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

4

• 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

5

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

6

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

7

BRCA1 and BRCA2 prevalence is similar to other Asian populations

8

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

9

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

10

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

11

Clinical and demographic characteristics of BRCA1or BRCA2 carriers and non‐carriers

NCCN (USA) vs Malaysian Clinical Practice Guidelines for BRCA1 and BRCA2 genetic testing

12

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

13

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

14

Acknowledgement

15

• 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