转移性结肠癌靶向治疗的未来治疗策略研究

KRAS基因突变者EGFR抑制剂的疗效差 －对化疗耐药mCRC进行的回顾性分析
Reference Lièvre A, et al.1
Treatment ERBITUX ± CT
Objective response,
No. of patients
n (%)
(wild-type:mutant)
Wild-type Mutant
Survival probability
0.75
0.50
5.6 months (95%CI: 2.8–10.6)
0.25
15.6 months (95% CI: 10.9–22) 10.7 months (95% CI: 8.3–16.3)
p=0.0008
0.00 0
10
20
30
Time (months)
爱必妥治疗mCRC （n=85）
1.0
1.0
p=0.05 0.8
p=0.7 0.8
0.6
0.6
EGFR FISH+
0.4
0.4
0.2
0.0 0
EGFR FISH-
10 TTP (months)
0.2
EGFR FISH-
EGFR FISH+
0.0
20
0
10
20
30
Survival time (months)
Lièvre A, et al.
89
27
29
0
31.4 vs 10.1 (p=0.0001)
14.3 vs 10.1 (p=0.026)
aIn the combination therapy group (mutant vs wild-type): PFS=12 vs 34 weeks (p=0.016); OS=6.3 vs 10.3 months (p=0.003)
Survival probability Survival probability
KRAS基因突变状态对生存期的影响
Progression-free survival (PFS)a
1.00
1.00
0.75
0.75
0.50
p=0.0001
0.50
0.25
0.25
0.00
0
20
an=88
40
60
80
Time (weeks)
7. Amado RG, et al. J Clin Oncol 2019;26:1626–1634
Pmab + BSC
BSC alone
Change (%)
Change (%)
靶病灶缩小百分比 －可评价KRAS基因状态患者的资料
Mutant
160
Wild-type
160
120
PR (0%) SD (12%) PD (70%)
89 (65:24)
26 (40) 0 (0)
Benvenuti S, et al.2
Panitumumab or ERBITUX or ERBITUX + CT
48 (32:16)
10 (31) 1 (6)
De Roock W, et al.3
Finocchiaro G, et al.4 Di Fiore F, et al.5 Khambata-Ford S, et al.6 Amado RG, et al.7
apoptosis)
Yarden Y, Sliwkowski MX. Nat Rev Mol Cell Biol 2019;2:127–137; Chakravarti A, et al. Cancer Res 2019;62:4307–4315; Baselga J. Eur J Cancer 2019;37(Suppl. 4):S16–S22; Kawanaka H, et al. Life Sci 2019;69:3019–3033
1. Cappuzzo F, et al. Ann Oncol 2019;19:717–723; 2. Moroni M, et al. Lancet 2019;6:279–286; 3. Personeni N, et al. J Clin Oncol 2019;25 (18S) (Abstract No. 10569)
Lièvre A, et al.1
30
43
37
0
–
16.3 vs 6.9 (p=0.016)
Di Fiore F, et al.2
59
37
20
0
23.9 vs 13.0 (p=0.015)
–
De Roock W, et al.3,a
113
41
25
0
24.0 vs 12.0 (p=0.074)
9.9 vs 6.3 (p=0.020)
VEGF: 潜在的生物标记物?
