基于外周血EGFR突变检测临床意义的深度思考_王洁
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• • • • •
EGFR M0 35 35
Total
False Positive Rate=0%
22 29 51
False negative Rate=57.7%
22 64 86
No false positive results Specificity and positive predictive value 100% 29/51 (56.9%) of tumor EGFR M+ were cfDNA EGFR M- (false negatives) Sensitivity 43.1% (22/51), negative predictive value 54.7% (35/64) 57/86 (66.3%) concordance
Probability of progression-free survival progression 1.0 0.8 0.6 0.4 0.2 0.0 0 Patients at risk : Gefitinib 66 C/P 74 4 61 56 8 40 15 12
Months
L858R
Probability of progression-free survival progression 1.0 0.8 0.6 0.4 0.2 0.0 0 64 47 4 48 39 8 30 17 12
Docetaxel
Progression Free Survival
1:1
Cisplatin
Primary endpoint: PFS Secondary endpoint: OS; ORR; QOL; Safety
Overall Survival
外周血EGFR突变检测 外周血EGFR突变检测 EGFR
Randomized Study on Japanese Population with EGFR Mutation: NEJGSG002
Gefitinib N=98 CR PR SD PD NE 缓解率
HR=0.357 95% CI: 0.252-0.507, P<0.001 Kobayashi K, et al. 2009 ASCO Abstract 8016.
P/C N=100 0 29 50 15 6 29(29%)
4 69 13 8 4 73 (74.5%) P<0.001
生物标记物检测的采样情况
不可评估的主要原因包括： 不可评估的主要原因包括：
1217 随机患者 (100%) 1038 同意检测生物 标记物 (85%) 683 提供样本 (56%)
ESMO 2009
IPASS:Comparison of EGFR mutation status in cfDNA and tumor samples
Patients with known cfDNA and tumor EGFR mutation status (n=86) Tumor tissue, n EGFR M+ cfDNA, n EGFR M+ EGFR MTotal
Response (all patients)‡
CR PR CR / PR SD PD SD / PD
n (%)
24 (12.2) 115 (58.4) 139 (70.6) 38 (19.3) 20 (10.2) 58 (29.4)
EGFR mutation, n (%)
del 19 L858R (%)* EGFR mutation in serum, n (%)* del 19 L858R Not detected 64 (39.0) 33 (20.1) 67 (40.9) False Negative Rate
Months
Gefitinib (n=66) Carboplatin/paclitaxel (n=74) HR (95% CI) = 0.377 (0.255, 0.560) No. events gefitinib, 46 (69.7%) No. events C/P, 65 (87.8%)
Gefitinib (n=64) Carboplatin/paclitaxel (n=47) HR (95% CI) = 0.553 (0.35源自文库, 0.868) No. events gefitinib, 48 (75.0%) No. events C/P, 40 (85.1%)
Patients recruited in Japan (n=233) DNA extracted from paraffin-embedded archival tumor tissue cfDNA extracted from pre-dose serum samples
and/or
EGFR mutations detected by ARMS cfDNA EGFR M+: ≥1/21 mutationsa (n=46) EGFR M-: 0/21 mutations (n=148) EGFR M unknownc: (n=39) Tumor tissue EGFR M+: ≥1/29 mutationsb (n=56) EGFR M-: 0/29 mutations (n=35) EGFR M unknownc: (n=142)
基于外周血EGFR突变检测临床意义的深度思考 突变检测临床意义的深度思考 基于外周血 王 洁
北京大学临床肿瘤学院 北京肿瘤医院
IPASS Study:Progression-free survival by EGFR mutation type (ITT population)
Exon 19 deletion
SLOG Study:Survival in patients with EGFR mutation+ disease
Median PFS HR (months) (95% CI) 14.0 11.3–16.7 Probability of OS 0.8 Median 1.0 n 217 OS (months) 27.0 HR (95% CI) 22.7–31.3
