)27 (6.6%)134 (33%)111 (27%)137 (33%)
‐
434265 (61%)169 (39%)
‐
481 (2%)
12 (25%)23 (48%)9 (19%)3 (6%)‐
4834 (71%)14 (29%)
‐
2,59267 (2.6%)351 (14%)827 (33%)806 (32%)495 (19%)
46
2,5921,245 (49%)1,301 (51%)
46
12311 (9%)39 (33%)38 (31%)22 (18%)10 (8%)
3
12388 (73%)32 (27%)
3
0.22
0.74
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Age‐distribution of BRCA1 and BRCA2 carriers: More similar than expected
% of BRCA1/2 carriers expressed as a function of overall carriers
Clinical variablesBRCA1 carriers
(N = 57)BRCA2 carriers
(N = 66)Non‐carriers(N = 2,469)
AgeFamily history of breast cancer (%)Up to first‐degree Up to second‐degree
Family history of ovarian cancer (%)Up to first‐degreeUp to second‐degree
Bilateral breast cancer (%)Ovarian cancer (%)Grade I/II/III (%)Stage I/II/III/IV (%)
ER+ (%)PR+ (%)HER2+ (%)TNBC (%)
40.9 ± 10.6*
33.3*42.1*
8.8*10.5*14.0*3.5*
2.8./22.2/75.0*23.8/50.0/23.8/2.419.1*16.3*6.5*78.0*
45.1 ± 10.2*
30.3*39.4*
4.5*4.57.61.5
0/51.1/48.9*24.0/34.0/26.0/16.0*
80.0*56.915.7*12.5
50.4 ± 10.7
12.720.4
1.01.74.50.6
12.1/49.4/38.430.0/51.1/14.4/4.5
66.557.129.317.1
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Clinical and demographic characteristics of BRCA1or BRCA2 carriers and non‐carriers
NCCN (USA) vs Malaysian Clinical Practice Guidelines for BRCA1 and BRCA2 genetic testing
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Shared criteria (NCCN, MyCPG)
Personal history of cancer Ovarian cancer
Bilateral breast cancer ≤50yo
Family history of cancer Male breast cancer
Ovarian cancer
Proband ≤50yo + ≥1 close blood relative with breast cancer
Different criteria
NCCN MyCPG
Personal history of cancer Primary breast cancer ≤45yo Primary breast cancer ≤35yo
Family history of cancer Breast cancer & pancreaticcancer
Breast cancer only
Pathology TNBC ≤60 years old TNBC ≤50 years old
NCCN has more relaxed criteria
Assessing current recommended guidelines for BRCA1 and BRCA2 genetic testing: NCCN vs. MyCPG
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Category % of patients(N = 2,592)
% BRCA1(N = 57)
% BRCA2 (N = 66)
% BRCA1/2(N = 123)
NCCN 45.7 89.5 72.7 80.4MyCPG 23.5 71.9 50.0 60.2
NCCN identified ~80% of BRCA1/2 carriers, but need to screen more patients
• 1 in 20 unselected Malaysian breast cancer patients are carriers of germline BRCA1 or BRCA2 deleterious mutation
• Based on NCCN guidelines for BRCA1/2 genetic testing• Half of breast cancer patients would need to be screened• 90% of BRCA1 carriers would be identified• 72% of BRCA2 carriers would be identified
• Our study provides the foundation for the calibration of risk assessment tools for the Asian population, and highlights the need for cost‐effective strategies to triage women for genetic counseling and testing in low resource settings.
Conclusions
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Acknowledgement
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• Wei Xiong Wen • Prof. Soo Hwang Teo• Dr. Weang Kee Ho• Cancer Research Malaysia• Universiti Malaya Medical Centre• Subang Jaya Medical Centre• University of Cambridge• University of Nottingham Malaysia Campus