Pharmacogenomics and clinical relevance in diverse populations. Mary V. Relling, Pharm.D.

Transcription

1 Pharmacogenomics and clinical relevance in diverse populations Mary V. Relling, Pharm.D.

2 Many factors influence drug disposition & response but inherited genetic variation has an underlying effect Pharmacogenetics E. Vessel, 1980s

3 Differences in the frequency of adverse effects and effectiveness among race/ethnic groups have long been recognized e.g. succinylcholine and muscle relaxation; INH and neurotoxicity

4 The minor allele in blacks is the major allele in whites for CYP3A5*3 Number of CYP3A5 functional alleles from INVEST-GENES participants. All pairwise comparisons after Bonferroni adjustment (black vs Hispanic, black vs white, Hispanic vs white). P< J A Johnson et al., Clinical Pharmacology & Therapeutics (2007) 81,

5 Patients on clopidogrel with poor metabolizer status for CYP2C19 (activates the drug) are at higher risk for death, MI, stroke Poor metabolizers for CYP2C19 differ by race: Whites 2-4% Blacks 4-7% Asians 20%

6 ~ 2 fold better response for the CC vs TT genotype, whatever the race group ~ Half the racerelated differences in viral response are explained by race-related differences in frequency of good response allele

7 ~ 2 fold better response for the CC vs TT genotype, whatever the race group

8 Diversity by Ancestry will increase in the US US Census Press Release

9 Lessons of the human HapMap, 1000 Genomes, and WTCC projects: Genomic diversity between individuals is common: 17 million SNPs (~1 in 150 bp) > 8000 CNVs (3.7% of genome) Chakravarti et al Nature 409, , 2001; The International HapMap Consortium Nature 449, and Nature 437, ; Conrad et al Nature 2009

10 Genomic Diversity between races (by ancestry) was set by out of Africa migration and persists 938 unrelated individuals from 51 populations of the Human Genome Diversity Panel at 650,000 SNPs Myers et al. Science 2008

11 Genetic variation between populations (Fst) is related to geographic distances from Africa Ramachandran et al PNAS 2005

12 Estimating geographic distances using waypoints more accurately reflects variation in FST than distances as the crow flies Ramachandran et al. PNAS 2005 and Cann et al (2002) Science

13 Genomics will permit ignoring self-declared race and will make mixed ancestry patients evaluable

14 ALL: acute lymphoblastic leukemia Most common childhood tumor Curable in 85-90% of patients using conventional chemotherapy alone Population-based coverage of patients on NCIsupported clinical trials (COG, SJ, DFCI)

15 ALL outcome differs by self-reported race and ethnicity N=4952 EFS Probability (%) American Indian Asian Blacks whites Hispanics Asians>whites> or = African Americans > Hispanics > Native American SEER Data Years After Diagnosis Kadan-Lottick, et al., 2005, JAMA 290:2008

16 Ancestral make-up (based on genomics) of Childhood ALL population in US (n=2534) can be used in place of (or in addition to) self-declared race/ethnicity % Genetic Ancestry 0 100% European African Asian Native American Yang J et al Nature Genetics 2011

17 Jun Yang

18 Genetic Differences by Race and Principal Component Analysis Blacks (Africa) Whites (Europe) AA AB BB

19 Genetic Differences by Race and Principal Component Analysis Blacks (Africa) Whites (Europe) Genotype: 0 (AA), 1 (AB), 2 (BB) AA AB BB Allele frequency at some SNPs can differ by race: race-informative SNPs Principal component analysis (PCA) mathematically summarizes genotypes at raceinformative SNPs into principal components (PC) PC quantitatively indicates ancestry Principal Component Yang J et al Nature Genetics 2011 Blacks (Africa) Whites (Europe) Whites (US) Blacks (US)

20 Used EIGENSTRAT to perform Principal Component Analysis (PCA) ALL patients (n=2534) St. Jude T13B and T15 COG 9904/9905/9906 Normal individuals (reference populations) 210 HapMap samples: YRI, CEU, CHB/JPT Affymetrix SNP arrays genotypes at ~600,000 germline SNPs Apply PCA to SNP genotype data set: PCs Each patient will have a score for each PC Yang J et al Nature Genetics 2011