HR (95% CI) = 0.29 (0.14, 0.60) p=0.0009
1.0
EGFR MHR (95% CI) = 0.88 (0.61, 1.28) p=0.5013
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0 0 4 8 12 Months 16 20 24
0.0 0 4 8 12 Months 16 20 24
Probability
1,0 0,8
135 (62.2) 82 (37.8)
‡Evaluated
in 197 patients
Time to Progression Exon 21
Time to Progression Exon 19
EGFR Serum
Mutated WT
1,0
EGFR Serum
Mutated WT
0,8
0,6
Probability
0,00 10,00 20,00 30,00 40,00 50,00
0,6
0,4
0,4
*Evaluated in the serum of 164 patients
0,2
0,2
0,0
0,0 0,00 10,00 20,00 30,00 40,00
16 6 2
20 2 1
24 0 0
16 5 0
20 1 0
24 0 0
18 4
13 2
Time from randomization (months)
Post-hoc Cox analysis with covariates p-values not calculated due to small patient numbers
WJTOG 3405
•ChemotherapyR naïve stage IIIb/IV NSCLC; • EGFR mutation (Exon 19 or 21); • PS 0–2; • Age ≥18y; A N D O M I S E
Gefitinib
Progression Free Survival
1.0
n 217
Probability of PFS
0.8
0.6
0.6
0.4
0.4
0.2 14.0 0 0 12 24 36 48
0.2 27.0 0 0 12 24 36 48
Time (months)
Time (months)
Rosell R, et al. N Eng J Med 2009;361:958–67
Patients at risk: Gefitinib 24 21 22 15 C/P
Japanese ITT population
Plasma DNA as Predictive Biomarker in IPASS (Japanese Subgroup)
Probability of progression-free survival progression 1.0
EGFR M+
外周血EGFR突变检测与组织的一致性 (敏感性与特异性)? 外周血EGFR突变检测能否预测疗效与生存?
Finding EGFR Mutation in Plasma DNA by PCR: Spanish Study
Value Erlotinib therapy, n (%) FirstFirst-line Second- thirdSecond- or third-line 113 (52.1) 104 (47.9)
血浆/血清游离 血浆 血清游离DNA 血清游离
患者血浆中有足够的游离DNA(是正常人的10倍)。 血浆中的游离DNA主要由凋亡和坏死的肿瘤细胞产 生，其遗传学特性与肿瘤基因组DNA相似。
CTC: NSCLC循环肿瘤
CTC
细胞-中位数74个/微升
蛋白组学:MALDI-MS 蛋白组学
血清/血浆游离 突变研究:争议的问题 血清 血浆游离DNA EGFR突变研究 争议的问题 血浆游离 突变研究
Months
Months
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease
Rosell R, et al. N Eng J Med 2009;361:958–67
北京肿瘤医院的研究
230 pts with tumor samples for EGFR mutation analysis DHPLC performed in plasma 102 pts received gefitinib (second line)
Bai and Wang JCO 27:2653, 2009
Comparison of cfDNA vs tumor tissue EGFR mutations based on 22 mutations analyzed for cfDNA
• 5 patients had a known mutation result by tumor tissue but not cfDNA • 108 patients had a known mutation result by cfDNA but not by tumor tissue • 86 patients had a known mutation status by both tumor tissue and cfDNA
•取样困难 取样困难 •样本量不足 样本量不足 •只有细胞学样本 只有细胞学样本 •样本取材于肿瘤外的其他部位 样本取材于肿瘤外的其他部位 样本取材于肿瘤外的其他部
可评估的: 可评估的 EGFR 突变 437 (36%) 突变: EGFR 基因表达数目 406 基因表达数目: (33%) EGFR 表达 365 (30%) 表达:
血浆DNA与原发瘤中EGFR突变的吻合度 血浆DNA与原发瘤中EGFR突变的吻合度 DNA与原发瘤中EGFR
False negative Rate=18.8%
False Positive Rate=20.2%
=
