個 人 化 醫 學 之 路 The Ways toward Personalized Medicine 沈 志 陽 執 行 長 / 教 授 中 央 研 究 院 台 灣 人 體 生 物 資 料 庫 中 央 研 究 院 生 物 醫 學 研 究 所
糖 尿 病 比 一 般 人 較 為 肥 胖 ( 有 較 高 的 BMI) 一 般 人 糖 尿 病 人 並 非 所 有 糖 尿 病 都 體 重 過 重 並 非 所 有 體 重 過 重 都 會 得 糖 尿 病 Nat Rev Genet 2007;8:657
吸 菸 者 得 肺 癌 的 機 率 是 不 抽 菸 者 的 四 倍, 80% 的 肺 癌 被 歸 咎 於 吸 菸, 但 只 有 15% 的 吸 菸 者 得 到 肺 癌, 況 且 不 吸 煙 照 樣 會 的 肺 癌
0.150 Cumulative hazard 0.125 0.100 0.075 0.050 0.025 Intervention 2,341 Randomized 4,690 Intervention Comparison 2,349 Comparison 0.000 0 2 4 6 8 10 12 14 16 18 Year
Calcification in the breast
Calcification of the breast ADH 15% 惡 性 的 乳 腺 細 胞
(postmenopausal) Letrozole
乳 癌 藥 Letrozole 11 月 起 健 保 給 付 10/22/2009 國 內 每 年 約 新 增 8000 名 乳 癌 患 者, 即 使 是 早 期 乳 癌, 如 果 荷 爾 蒙 接 受 體 為 陽 性, 淋 巴 結 遭 侵 犯, 將 有 四 分 之 一 患 者 會 復 發 為 了 降 低 復 發 率, 健 保 局 將 於 11 月 1 日 給 付 芳 香 環 酶 抑 制 劑 藥 物, 降 低 患 者 的 死 亡 風 險 預 估 每 年 全 台 約 有 1000 多 名 乳 癌 病 友 受 惠 不 過, 乳 癌 患 者 服 用 Letrozole 後, 容 易 出 現 關 節 酸 痛 骨 鬆 潮 熱 疲 勞 頭 痛 的 副 作 用, 不 少 患 者 因 此 中 斷 服 藥 陳 訓 徹 強 調, 臨 床 發 現, 關 節 疼 痛 代 表 治 療 效 果 好, 患 者 可 能 得 忍 一 下 痛, 以 求 身 體 早 日 康 復
Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN) Patient No. 69, 22F, Drug: Tegretol a life-threatening adverse drug reaction with massive skin and mucosal cells death Phenotype: severe mucosal erosions, widespread cutaneous erythematous, macules with blisters, target-like lesions Incidence of SJS: In Caucasians: 2~3 cases per million person-years In Han Chinese: 8 cases per million person-years
發 生 我 為 什 麼 會 生 病? 進 展 要 不 要 積 極 治 療? 治 療 用 什 麼 藥 才 有 效? 會 不 會 有 副 作 用?
Risk, Progression and Treatment of Disease Individual Variation Genetic Susceptibility Somatic Genomic/Epigenomic alteration
個 人 化 醫 學 - 以 個 人 為 基 礎 的 疾 病 治 療 與 預 防
現 代 醫 學 - 對 症 下 藥 治 療 沒 反 應 / 強 烈 過 敏 副 作 用 相 同 的 病 相 同 的 治 療 有 反 應, 沒 副 作 用, 治 療 效 果 良 好
個 人 化 醫 學 - 對 人 下 藥 用 藥 前 的 基 因 篩 檢 CHIP 有 反 應, 沒 副 作 用, 治 療 效 果 良 好
Carbamazepine (CBZ) Indications of CBZ Epilepsy, Trigeminal Neuralgia, Neuropathic pain, Bipolar depression, Psychiatric disorders Commonly prescribed/first-line anti-convoulsant Common market names: Tegretol, Carbatrol, Neurotol, etc.
