Panel Testing and SNP Testing (Polygenic Risk Score) in Asian Women Soo Teo PhD FASc Head of Breast Cancer Research Programme Cancer Research

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1 Panel Testing and SNP Testing (Polygenic Risk Score) in Asian Women Soo Teo PhD FASc Head of Breast Cancer Research Programme Cancer Research Malaysia E mail: soohwang.teo@cancerresearch.my

2 How much of cancer is genetic? HERITABILITY The proportion of variability in disease risk due to genetic factors. Analysis of a Scandinavian twin registry [Mucci et al., JAMA 2016] Breast Cancer Prostate Cancer 57% Stomach Cancer 22% 6% Ovarian Cancer 39% Lung Cancer 18% 24% 31% 16% Head & Neck Cancer 9% 26% Genetics Shared Environment Soo Teo, GBCC 2017 Reversing Cancer 2

3 Genetic predisposition aka 2017 Caucasian Asian Unexplained: 50% Unexplained: 63% Other icogs SNPs, 3.8% icogs SNPs, 4.5% pre icogs SNPs, 9.7% TP53, PTEN, ATM, ~3%* BRCA1/2, ~16%* 18% SNPs 19% rare variants *No Asian estimates currently available. Estimated from Peto et al (1999) JNCI, and Easton (1999) BCR Soo Teo, GBCC 2017 Reversing Cancer 3

4 Why do we do genetic testing? Population Reason What treatment is right for me? NEW Genes BRCA1, BRCA2 Cancer patient Unaffected woman/ relatives Why did I get cancer? Am I at risk of more cancers? What screening/prevention is right for me? Is my family at risk? Am I at risk? How much risk? What screening/prevention is right for me? High penetrant genes Polygenic risk score High penetrant genes Polygenic risk score Soo Teo, GBCC 2017 Reversing Cancer 4

5 Improved survival from therapy Olaparib in ovarian cancer Nerapanib in ovarian cancer Ledermann et al., NEJM 2016 Olaparib in breast cancer Mirza et al., NEJM 2016 many other PARP inhibitors Soo Teo, GBCC 2017 Tutt et al., Lancet 2010 Reversing Cancer 5

6 Gaps in access to genetic testing in Asia UK: 60 (2,000) Germany: 80 (2,000) 1,300 (50+176) 60 (10) 50 (364) 100 1,500 (48) (40) 7 (69) 28 (115) 5 (25) 240 (9) Population (millions) Carrier families (number) Challenge Severe under testing in Asia In Asia, <1% of newly diagnosed breast cancer patients receive genetic testing Our approach To develop a high throughput genetic testing method and to establish mainstreaming to increase affordability and accessibility Soo Teo, GBCC 2017 Reversing Cancer 6

7 The MaGiC Study Mainstreaming Genetic Counselling for genetic testing of BRCA1 and BRCA2 in ovarian cancer patients in Malaysia: MaGiC Objectives: Establish a population based cohort of ovarian cancer patients Determine the feasibility of training non genetics specialists (oncologists, gynae oncologists) to provide genetic counselling Recruitment open: 1 Jul 2016, currently in 20 sites, 106 patients Genetic testing at Cancer Research Malaysia (cost covered through research) Principal investigator: Ms Yoon Sook Yee, genetic counsellor Head of Lab: Dr Joanna Lim; genetics@cancerresearch.my Soo Teo, GBCC 2017 Reversing Cancer 7

8 Why do we do genetic testing? Population Reason What treatment is right for me? Genes BRCA1, BRCA2 Cancer patient Unaffected woman/ relatives Why did I get cancer? Am I at risk of more cancers? What screening/prevention is right for me? Is my family at risk? Am I at risk? How much risk? What screening/prevention is right for me? High penetrant genes Polygenic risk score High penetrant genes Polygenic risk score Soo Teo, GBCC 2017 Reversing Cancer 8