21 PC1 separates African ancestry in reference; self-declared blacks in patients with ALL Reference Patients with ALL

22 PC2 separates Asian ancestry in reference; self-declared Asians in patients with ALL Patients with ALL Reference

23 PC3 is highest in self-declared Hispanic patients, which was not present in CEU, YRI, or Asian reference groups

24 Principal Component Analysis (PCA): EIGENSTRAT ALL patients (n=2534) St. Jude T13B and T15 COG 9904/9905/9906 Normal individuals (reference populations) 210 HapMap samples: YRI, CEU, CHB/JPT 105 Native Americans: 25 Maya, 30 Nahua, 25 Aymara, 25 Quecha Mao et al., Am J Hum Genet (6):1171 Affymetrix SNP arrays genotypes at ~600,000 germline SNPs Apply PCA to SNP genotype data set: PCs Each patient will have a score for each PC Yang J et al Nature Genetics 2011

25 Distribution of Native Americans in the Reference population 30 Nahua 25 Maya 25 Quecha 25 Aymara Mao X, et al. (2007) Am.J.Hum.Genet. 80(6):

26 High PC3 in Native American reference group

27 A Clustering by the Top 3 PCs: Hispanic patients cluster closest to Native American group; more admixture in patients than in reference populations B Population References Patients with ALL European ancestry African ancestry Native American ancestry Asian ancestry Self-reported White Self-reported Black Self-reported Hispanic Self-reported Asian Yang J et al Nature Genetics 2011

28 Only PC3 (Native American ancestry) was Associated with ALL Relapse (not PC1 or PC2) PC3>0.005 (N=553) PC3<0.005 (N=1980) P= Yang J et al Nature Genetics 2011

29 PC3 was Highly Correlated with Proportion NA Genetic Ancestry (assessed using STRUCTURE) PC3 pc P<10-16, r 2 = Proportion of Native American Ancestry indian Yang J et al Nature Genetics 2011

30 High Native American ancestry was associated with higher risk of relapse P =.0003 NA ancestry < vs > 10% P =.003 Hispanic vs non- Hispanic NA ancestry continuous Yang J et al Nature Genetics 2011

31 High Native American ancestry was associated with higher risk of relapse even among self-reported whites only P =.033 for NA ancestry < vs > 10% For NA ancestry continuous Yang J et al Nature Genetics 2011

32 Multivariate analysis shows prognostic importance of NA ancestry compared to other prognostic features in ALL Yang J et al Nature Genetics 2011

33 Treatment Regimens: All included glucocorticoids, VCR, anthracycline, asparaginase, MP, MTX Treatment Phase Remission Induction Consolidation Intensification Interim Maintenance and Continuation Length of Therapy St. Jude Total XIIIB a PVDA + VP/AraC MTX, 6MP St. Jude Total COG P9906 c COG XV b P9904/9905 c,d PVDA + 6MP/Cyclo/AraC MTX, 6MP Repeat induction 1 Repeat induction 2 Low risk: MTX/6MP, VCR/Dex Standard/High risk: MTX/6MP, VCR/Dex, VP/Cyclo, Ara C Low risk: MTX/6MP, VCR/Dex Standard/High risk: MTX/6MP, VCR/Dex, Dox, Asp PVDA 6MP, Cylco, AraC, VCR, Asp Delayed Intensification (DVDA, 6TG, Cyclo, AraC) 2 MTX/6MP, VCR/Dex Interim Maintenance (MTX, VCR, Asp) 2 PVDA or DVA MTX, 6MP, VCR, Dex +/- Delayed Intensification (DVDA, 6TG, Cyclo, AraC) MTX/6MP, VCR/Dex 120 weeks 120 weeks 130 weeks 130 weeks Yang J et al Nature Genetics 2011

34 Poor prognostic impact of high NA ancestry is attenuated by one extra phase of chemotherapy (DI) Yang J et al Nature Genetics 2011

