中国癌症杂志
中國癌癥雜誌
중국암증잡지
CHINA ONCOLOGY
2014年
9期
657-668
,共12页
王芬%王洁%白桦%王书航%王树滨%申东兰
王芬%王潔%白樺%王書航%王樹濱%申東蘭
왕분%왕길%백화%왕서항%왕수빈%신동란
晚期非小细胞肺癌%表皮生长因子受体磷酸化酪氨酸%表皮生长因子受体基因突变%表皮生长因子受体酪氨酸激酶抑制剂%预测因子
晚期非小細胞肺癌%錶皮生長因子受體燐痠化酪氨痠%錶皮生長因子受體基因突變%錶皮生長因子受體酪氨痠激酶抑製劑%預測因子
만기비소세포폐암%표피생장인자수체린산화락안산%표피생장인자수체기인돌변%표피생장인자수체락안산격매억제제%예측인자
Advanced non-small-cell lung cancer%Epidermal growth factor receptor phosphorylation%Epidermal growth factor receptor mutation%Epidermal growth factor receptor-tyrosine kinase inhibitors%Predictive factor
背景与目的：近年来以吉非替尼和厄洛替尼为代表的表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors，EGFR-TKI)，因其在晚期非小细胞肺癌(advanced non-small cell lung cancer，NSCLC)治疗中独特的临床疗效和较低的不良反应而备受关注。尽管EGFR基因突变是目前认为最确切的预测EGFR-TKI疗效的指标，但与临床疗效间并非“全或无”的关系，提示仍有其他机制参与其中。本研究旨在探讨晚期NSCLC组织标本中EGFR磷酸化酪氨酸1068(EGFR-pTyr1068)、1173(EGFR-pTyr1173)表达与EGFR基因突变的关系，及其在EGFR-TKI治疗中的疗效预测价值。方法：采用变性高效液相色谱法(denaturing high performance liquid chromatography，DHPLC)检测205例晚期NSCLC患者组织中EGFR基因突变(19、21外显子突变)情况；并采用免疫组化方法检测其EGFR-pTyr1068、EGFR-pTyr1173表达。结果：晚期NSCLC患者组织中EGFR-pTyr1068和1173表达阳性率分别为80.0%(164/205)、57.6%(95/165)；其表达与临床病理特征(年龄、性别、病理类型、吸烟状态、疾病分期)无相关性。全组EGFR基因突变率为44.9%(92/205)，与吸烟状态有关(P=0.024)，而与其他临床病理特征(性别、年龄、病理类型、疾病分期)无关。EGFR基因突变与EGFR-pTyr1068表达呈弱相关性(P<0.001)，与EGFR-pTyr1173无相关性(P=0.297)。EGFR基因突变型患者EGFR-TKI治疗的客观缓解率(objective response rate，ORR)、疾病控制率(disease control rate，DCR)和中位无进展生存期(progress free survival，PFS)分别为48.3%(43/89)、80.9%(72/89)和8.8个月(95%CI：6.11~11.42)，均明显高于EGFR基因野生型患者[16.2%(17/105)、56.2%(59/105)和2.1个月，95%CI：0.89~3.24]，差异有统计学意义(P<0.001，P<0.001，P=0.024)；EGFR-pTyr1068表达阳性患者ORR和DCR分别为37.7%(58/154)和74.7%(115/154)，均明显高于表达阴性患者[5.0%(2/40)和40.0%(16/40)]，差异有统计学意义(P<0.001)。EGFR-pTyr1068表达阳性患者中位PFS为7.0个月，较表达阴性患者(1.2个月)明显延长，差异有统计学意义(P<0.001)。而EGFR-pTyr1173表达与EGFR-TKI疗效呈负相关性，EGFR-pTyr1173阳性者ORR、DCR和PFS分别为27.8%(25/90)、64.4%(58/90)和4.8个月，显著低于阴性患者[37.9%(25/66)、83.3%(55/66)和7.7个月，P=0.123，P=0.007，P=0.016]。以EGFR基因突变状态分层进行亚组分析显示，在EGFR基因野生型患者中，EGFR-pTyr1068表达阳性率为69.0%(69/100)， EGFR-pTyr1068表达阳性和阴性患者ORR分别为23.2%(16/69)和3.2%(1/31)，DCR分别为69.6%(48/69)和35.5%(11/31)，差异均有统计学意义(P=0.010，P=0.001)；EGFR-pTyr1068表达阳性患者中位PFS为3.6个月，较表达阴性患者(1.2个月)明显延长，差异有统计学意义(P<0.001)。16例EGFR-pTyr1068阳性表达且对EGFR-TKI有效患者，中位PFS为15.6个月(95%CI：7.28~23.9)。多因素分析显示，EGFR-pTyr1068是EGFR基因野生型患者EGFR-TKI治疗的独立疗效预测因子(OR=0.24，95%CI：0.16~0.37，P<0.001)。结论：EGFR-pTyr1068可作为晚期NSCLC患者接受EGFR-TKI治疗的有效预测因子，尤其对从EGFR基因野生型患者中筛选EGFR-TKI治疗有效者具有重要作用。