9 Key considerations for cancer patients Cancer patients already have a lot to deal with, dealing with future cancers may make it worse, therefore important to have strong evidence of benefit Good consequences of genetic testing: improved survival from appropriate therapy (for some) reduced risk of death from future cancers (provided there is high risk of such cancers and there is uptake of preventative surgery) reduced worry that their families are at risk (provided that this was a major concern in the first place) Bad consequences of genetic testing: false alarms (false positive tests, inaccurate estimates of risk) increase cancer worry (adding to the list of worries) Soo Teo, GBCC 2017 Reversing Cancer 9

10 Key considerations for Asian BRCA carriers Breast cancer patient 1 BRCA carrier 2 Increased risk of contralateral cancer 2 Increased risk of ovarian cancer Increased worry about cancer in family Improved survival? Improved survival? Improved QOL? 1. Is the prevalence similar in Asians vs Caucasians? 2. Is the penetrance (risk) similar in Asians vs Caucasians? 3. Is the uptake of preventative surgery/ screening similar in Asians vs Caucasians? Is the improvement in survival/qol similar in Asians vs Caucasians? 4. Is genetic testing cost effective in Asia? Soo Teo, GBCC 2017 Reversing Cancer 10

11 Challenges of risk assessment in Asia CHALLENGES Population risk of cancer changing rapidly. Changes in birth cohort, parity, hormone exposure are known to modify risk Risk of cancer among mutation carriers not accurate because studies in Asia still small Population based studies needed to provide more accurate estimates of risk Soo Teo, GBCC 2017 Reversing Cancer 11

12 Malaysian breast cancer genetic study 2592 Cases [incident & prevalent] Jan 2003 Apr 2015 Invasive, female, CMI 2815 Controls [opportunistic screening] Jan 2011 Apr 2015 No personal history of cancer, CMI Amplicon based targeted sequencing [31 breast cancer associated genes] Variant calling [GATK Recommended Best Practices] Variant reconfirmation [Sanger sequencing] Fluidigm Access Array Illumina HiSeq 2000 Current study Number of genes 31 # confirmed variant 371 out of 419 Sensitivity12 89% [86 92%] Soo Teo, GBCC 2017 Reversing Cancer 12

13 Prevalence of BRCA variants Class Non carriers BRCA1 Deleterious Non C0 rare MS BRCA2 Deleterious Non C0 rare MS Cases (N = 2,592) 2, (2.2%) 15 c (0.6%) 66 (2.5%) 32 d (1.2%) Controls (N = 2,815) 2,758 5 (0.2%) 6 (0.2%) 6 (0.2%) 40 (1.4%) ExAC EA (N = 4,327) 4,254 7 (0.2%) 7 e (0.2%) 9 (0.2%) 51 (1.2%) OR (95% Cl) a (reference) 13.0 ( ) 2.8 ( ) 12.5 ( ) 0.9 ( ) OR (95% Cl) b (reference) 14.3 ( ) 3.8 ( ) 12.9 ( ) 1.1 ( ) 1. ~5% breast cancer patients = BRCA1 or BRCA2 carriers 2. <2% = non C0 variants in BRCA1 or BRCA2 3. OR 13. If population risk = 5%, BRCA risk 45% [< Caucasians] a Cases vs. controls b Cases vs. ExAC East Asian c 2 Class 5 (deleterious variants were also classified as C65 variants d 1 Class 5 (deleterious) variants were also classified as C25 variant e 1 Class Author, 5 (deleterious) Occasion variant were also classified as C65 variant Reversing Cancer 13