35 Delayed Intensification (DI) Dexamethasone, vincristine, daunorubicin, asparaginase, thioguanine, cyclophosphamide, and cytarabine over 8 weeks Adds ~ 5 days hospitalization (of 134 weeks tx) [Gaynon et al J. Clin. Oncol. 2001; 19: ] Benefit in lower-risk pts has been questioned Possible that high % NA ancestry could be used as marker to identify pts likely to benefit from DI

36 Next steps Further validation in additional treatment contexts (COG trials AALL03B1, AALL08B1) Follow up on the mechanisms by which SNPs (race-related and not) associate with relapse (Dr. Jun Yang) In the future: consider modifying therapy in those with high-risk germline genomic profiles

37 Provocative questions Opportunities to address biologic differences among populations Streamline ID of causes of disparities to explore both underlying biological and social determinants Utilization of team science and multi-institutional approach nationwide Incorporate genome-wide germline studies into all cancer clinical trials Capitalize on pharmacogenomic findings from other diseases Evidence-based intervention strategies Consider using genomics to define subgroups to receive more intense therapy Race-agnostic gene/drug guidelines (CPIC, CPT)

38 Pharmaceutical Dept Hartwell Center St. Jude COG Jun Yang Geoff Neale Ching-Hon Pui Meenakshi Devidas Wenjian Yang Yiping Fan Dario Campana Michael J. Borowitz Jitesh Kawedia James Downing Cheryl L. Willman Laura Ramsey Biostatistics Susana Raimondi Gregory H. Reaman Shane Cross Cheng Cheng Sue Kaste William L. Carroll Jen Pauley Stan Pounds Sima Jeha Stephen P. Hunger PK RNs Deqing Pei Clinical & Res. Staff Naomi Winick Carl Panetta Xueyuan Cao PGRN Julie Gastier-Foster Kris Crews Kathy Giacomini Mignon Loh James Hoffman William Evans Nancy Cox Paul Scheet

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40 a Genetic ancestry was estimated using STRUCTURE Yang J et al Nature Genetics 2011

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42 Native American Ancestry was Associated with ALL Relapse Even within Patients with Negative MRD NA Ancestry 10% NA Ancestry <10% P=0.006 N=334 N=1500 Yang J et al Nature Genetics 2011

43 Q-Q Plot for the 444,044 Single SNP P values indicates excessive deviation from the null distribution when genetic ancestry was not adjusted for in GWAS Not adjusting ancestry Adjusting ancestry Observed P Value (-log10) N=2,534 Children Expected P Value (-log10)

44 N=54 N=95 N=360 N=164 N=292 N=73 N=696 N=517 N=241 P=0.03 P= P= Figure S8. Cumulative Incidence of Relapse by Genotypes at the PDE4B SNP (rs ) in the St. Jude Total Therapy XIIIB/XV (left panel), COG P9906 (middle panel), and COG P9904/9905 cohorts (right panel). P values were estimated by Fine and Gray s regression model after adjusting for treatment arms and genetic ancestry, as described in Methods.

45 Associations between Genetic Ancestry and Risk of ALL Relapse Genetic Ancestry P Value Hazard Ratio b (95% CI) European (0.67, 0.90) African (0.96, 1.41) Asian (0.85, 1.59) Native American (1.13, 1.81) a Genetic ancestry was treated as a continuous variable and assessed individually for association with risk of relapse; b The relative change (increase or decrease) in hazard rate of ALL relapse for each 50% increase in ancestry, e.g. the rate of relapse increases 1.43-folder for every additional 50% Native American ancestry. Yang J et al Nature Genetics 2011

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47 Patients (n=2534) St. Jude Total XIIIB a St. Jude Total COG P9906 c COG XV b P9904/9905 c,d Sample size Protocols similar with respect to: Gender, age, WBC, CNS status, DNA index, and MRD Yang J et al Nature Genetics 2011

48 ~ 20% of ALL pts in US with > 10% NA ancestry 10% Native American Ancestry Log 2 (Percent Native American Ancestry) Yang J et al Nature Genetics 2011