Rennert Gad, Gottfried Maya, Rennert Hedy S, Lejbkowicz Flavio, Frank Meira, Cohen Ilana, Kelt Shiri, Agbarya Abed, Dudnik Elizabeta, Dudnik Julia, Katznelson Rivka, Mishali Moshe, Maimon Rabinovich Natalie, Nechushtan Hovav, Onn Amir, Keren Rosenberg Shoshana, Wollner Mariana, Zer Alona, Bar Jair, Gronich Naomi
Clalit Health Services National Cancer Control Center and Personalized Medicine Program, Israel; Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Office of Chief Physician, Clalit Health Services Headquarters, Tel Aviv, Israel.
Lung Cancer Unit, Meir Medical Center, 4428164 Kfar Saba, Israel.
Transl Oncol. 2021 Jan;14(1):100934. doi: 10.1016/j.tranon.2020.100934. Epub 2020 Nov 10.
A substantial fraction of all non-small cell lung cancers(NSCLC) carry a mutation in the EGFR gene for which an effective treatment with anti-tyrosine kinases(TKIs) is available. We studied the long term survival of these patients following the introduction of TKIs.
All consecutive cases of NSCLC newly diagnosed with advanced disease were referred for free tumor EGFR mutation testing at Clalit's national personalized medicine laboratory. Mutations and deletions in target codons 18-21 of EGFR were sought using RT-PCR and fragment analysis. Comprehensive EMRs were used to collect full data on treatments and clinical status.
A cohort of 3,062 advanced NSCLC cases, included 481(15.7%) somatic EGFR mutation carriers (17.5% of all adenocarcinomas, 26.7% of females with adenocarcinomas). TKIs treatment to EGFR mutation carriers was provided to 85% of all eligible. After a median follow up period of 15.9 months for EGFR mutated cases the hazard ratio for overall survival of EGFR-mutated NSCLC treated with TKIs was 0.55(0.49-0.63, p<0.0001) when compared with EGFR wild-type(WT) tumors under usual care. After adjusting for age, sex, ethnicity, smoking history and tumor histology, all of which had an independently significant effect on survival, the HR for TKI-treated, EGFR-mutated tumors, was 0.63 (0.55-0.71, p<0.0001). Treating EGFR-WT cases with TKIs yielded a high HR=1.32 (1.19-1.48).
TKIs given to EGFR mutated advanced NSCLC demonstrated a substantial survival benefit for at least five years. Squamous histology, smoking, male sex and Arab ethnicity were associated with higher NSCLC mortality hazard. Treating non-EGFR-mutated NSCLC with TKIs seems detrimental. Statement of Significance: • TKIs given to EGFR mutated advanced NSCLC demonstrated a substantial survival benefit for at least five years but not much longer. • Treating non-EGFR-mutated NSCLC with TKIs seems detrimental and should probably be avoided. • Squamous histology of non-small cell lung cancer, smoking history, male sex and Arab ethnicity were associated with altogether higher NSCLC mortality hazard.
在所有非小细胞肺癌（NSCLC）中，相当一部分患者的表皮生长因子受体（EGFR）基因发生突变，针对该突变有有效的抗酪氨酸激酶（TKIs）治疗方法。我们研究了TKIs引入后这些患者的长期生存情况。
所有新诊断为晚期疾病的NSCLC连续病例均被转诊至Clalit国家个性化医学实验室进行免费肿瘤EGFR突变检测。使用逆转录聚合酶链反应（RT-PCR）和片段分析寻找EGFR基因第18 - 21位目标密码子的突变和缺失。利用综合电子病历收集治疗和临床状态的完整数据。
一组3062例晚期NSCLC病例中，包括481例（15.7%）体细胞EGFR突变携带者（占所有腺癌的17.5%，腺癌女性患者的26.7%）。85%符合条件的EGFR突变携带者接受了TKIs治疗。EGFR突变病例的中位随访期为15.9个月，与接受常规治疗的EGFR野生型（WT）肿瘤相比，接受TKIs治疗的EGFR突变NSCLC的总生存风险比为0.55（0.49 - 0.63，p < 0.0001）。在调整了年龄、性别、种族、吸烟史和肿瘤组织学等所有对生存有独立显著影响的因素后，接受TKI治疗的EGFR突变肿瘤的风险比为0.63（0.55 - 0.71，p < 0.0001）。用TKIs治疗EGFR - WT病例产生的高风险比为1.32（1.19 - 1.48）。
给予EGFR突变的晚期NSCLC患者TKIs显示出至少五年的显著生存获益。鳞状组织学、吸烟、男性性别和阿拉伯族裔与较高的NSCLC死亡风险相关。用TKIs治疗非EGFR突变的NSCLC似乎有害。重要性声明：• 给予EGFR突变的晚期NSCLC患者TKIs显示出至少五年的显著生存获益，但时间不会更长。• 用TKIs治疗非EGFR突变的NSCLC似乎有害，可能应避免。• 非小细胞肺癌的鳞状组织学、吸烟史、男性性别和阿拉伯族裔总体上与较高的NSCLC死亡风险相关。