14 Prevalence across populations Population Country Patients Mean age Asian Caucasian African American Hispanic China 1 5,931 NOS 110 (1.9%) BRCA1 BRCA2 Either % 122 (2.1%) % Malaysia 2 2, (2.2%) 66 (2.5%) % China (3.6%) 22 (4.3%) % USA (1.4%) 3 1.4% USA (0.3%) 1 0.3% Norway (1.5%) 1 (0.2%) 7 1.7% German (3.7%) 12 (2.5%) % Sweden (3.6%) 10 (3.6%) % USA (7.1%) 17 (3.9%) % USA (7.4%) 9 (6.0%) % Columbia (0.8%) 1 (0.4%) 3 1.2% Peru (4.1%) 2 (0.8%) % 1 Zhang, BCRT, 2016; 2 This study; 3 Zhong,PLoSOne,2016; 4 Newman, JAMA, 1998; 5 Kim, JMG, 2005; 6 Hoberg Vetti, EJHG, 2016; 7 Tung, JCO, 2016; 8 Winter, Ann Oncol, 2016; 9 Fackenthal, IJC, 2012; 10 Lyce, BCRT, 2015; 11 Koumpis, HCCP, 2011; 12 Abugattas, Clin Genet, 2015 Soo Teo, GBCC 2017 Reversing Cancer % 0.3 2% 6 13% 11 13% 1 5%

15 Assessing current recommended guidelines for genetic testing: NCCN vs Malaysian guidelines Category % of patients (N = 2,592) %BRCA1 (N = 57) % BRCA2 (N = 66) %BRCA1/2 (N = 123) NCCN MyCPG NCCN guidelines: identifies 80% of BRCA carriers in Malaysian breast cancer patients but may not be attainable because of cost and access to genetic counselling 2. Malaysian guidelines: More stringent criteria for genetic testing (fewer patients referred for genetic counselling and testing) but may miss up to 40% of carriers Soo Teo, GBCC 2017 Reversing Cancer 15 15

16 Summary (1): BRCA tests in cancer patients 1 in 20 (5%) of Malaysian breast cancer patients have deleterious variants in BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 could affect breast cancer treatment choices Cancer patients already have a lot to deal with, dealing with future cancers may make it worse Gaps in knowledge in Asians: Is mainstreaming genetic counselling to improve access feasible? Estimates of future risk of cancers (e.g. contralateral breast cancer, ovarian cancer) Impact of genetic (e.g. polygenic risk score) and lifestyle modifiers of risk in Asian women Impact on survival Extent of cancer worry (negative effects of genetic testing) Cost effectiveness analyses Soo Teo, GBCC 2017 Reversing Cancer 16

17 Why do we do genetic testing? Population Reason What treatment is right for me? Genes BRCA1, BRCA2 Cancer patient Unaffected woman/ relatives Why did I get cancer? Am I at risk of more cancers? What screening/prevention is right for me? Is my family at risk? Am I at risk? How much risk? What screening/prevention is right for me? High penetrant genes Polygenic risk score High penetrant genes Polygenic risk score Soo Teo, GBCC 2017 Reversing Cancer 17

18 Key considerations for healthy people Hippocrates oath: First, do no harm Difficult to make healthy people better off than they already are (easy to make healthy people worse off) Strong evidence of benefit is important Good consequences of genetic testing: reduced risk of death (challenging in absence of an RCT) reassurance (assuming healthy people need reassurance) Bad consequences: false alarms (false positive tests, inaccurate estimates of risk) For carriers: potentially spend more of your life worrying about cancer For non carriers: false reassurance of low risk Soo Teo, GBCC 2017 Reversing Cancer 18

19 Cumulative cancer risk BRCA1 BRCA2 PALB2 Breast: 65% [44% 78%] 45% [31% 45%] 33% [25% 44%] Ovary: 39% [18% 54%] 11% [2.4% 19%] Antoniou et al., Am J Hum Genet (2003) Antoniou et al., NEJM (2014) Soo Teo, GBCC 2017 Reversing Cancer 19