VEGF
TSP-1 GAPDH
Tumor volume (mm3)
2500 2000 1500 1000
500 0 0
5
10
15
Time (days)
© 2000 American Association for Cancer Research
IEC-18
IEC-18/4A
EGF 受体信号传导通路：个性化治疗的合理性
Ligand: AREG/EREG Target for EGFR-ERBITUX
Target for EGFT-TK
inhibitor
pY
P13K pY
EGFR-TK
pY GRB2
SOS
RAS RAF
PTEN
STAT AKT
PP
Gene transcription Cell-cycle progression
扩增基因的表现形式
• 双微染色体
• 染色体区域扩增
• 在基因组内广泛分布
Albertson DG. Trends Genet 2019;22:447–455
EGFR 基因转录（mRNA）水平与生存期无关
a
• EGFR基因表达水平与爱必妥治疗后患者的生存期无明显相关 性（小样本研究）1
95% CI: 8 4.4–13.5 months
80
40
40
0
0
-40
-40
-80 Patient
-80 Patient
BSC = Best supportive care; Pmab = panitumumab
Amado RG, et al. J Clin Oncol 2019;26:1626–1634
KRAS基因突变可预测 爱必妥治疗患者的生存期和有效率
FISH法检测的EGFR基因表达
Cumulative distribution function Cumulative survival function
• 回顾性研究：FISH法检测的EGFR表达水平有可能预测爱必妥疗效1,2
• 但近期的一项研究并未发现EGFR表达水平与疗效之间的具有相关性3
Reference
No. of patients
KRAS mutant
(%)
Objective response rate (%)
Wild-type vs mutant (KRAS-evaluable population)
All patients KRAS mutant PFS (weeks) OS (months)
2 (6) 0 (0) 0 (0) 0 (0)
1. Lièvre A, et al. J Clin Oncol 2019;26:374–379; 2. Benvenuti S, et al. Cancer Res 2019;67:2643–2648; 3. De Roock W, et al. Ann Oncol 2019;19:508–515; 4. Finocchiaro G, et al. ASCO 2019 (Abstract No. 4021); 5. Di Fiore F, et al. Br J Cancer 2019;96:1166–1169; 6. Khambata-Ford S, et al. J Clin Oncol 2019;25:3230–3237;
MYC
JUN FOS
Proliferation/ maturation Chemotherapy/ radiotherapy resistance
MYC Angiogenesis
MEK MAPK
Cyclin D1
Cyclin D1
Invasion and metastasis
Survival (anti-
KRAS mutant
10.1 (8–16) 10.1 (5.1–13)
an=88
Lièvre A, et al. J Clin Oncol 2019;26:374–379
KRAS突变状态和爱必妥皮肤毒性与总生存期（OS）的关系
1.00
2 good prognostic factors (wild-type and grade 2/3 skin toxicity) 1 good prognostic factor (wild-type or grade 2/3 skin toxicity) 0 good prognostic factors (KRAS mutant and grade 0/1 skin toxicity)
Lièvre A, et al. AACR Annual Meeting 2019 (Abstract 5671)
IEC-184B
RAS-3
RAS-4
SRC-3
20
25
SRC-4
Rak J, et al. Cancer Res 2000;60:490–498
KRAS基因突变的理论假设
• KRAS基因突变能够激活下游RAS/MAPK信号 传导通路，这种激活无需配体诱导的EGFR激活
– 导致爱必妥耐药 – KRAS基因突变预测爱必妥疗效和判断mCRC预后的
1. Lièvre A, et al. Cancer Res 2019;66:3992–3995; 2. Di Fiore F, et al. Br J Cancer 2019;96:1166–1169; 3. De Roock W, et al. Ann Oncol 2019;19:508–515; 4. Lièvre A, et al. J Clin Oncol 2019;26:374–379
作用有待证实
MAPK = 丝裂原激活的蛋白激酶
Lièvre A, et al. J Clin Oncol 2019;26:374–379
40%的CRC具有KRAS基因突变 KRAS基因突变是CRC发生的早期事件
Fodde R, et al. Nature Rev Cancer 2019;1:55–67
0.00
100
0
Overall survival (OS)a
mutant Wild-type
p=0.026
10
20
30
Time (months)
Median PFS (95% CI), weeks Median OS (95% CI), months
KRAS wild-type
31.4 (19.4–36) 14.3 (9.4–20)
KRAS基因突变并非CRC的孤立事件
• KRAS突变与BRAF突变相联系，后者与CpG 岛甲基化表型（CIMP）1，2有关
• KRAS突变与PI3K突变相关3
1. Yuen ST, et al. Cancer Res 2019;62:6451–6455; 2. Weisenberger DJ, et al. Nat Genet 2019;38:787–793; 3. Lièvre A, et al. Cancer Res 2019;66:3992–3995
120
PR (17%) SD (34%) PD (36%)
Change (%)
80
80
40
40
0
0
-40
-40
-80 Patient
160
-80 Patient
160
120
PR (0%) SD (8%) PD (60%)
120
PR (0%) SD (12%) PD (75%)
Change (%)
80
Median survival (monthΒιβλιοθήκη Baidu)
6
7.3
p=0.09
months
4
95% CI:
1.7–4.5 months 2
2.2
0 Low
months
High
EGFR mRNA levels
a39例伊诺替康和奥沙利铂耐药的mCRC接受 爱必妥单药治疗
1. Vallböhmer D, et al. J Clin Oncol 2019;23:3536–3544
ERBITUX or ERBITUX + irinotecan
ERBITUX ± CT ERBITUX + CT
ERBITUX Panitumumab
113 (67:46)
27 (41) 0 (0)
81 (49:32) 59 (37:22) 80 (50:30) 208 (124:84)
13 (27) 12 (32) 5 (10) 21 (17)