Bai and Wang JCO 27:2653, 2009
IPASS: Japanese Population
EGFR M0 35 35
Total
False Positive Rate=0%
22 29 51
False negative Rate=57.7%
22 64 86
No false positive results Specificity and positive predictive value 100% 29/51 (56.9%) of tumor EGFR M+ were cfDNA EGFR M- (false negatives) Sensitivity 43.1% (22/51), negative predictive value 54.7% (35/64) 57/86 (66.3%) concordance
Probability of progression-free survival progression 1.0 0.8 0.6 0.4 0.2 0.0 0 Patients at risk : Gefitinib 66 C/P 74 4 61 56 8 40 15 12
Months
L858R
Probability of progression-free survival progression 1.0 0.8 0.6 0.4 0.2 0.0 0 64 47 4 48 39 8 30 17 12
Docetaxel
Progression Free Survival
1:1
Cisplatin
Primary endpoint: PFS Secondary endpoint: OS; ORR; QOL; Safety
Overall Survival
外周血EGFR突变检测 外周血EGFR突变检测 EGFR
Randomized Study on Japanese Population with EGFR Mutation: NEJGSG002
Gefitinib N=98 CR PR SD PD NE 缓解率
HR=0.357 95% CI: 0.252-0.507, P<0.001 Kobayashi K, et al. 2009 ASCO Abstract 8016.
P/C N=100 0 29 50 15 6 29(29%)
4 69 13 8 4 73 (74.5%) P<0.001
生物标记物检测的采样情况
不可评估的主要原因包括： 不可评估的主要原因包括：
1217 随机患者 (100%) 1038 同意检测生物 标记物 (85%) 683 提供样本 (56%)
ESMO 2009
IPASS:Comparison of EGFR mutation status in cfDNA and tumor samples
Patients with known cfDNA and tumor EGFR mutation status (n=86) Tumor tissue, n EGFR M+ cfDNA, n EGFR M+ EGFR MTotal
Response (all patients)‡
CR PR CR / PR SD PD SD / PD
n (%)
24 (12.2) 115 (58.4) 139 (70.6) 38 (19.3) 20 (10.2) 58 (29.4)
EGFR mutation, n (%)
del 19 L858R (%)* EGFR mutation in serum, n (%)* del 19 L858R Not detected 64 (39.0) 33 (20.1) 67 (40.9) False Negative Rate
Months
Gefitinib (n=66) Carboplatin/paclitaxel (n=74) HR (95% CI) = 0.377 (0.255, 0.560) No. events gefitinib, 46 (69.7%) No. events C/P, 65 (87.8%)
Gefitinib (n=64) Carboplatin/paclitaxel (n=47) HR (95% CI) = 0.553 (0.35源自文库, 0.868) No. events gefitinib, 48 (75.0%) No. events C/P, 40 (85.1%)
Patients recruited in Japan (n=233) DNA extracted from paraffin-embedded archival tumor tissue cfDNA extracted from pre-dose serum samples
and/or
EGFR mutations detected by ARMS cfDNA EGFR M+: ≥1/21 mutationsa (n=46) EGFR M-: 0/21 mutations (n=148) EGFR M unknownc: (n=39) Tumor tissue EGFR M+: ≥1/29 mutationsb (n=56) EGFR M-: 0/29 mutations (n=35) EGFR M unknownc: (n=142)
基于外周血EGFR突变检测临床意义的深度思考 突变检测临床意义的深度思考 基于外周血 王 洁
北京大学临床肿瘤学院 北京肿瘤医院
IPASS Study:Progression-free survival by EGFR mutation type (ITT population)
Exon 19 deletion
SLOG Study:Survival in patients with EGFR mutation+ disease
Median PFS HR (months) (95% CI) 14.0 11.3–16.7 Probability of OS 0.8 Median 1.0 n 217 OS (months) 27.0 HR (95% CI) 22.7–31.3