20 Gene panel testing: clinical validity for 12 genes Genes Breast Ovarian Other BRCA1 Y (OR >10) Y (OR >10) Prostate BRCA2 Y (OR >10) Y (OR >10) Prostate, Pancreas TP53 Y (OR >10) N Many PALB2 Y (OR 5.3) N Pancreas? CDH1 Y PTEN Y STK11 Y ATM Y (OR 2.8) N? CHEK2 Y (OR 3.0) N? BRIP1 N Y (OD >3) RAD51C N Y (OD >3) RAD51D N Y (OD >3) Risk estimates available Clinical evidence for screening (some) Clinical evidence for RRM (some) Clinical evidence for RRSO (some) Note that risk estimates for these genes not available in Asians If relative risk is the same, lifetime risk may be <10 15% If absolute risk is the same, lifetime risk may be >20% Adapted Easton et al., NEJM 2015 Soo Teo, GBCC 2017 Reversing Cancer 20

21 Gene panel testing in healthy individuals Ensure appropriate genetic counselling E.g. implications of finding high penetrance gene with no/limited evidence of screening/prophylactic surgery, CDH1 Ensure appropriate clinical interpretation of moderate penetrance genes What should optimal management be? What does negative for a moderate penetrance gene mean? What does combination of risk alleles mean? Ensure appropriate interpretation of variants of uncertain significance Do not use bioinformatic tools in isolation Recommend: panels are studied in longitudinal cohorts Domchek et al., JCO 2013; Balmana et al., JCO 2016; Tung et al., Nat Rev Clin Oncol 2016 Soo Teo, GBCC 2017 Reversing Cancer 21

22 Population based testing may identify many variants with uncertain clinical validity Warren Gash et al., Hered Can Clin Practice 2016 Soo Teo, GBCC 2017 Reversing Cancer 22

23 Exceptional populations? 2.5% carriers in Ashkenazi population 11% of breast cancers 40% of ovarian cancers Malaysian population <0.4% carriers ~5% ~11% Compared population based screening versus family history (>10% probability) Uptake of screening: 71% Uptake of RRSO: min 30% Conclude: more cost effective to offer population based screening Manchanda et al. JCO 2015 Soo Teo, GBCC 2017 Reversing Cancer 23

24 Summary (2): panel tests for cancer patients 1 in 20 (5%) of Malaysian breast cancer patients have variants in panel of other genes Risk estimates for the majority of these variants unknown Cancer patients already have a lot to deal with, dealing with uncertainty of future cancers may make it worse Gaps in knowledge in Asians: Estimates of future risk of cancers Impact on treatment and survival Extent of cancer worry in dealing with uncertainty Cost effectiveness analyses Soo Teo, GBCC 2017 Reversing Cancer 24

25 Genetic predisposition aka 2017 Caucasian Asian Unexplained: 50% Unexplained: 63% Other icogs SNPs, 3.8% icogs SNPs, 4.5% pre icogs SNPs, 9.7% TP53, PTEN, ATM, ~3%* BRCA1/2, ~16%* 18% SNPs 19% rare variants *No Asian estimates currently available. Estimated from Peto et al (1999) JNCI, and Easton (1999) BCR Soo Teo, GBCC 2017 Reversing Cancer 25

26 Breast Cancer Association Consortium Main paper Breast: 35,084 SNPs selected from previous GWAS Ovarian: 22,252 SNPs selected from previous GWAS Breast: 45,290 cases Ovarian: 18,174 cases Breast: 41,880 controls Ovarian: 26,134 controls 41 new breast cancer loci 3 new ovarian cancer loci Mikailidou et al Nature Genet 2013 Pharoah et al Nature Genet 2013 Soo Teo, GBCC 2017 Reversing Cancer 26

27 Asian Breast Cancer Association Consortium Main paper Breast: 70 SNPs in 67 independent loci selected from previous European GWAS Breast: 23,637 cases Breast: 25,579 controls 21 breast cancer loci confirmed Zheng W et al Hum Mol Genet 2013; Cao et al., 2015 Soo Teo, GBCC 2017 Reversing Cancer 27