Stevens-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN) Patient No. 69, 22F, Drug: Tegretol a life-threatening adverse drug reaction with massive skin and mucosal cells death Phenotype: severe mucosal erosions, widespread cutaneous erythematous, macules with blisters, target-like lesions Incidence of SJS: In Caucasians: 2~3 cases per million person-years In Han Chinese: 8 cases per million person-years
Epilepsy Trigeminal Neuralgia Carbamazepine HLA-B*1502 Stevens-Johnson Syndrome
Personalized Medicine Consideration Strength/Consistency of association Direct cause or LD-based marker Single cause/multiple causes Functional Evidence Sensitivity/Specificity/PPV/NPV Spectrum of clinical manifestation and Other ADRs Clinical feasibility (Would pt wait? Could MT do?) Alternative medicine Pharmacoeconomics
Candidate-Gene Approach 157 CYP450 SNPs All HLA B, C, A and DRB1 alleles CBZ-SJS Genotyping Vt/Vt Vt/Wt Wt/Wt A B C DNA CBZ-Tolerant D E F No significant association between any of the CYP450 SNPs and CBZ SJS, however, the alleles B*1502, Cw*0801, A*1101 and DRB1*1202 within the HLA region occurred at increased frequency in CBZ SJS patients relative to the controls. Nature 428:486, 2004
A marker for CBZ-induced SJS/TEN: HLA-B*1502 Nature 428:486, 2004
Association of HLA-B*1502 with CBZinduced SJS/TEN in different populations. Country/ Major 1502 SJS/TEN Region Population a.f. Association Taiwan Han-Chinese 5.9 Strong Hong Kong Han-Chinese 10.2 Strong Thailand Thai 8.5 Strong China Southern Han-Chinese 7.1 Strong China Northern Han-Chinese 1.9 NA Japan Japanese 0.1 No Korea Korean 0.2 No Germany European 0 No France European 0 No
Personalized Medicine Consideration Strength/Consistency of association Direct cause or LD-based marker Single cause/multiple causes Functional Evidence Sensitivity/Specificity/PPV/NPV Spectrum of clinical manifestation and Other ADRs Clinical feasibility (Would pt wait? Could MT do?) Alternative medicine Pharmacoeconomics
The cellular nuclei were counterstained by DAPI (blue), and apoptotic keratinocytes were revealed by staining with PE-conjugated annexin V (red).
Cytotoxicity of CBZ-specific T cell clones via granulysin pathway. PBMCs from CBZ-SJS/TEN patients were stimulated with vehicle or CBZ, respectively; At day 6, both supernatant and cells were collected for analysis. Wei et al., J Allergy Clin Immunol. 2012
CBZ acts as an antigen and is presented by HLA. This HLA-peptide-drug complex is sufficient activate specific CD8+ T cells. CBZ (CBZ) Antigen presentation J Allergy Clin Immun 2007;120:870
Wei et al., J Allergy Clin Immunol. 2012 CBZ and its analog are presented by HLA-B*1502 in the absence of antigen processing. Drug Drug + B-LCL then washed extensively B-LCL prefixed with paraformaldehy then adding drug+ctls
Wei et al., J Allergy Clin Immunol. 2012
Personalized Medicine Consideration Strength/Consistency of association Direct cause or LD-based marker Single cause/multiple causes Functional Evidence Sensitivity/Specificity/PPV/NPV Spectrum of clinical manifestation and Other ADRs Clinical feasibility (Would pt wait? Could MT do?) Alternative medicine Pharmacoeconomics
HLA-B*1502 CBZ-SJS/TEN (+) (-) Yes A B Sen=A/(A+B),98.3% No C D Spc=D/(C+D),95.8% PPV=A/(A+C) NPV=D/(B+D) 5.6% 99.9% OR,1357; Incidence of CBZ-SJS/TEN,0.25% (A/B) / (C/D) A <<< C; B <<< D
All subjects, regardless of HLA-B status, were followed for 2 months, with weekly telephone interviews.
Indication for CBZ no. (%) HLA-B*1502 Positive Negative Total (n=372) (n=4483) (n=4855) Epilepsy 57 (15.3) 632 (14.1) 689 (14.2) Neuralgia 195 (52.4) 2430 (54.2) 2625 (54.1) Diabetes-related neuropathic pain 53 (14.2) 515 (11.5) 568 (11.7) Tinnitus 8 (2.2) 168 (3.7) 176 (3.6) Bipolar or other psychiatric disorder 12 (3.2) 122 (2.7) 134 (2.8) Other conditions 47 (12.6) 647 (14.4) 694 (14.3)
HLA-B*1502 (+) HLA-B*1502 (-) with Alter. Medication with CBZ (N = 215) (N = 4120) number of events Mild cutaneous events Rash and itching 5* 206 Rash, itching, and blisters 1 20 Rash, itching, and oral ulcers 0 14 Rash, itching, blisters, and oral ulcers 0 7 Itching, blisters, and oral ulcers 0 2 Blisters and oral ulcers 0 3 * Among these 5 subjects, the alternative drugs were gabapentin, lamotrigine, naproxen, imipramine, and prednisolone. This subject had rash, itching, and blisters after taking gabapentin as an alternative treatment. These symptoms were mild and disappeared in 7 days. Most occurred in the subjects were mild, localized, and transient. In some subjects, blisters developed only after the rash subsided (i.e, blisters were sporadic and tended not to occur at the same time as rash). Furthermore, many HLA-B*1502 negative subjects resumed taking CBZ without a recurrence of skin lesions.