HR (95% CI) = 0.29 (0.14, 0.60) p=0.0009
1.0
EGFR MHR (95% CI) = 0.88 (0.61, 1.28) p=0.5013
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0 0 4 8 12 Months 16 20 24
0.0 0 4 8 12 Months 16 20 24
Probability
1,0 0,8
135 (62.2) 82 (37.8)
‡Evaluated
in 197 patients
Time to Progression Exon 21
Time to Progression Exon 19
EGFR Serum
Mutated WT
1,0
EGFR Serum
Mutated WT
0,8
0,6
Probability
0,00 10,00 20,00 30,00 40,00 50,00
0,6
0,4
0,4
*Evaluated in the serum of 164 patients
0,2
0,2
0,0
0,0 0,00 10,00 20,00 30,00 40,00
16 6 2
20 2 1
24 0 0
16 5 0
20 1 0
24 0 0
18 4
13 2
Time from randomization (months)
Post-hoc Cox analysis with covariates p-values not calculated due to small patient numbers
WJTOG 3405
•ChemotherapyR naïve stage IIIb/IV NSCLC; • EGFR mutation (Exon 19 or 21); • PS 0–2; • Age ≥18y; A N D O M I S E
Gefitinib
Progression Free Survival
1.0
n 217
Probability of PFS
0.8
0.6
0.6
0.4
0.4
0.2 14.0 0 0 12 24 36 48
0.2 27.0 0 0 12 24 36 48
Time (months)
Time (months)
Rosell R, et al. N Eng J Med 2009;361:958–67
Patients at risk: Gefitinib 24 21 22 15 C/P
Japanese ITT population
Plasma DNA as Predictive Biomarker in IPASS (Japanese Subgroup)
Probability of progression-free survival progression 1.0
EGFR M+
外周血EGFR突变检测与组织的一致性 (敏感性与特异性)? 外周血EGFR突变检测能否预测疗效与生存?
Finding EGFR Mutation in Plasma DNA by PCR: Spanish Study
Value Erlotinib therapy, n (%) FirstFirst-line Second- thirdSecond- or third-line 113 (52.1) 104 (47.9)
血浆/血清游离 血浆 血清游离DNA 血清游离
患者血浆中有足够的游离DNA(是正常人的10倍)。 血浆中的游离DNA主要由凋亡和坏死的肿瘤细胞产 生，其遗传学特性与肿瘤基因组DNA相似。
CTC: NSCLC循环肿瘤
CTC
细胞-中位数74个/微升
蛋白组学:MALDI-MS 蛋白组学
血清/血浆游离 突变研究:争议的问题 血清 血浆游离DNA EGFR突变研究 争议的问题 血浆游离 突变研究
Months
Months
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease
Rosell R, et al. N Eng J Med 2009;361:958–67
北京肿瘤医院的研究
230 pts with tumor samples for EGFR mutation analysis DHPLC performed in plasma 102 pts received gefitinib (second line)
Bai and Wang JCO 27:2653, 2009
Comparison of cfDNA vs tumor tissue EGFR mutations based on 22 mutations analyzed for cfDNA
• 5 patients had a known mutation result by tumor tissue but not cfDNA • 108 patients had a known mutation result by cfDNA but not by tumor tissue • 86 patients had a known mutation status by both tumor tissue and cfDNA
•取样困难 取样困难 •样本量不足 样本量不足 •只有细胞学样本 只有细胞学样本 •样本取材于肿瘤外的其他部位 样本取材于肿瘤外的其他部位 样本取材于肿瘤外的其他部
可评估的: 可评估的 EGFR 突变 437 (36%) 突变: EGFR 基因表达数目 406 基因表达数目: (33%) EGFR 表达 365 (30%) 表达:
血浆DNA与原发瘤中EGFR突变的吻合度 血浆DNA与原发瘤中EGFR突变的吻合度 DNA与原发瘤中EGFR
False negative Rate=18.8%
False Positive Rate=20.2%
=
Bai and Wang JCO 27:2653, 2009
IPASS: Japanese Population