揹景與目的：近年來以吉非替尼和阨洛替尼為代錶的錶皮生長因子受體酪氨痠激酶抑製劑(epidermal growth factor receptor-tyrosine kinase inhibitors，EGFR-TKI)，因其在晚期非小細胞肺癌(advanced non-small cell lung cancer，NSCLC)治療中獨特的臨床療效和較低的不良反應而備受關註。儘管EGFR基因突變是目前認為最確切的預測EGFR-TKI療效的指標，但與臨床療效間併非“全或無”的關繫，提示仍有其他機製參與其中。本研究旨在探討晚期NSCLC組織標本中EGFR燐痠化酪氨痠1068(EGFR-pTyr1068)、1173(EGFR-pTyr1173)錶達與EGFR基因突變的關繫，及其在EGFR-TKI治療中的療效預測價值。方法：採用變性高效液相色譜法(denaturing high performance liquid chromatography，DHPLC)檢測205例晚期NSCLC患者組織中EGFR基因突變(19、21外顯子突變)情況；併採用免疫組化方法檢測其EGFR-pTyr1068、EGFR-pTyr1173錶達。結果：晚期NSCLC患者組織中EGFR-pTyr1068和1173錶達暘性率分彆為80.0%(164/205)、57.6%(95/165)；其錶達與臨床病理特徵(年齡、性彆、病理類型、吸煙狀態、疾病分期)無相關性。全組EGFR基因突變率為44.9%(92/205)，與吸煙狀態有關(P=0.024)，而與其他臨床病理特徵(性彆、年齡、病理類型、疾病分期)無關。EGFR基因突變與EGFR-pTyr1068錶達呈弱相關性(P<0.001)，與EGFR-pTyr1173無相關性(P=0.297)。EGFR基因突變型患者EGFR-TKI治療的客觀緩解率(objective response rate，ORR)、疾病控製率(disease control rate，DCR)和中位無進展生存期(progress free survival，PFS)分彆為48.3%(43/89)、80.9%(72/89)和8.8箇月(95%CI：6.11~11.42)，均明顯高于EGFR基因野生型患者[16.2%(17/105)、56.2%(59/105)和2.1箇月，95%CI：0.89~3.24]，差異有統計學意義(P<0.001，P<0.001，P=0.024)；EGFR-pTyr1068錶達暘性患者ORR和DCR分彆為37.7%(58/154)和74.7%(115/154)，均明顯高于錶達陰性患者[5.0%(2/40)和40.0%(16/40)]，差異有統計學意義(P<0.001)。EGFR-pTyr1068錶達暘性患者中位PFS為7.0箇月，較錶達陰性患者(1.2箇月)明顯延長，差異有統計學意義(P<0.001)。而EGFR-pTyr1173錶達與EGFR-TKI療效呈負相關性，EGFR-pTyr1173暘性者ORR、DCR和PFS分彆為27.8%(25/90)、64.4%(58/90)和4.8箇月，顯著低于陰性患者[37.9%(25/66)、83.3%(55/66)和7.7箇月，P=0.123，P=0.007，P=0.016]。以EGFR基因突變狀態分層進行亞組分析顯示，在EGFR基因野生型患者中，EGFR-pTyr1068錶達暘性率為69.0%(69/100)， EGFR-pTyr1068錶達暘性和陰性患者ORR分彆為23.2%(16/69)和3.2%(1/31)，DCR分彆為69.6%(48/69)和35.5%(11/31)，差異均有統計學意義(P=0.010，P=0.001)；EGFR-pTyr1068錶達暘性患者中位PFS為3.6箇月，較錶達陰性患者(1.2箇月)明顯延長，差異有統計學意義(P<0.001)。16例EGFR-pTyr1068暘性錶達且對EGFR-TKI有效患者，中位PFS為15.6箇月(95%CI：7.28~23.9)。多因素分析顯示，EGFR-pTyr1068是EGFR基因野生型患者EGFR-TKI治療的獨立療效預測因子(OR=0.24，95%CI：0.16~0.37，P<0.001)。結論：EGFR-pTyr1068可作為晚期NSCLC患者接受EGFR-TKI治療的有效預測因子，尤其對從EGFR基因野生型患者中篩選EGFR-TKI治療有效者具有重要作用。
배경여목적：근년래이길비체니화액락체니위대표적표피생장인자수체락안산격매억제제(epidermal growth factor receptor-tyrosine kinase inhibitors，EGFR-TKI)，인기재만기비소세포폐암(advanced non-small cell lung cancer，NSCLC)치료중독특적림상료효화교저적불량반응이비수관주。진관EGFR기인돌변시목전인위최학절적예측EGFR-TKI료효적지표，단여림상료효간병비“전혹무”적관계，제시잉유기타궤제삼여기중。본연구지재탐토만기NSCLC조직표본중EGFR린산화락안산1068(EGFR-pTyr1068)、1173(EGFR-pTyr1173)표체여EGFR기인돌변적관계，급기재EGFR-TKI치료중적료효예측개치。