HLA-B*1502 (+) HLA-B*1502 (-) with Alter. Medication with CBZ (N = 215) (N = 4120) number of events Severe cutaneous events Maculopapular eruption 0 3 Hypersensitivity syndrome 0 2 Urticaria 1* 1 * This subject had taken oxcarbazepine before study enrollment. Binding to 1502 Wei et al., J Allergy Clin Immunol. 2012
maculopapular hypersensitivity SJS TEN eruption syndrome HLA-A3101 rs2894342 in MHC HLA-B*1502
HLA-B*1502 (+) HLA-B*1502 (-) with Alter. Medication with CBZ (N = 215) (N = 4120) number of events Severe cutaneous events Maculopapular eruption 0 3 Hypersensitivity syndrome 0 2 Urticaria 1* 1 Steven-Johnson syndrome or Toxic epidermal necrolysis 0 0
Variable 2002 2003 2004 New recipients of carbamazepine (no.) 50,917 48,522 49,670 Subjects with ICD-9-CM diagnostic code 695.1 (no.) 1441 1261 1354 Carbamazepine-induced SJS TEN (no.) 123 108 116 Incidence of carbamazepine -induced SJS TEN (%) 0.24 0.22 0.23 P value for comparison between historical incidence and incidence among study subjects <0.001 <0.001 <0.001
The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects was strongly associated with a decrease in the incidence of carbamazepine-induced SJS TEN.
Prevention of ADR by genetic screening can be possible in a proper clinical setting High quality of medical/ public health practices Almost 100% NPV Two-day window period Alternative Medicine
Personalized Medicine Consideration Strength/Consistency of association Direct cause or LD-based marker Single cause/multiple causes Functional Evidence Sensitivity/Specificity/PPV/NPV Spectrum of clinical manifestation and Other ADRs Clinical feasibility (Would pt wait? Could MT do?) Alternative medicine Pharmacoeconomics
Media A: A Breakthrough of Personalized Medicine Media B: 3-Dollar Drug, 3-Thousand-Dollar Test
癲 癇 控 制 的 考 量. Drug DDD PDD/DDD Dose(mg)/ Cost/Tab Cost/Yr (mg) Tab. NT$ NT$ CBZ with 1000 0.522 200 3.0 2349 Genetic test 3000 Valproic acid 1500 0.667 500 13.0 7,804 Gabapentin 1800 0.523 300 11.4 10,732 Oxcarbazepine 1000 0.710 300 14.2 10,082 DDD: Defined daily dose, PDD: Prescribed daily dose. Cost/Yr = DDD x PDD/DDD xdose/tab x Cost/Tab x 300 days
三 叉 神 經 痛, 關 節 痛 的 考 量 CBZ the first-choice drug, no better alternative medicine Cost of genotyping (Real-time PCR) 1000 cases x 3000NT$/per assay = 3,000,000NT$ Estimated incidence of CBZ-SJS/TEN, 0.24% 1000 CBZ users are expected to have 2 SJS/TEN 3,000,000NT$/2 cases = 1,500,000NT$ to prevent one SJS SJS/TEN receiving compensation (TDRF, 1999-2008): 92.48%, 沒 有 嚴 重 後 遺 症 (400,000NT$); 2.26%, 有 嚴 重 後 遺 症 (1,000,000NT$); 5.26% 死 亡 (2,000,000NT$) 500,000NT$ to treat and compensate one SJS 生 產 力 的 損 失? 倫 理 的 合 理 性? 社 會 的 負 擔 能 力?
Personalized Medicine Consideration Strength/Consistency of association Direct cause or LD-based marker Single cause/multiple causes Functional Evidence Sensitivity/Specificity/PPV/NPV Spectrum of clinical manifestation and Other ADRs Clinical feasibility (Would pt wait? Could MT do?) Alternative medicine Pharmacoeconomics