28 APOBEC3B deletion and breast cancer risk 0.6% Caucasians Chinese Malaysians 19.6% 11.4% 12.0% 43.4% 46.5% 79.8% 45.3% 41.5% Odds ratio 1 copy deletion: copy deletion: 2.29 No deletion 1 copy deletion 2 copy deletion Odds ratio 1 copy deletion: copy deletion: 1.76 Odds ratio 1 copy deletion: copy deletion: 1.38 Xuan, 2013 Long, 2012 Wen, BCR 2016 Soo Teo, GBCC 2017 Reversing Cancer 28

29 Are polygenic risk scores useful in Asians? > 100 genetic loci that are associated with breast cancer risk have been identified thus far. GAP: most have not been validated in South East Asian women It has been shown that Polygenic Risk Scores (PRS) can achieve useful level of risk stratification in European population. GAP: no risk assessment model is currently available for SEA women and it is unclear if PRS built on European women are appropriate for women of other ethnicities. Soo Teo, GBCC 2017 Reversing Cancer 29

30 Using European PRS in SE Asian women Mean SD Observed Theoretical Control Case Control 0.41 Case PRS Controls Cases Percentile, % OR (95% CI) < ( ) ( ) ( ) ( ) ref ( ) ( ) ( ) ( ) OR adjusted for study and age. c statistic = Soo Teo, GBCC 2017 Reversing Cancer 30

31 Using population specific PRS Mea n SD Observed Theoretical Control Case Control 0.76 Case PRS % Controls Cases OR (95% CI) OR (95% CI)* < ( ) 0.32 ( ) ( )0.44 ( ) ( ) 0.67 ( ) ( ) 0.66 ( ) ref ref ( ) 1.08 ( ) ( ) 1.2 ( ) ( ) 1.49 ( ) ( ) 1.83 ( ) OR adjusted for study and age; *corrected for over fitting using internal validation c statistic = c statistic* = Soo Teo, GBCC 2017 Reversing Cancer 31

32 Risk stratified approaches to screening UK NICE guidelines: enhanced surveillance for women with a FH with lifetime risk of developing breast cancer over 17% 8% of UK population at this level of risk Screening to start at earlier age? Mavaddat et al., JNCI 2015 Soo Teo, GBCC 2017 Reversing Cancer 32

33 Summary (3): PRS for healthy individuals 31 out 91 SNPs have confirmed association with breast cancer risk at p value < 0.05, of which 13 were previously identified/validated in East Asian populations. Discriminatory accuracy of the Caucasian SNPs PRS in our populations is similar to European population Women at the top 10% of the 30 SNPs population specific PRS have two fold increase risk of developing breast cancer compared to those in the middle quintile. The estimated AUC of the 30 SNPs PRS model is after correcting for potential over fitting Using a 30 SNPs PRS could help discriminate breast cancer risk in Chinese women from Malaysia and Singapore, although the discriminatory accuracy is not sufficient for clinical application Soo Teo, GBCC 2017 Reversing Cancer 33

34 Conclusions BRCA1 and BRCA2 testing: approaches for mainstreaming important to ensure appropriate interpretation of genetic tests and its use to guide treatment choices and risk management Panel testing for other genes: still in the research domain because of uncertainty regarding risk estimates. More Asian studies needed SNP testing for risk stratification: still in the research domain for Asian populations. Potential for impact in risk stratification for screening, but more Asian studies needed. Soo Teo, GBCC 2017 Reversing Cancer 34

35 Acknowledgements Doug Easton Antonis Antoniou Alison Dunning Nur Aishah Mohd Taib Yip Cheng Har Sean Wen Ho Weang Kee Patsy Ng Tan Min Min Joanna Lim Kwan Pui Yoke Nurhidayu Hasan Yoon Sook Yee Soo Teo, GBCC 2017 Reversing Cancer 35 35