방법：채용변성고효액상색보법(denaturing high performance liquid chromatography，DHPLC)검측205례만기NSCLC환자조직중EGFR기인돌변(19、21외현자돌변)정황；병채용면역조화방법검측기EGFR-pTyr1068、EGFR-pTyr1173표체。결과：만기NSCLC환자조직중EGFR-pTyr1068화1173표체양성솔분별위80.0%(164/205)、57.6%(95/165)；기표체여림상병리특정(년령、성별、병리류형、흡연상태、질병분기)무상관성。전조EGFR기인돌변솔위44.9%(92/205)，여흡연상태유관(P=0.024)，이여기타림상병리특정(성별、년령、병리류형、질병분기)무관。EGFR기인돌변여EGFR-pTyr1068표체정약상관성(P<0.001)，여EGFR-pTyr1173무상관성(P=0.297)。EGFR기인돌변형환자EGFR-TKI치료적객관완해솔(objective response rate，ORR)、질병공제솔(disease control rate，DCR)화중위무진전생존기(progress free survival，PFS)분별위48.3%(43/89)、80.9%(72/89)화8.8개월(95%CI：6.11~11.42)，균명현고우EGFR기인야생형환자[16.2%(17/105)、56.2%(59/105)화2.1개월，95%CI：0.89~3.24]，차이유통계학의의(P<0.001，P<0.001，P=0.024)；EGFR-pTyr1068표체양성환자ORR화DCR분별위37.7%(58/154)화74.7%(115/154)，균명현고우표체음성환자[5.0%(2/40)화40.0%(16/40)]，차이유통계학의의(P<0.001)。EGFR-pTyr1068표체양성환자중위PFS위7.0개월，교표체음성환자(1.2개월)명현연장，차이유통계학의의(P<0.001)。이EGFR-pTyr1173표체여EGFR-TKI료효정부상관성，EGFR-pTyr1173양성자ORR、DCR화PFS분별위27.8%(25/90)、64.4%(58/90)화4.8개월，현저저우음성환자[37.9%(25/66)、83.3%(55/66)화7.7개월，P=0.123，P=0.007，P=0.016]。이EGFR기인돌변상태분층진행아조분석현시，재EGFR기인야생형환자중，EGFR-pTyr1068표체양성솔위69.0%(69/100)， EGFR-pTyr1068표체양성화음성환자ORR분별위23.2%(16/69)화3.2%(1/31)，DCR분별위69.6%(48/69)화35.5%(11/31)，차이균유통계학의의(P=0.010，P=0.001)；EGFR-pTyr1068표체양성환자중위PFS위3.6개월，교표체음성환자(1.2개월)명현연장，차이유통계학의의(P<0.001)。16례EGFR-pTyr1068양성표체차대EGFR-TKI유효환자，중위PFS위15.6개월(95%CI：7.28~23.9)。다인소분석현시，EGFR-pTyr1068시EGFR기인야생형환자EGFR-TKI치료적독립료효예측인자(OR=0.24，95%CI：0.16~0.37，P<0.001)。결론：EGFR-pTyr1068가작위만기NSCLC환자접수EGFR-TKI치료적유효예측인자，우기대종EGFR기인야생형환자중사선EGFR-TKI치료유효자구유중요작용。
Background and purpose:EGFR-TKI (EGFR-tyrosine kinase inhibitors), represented by geiftinib and erlotinib, have exhibited signiifcant antiproliferative effects against non-small cell lung cancer (NSCLC) with low toxicity.EGFR gene mutation was discovered to be a predictive biomarker for EGFR-TKI treatment. Although the efifcacy of EGFR-TKI is limited toEGFR wild-type patients, it is still noticeable suggesting that some other mechanisms are responsible for it. The current study is aimed at evaluating the expression of phosphorylated EGFR in advanced NSCLC, investigating its relationship withEGFR mutations and EGFR-TKI efifcacy.Methods:EGFR gene mutations were detected by denaturing high performance liquid chromatography (DHPLC) in 205 stageⅢB-ⅣNSCLC patients. The expressions of phosphorylated tyrosine 1068 (pTyr1068) and 1173 (pTyr1173) were detected by immunohistochemistry.Results:The positive expressions of pTyr1068 and pTyr1173 were 80.0% (164/205) and 57.6% (95/165) respectively. None of them were related to clinical pathological characteristics (age, gender, pathological type, smoking status, disease stage).EGFR gene mutation rate was 44.9% (92/205), which was only related to smoking status (P=0.024) compared to other clinical pathological characteristics.EGFR gene mutations were poorly related to pTyr1068 expression (P<0.001) and not related to pTyr1173 expression (P=0.297). The objective response rate (ORR),disease control rate (DCR), and progressive free survival (PFS) of EGFR-TKI treatment in patients withEGFR mutations were 48.3% (43/89), 80.9% (72/89) and 8 months (95%CI: 6.11-11.42) respectively, which were signiifcantly higher than that ofEGFR wild-type patients [ORR=16.2% (17/105,P<0.001); DCR=56.2%(59/105,P<0.001); Median PFS: 2.1 months, (95%CI: 0.89-3.24;P=0.001)]. Superior ORR: DCR and PFS appeared in patients with pTyr1068 positive expression compared to negative [ORR: 37.7% (58/154)vs 5.0% (2/40,P<0.001); DCR: 74.7% (115/154)vs 40.0% (16/40,P<0.001); Median PFS: 7.0 monthsvs 1.2 months,P<0.001)]. Inversely, the patients with pTyr1173 positive expression had lower ORR, DCR and shorter PFS [ORR: 27.8% (25/90)vs 37.9%(25/66,P=0.123); DCR: 64.4% (58/90)vs 83.3% (55/66,P=0.007); Median PFS: 4.8 monthsvs 7.7 months (P=0.016)]. In subgroup ofEGFR wild-type patients, positive expression of pTyr1068 was 69.0% (69/100).EGFR wild-type patients with pTyr1068 positive expression had a prolonged PFS and elevated ORR and DCR compared to negative [median PFS: 3.6 monthsvs 1.2 months (P<0.001); ORR: 23.2%vs 3.2% (P=0.010); DCR: 69.6%vs 35.5% (P=0.001)]. Sixteen patients with pTyr1068 positive expression who responded to EGFR-TKI treatment in this subgroup had a remarkable PFS [median PFS: 15.6 months (95%CI:7.28-23.9)]. Multiple factor analysis showed that the expression of pTyr1068 was an independence predictor factor for EGFR-TKI treatment (OR=0.24, 95%CI: 0.16~0.37,P<0.001). Conclusion:Phosphorylation at Tyr1068 of EGFR might be a potential predictive factor for clinical response and survival of EGFR-TKI treatment in patients with advanced NSCLC, especially inEGFR wild-type patients.
