Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation.
OBJECTIVE
We investigated the incidence of concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements in Chinese patients with non-small cell lung cancer (NSCLC), and assessed responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib in such tumors.


METHODS
We screened 977 consecutive patients with NSCLC for the presence of concomitant EGFR mutations and ALK rearrangements by rapid amplification of cDNA ends-coupled PCR sequencing and FISH. Immunohistochemistry (IHC) and Western blotting were used to correlate the activation of EGFR, ALK, and downstream proteins with responses to EGFR-TKIs and crizotinib.


RESULTS
The overall frequency of concomitant EGFR mutations and ALK rearrangements was 1.3% (13/977). EGFR/ALK co-alterations were found in 3.9% (13/336) EGFR-mutant and 18.6% (13/70) ALK-rearranged patients. Ten tumors were treated with first-line EGFR-TKIs, with a response rate of 80% (8/10). Two tumors with high phospho-ALK levels and low phospho-EGFR levels achieved stable and progressive disease, respectively. Median progression-free survival was 11.2 months. Coexpression of mutant EGFR and ALK fusion proteins in the same tumor cell populations was detected by IHC. Two cases with high phospho-ALK levels treated with crizotinib achieved partial responses; two cases with low phospho-ALK levels had progressive or stable disease.


CONCLUSIONS
ALK rearrangements and EGFR mutations could coexist in a small subgroup of NSCLC. Advanced pulmonary adenocarcinomas with such co-alterations could have diverse responses to EGFR-TKIs and crizotinib. Relative phospho-ALK and phospho-EGFR levels could predict the efficacy of EGFR-TKI and crizotinib.
Authors' Affiliations: Division of Pulmonary Oncology, Cancer Center, Guangdong Lung Cancer Institute; Medical Research Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou; and State Key Laboratory of Southern China, The Chinese University of Hong Kong, Sir YK Pau Cancer Center, Prince of Wales Hospital, Hong Kong, China.
Jin-Ji
JJ
Yang
Xu-Chao
XC
Zhang
Jian
J
Su
Chong-Rui
CR
Xu
Qing
Q
Zhou
Hong-Xia
HX
Tian
Zhi
Z
Xie
Hua-Jun
HJ
Chen
Yi-Sheng
YS
Huang
Ben-Yuan
BY
Jiang
Zhen
Z
Wang
Bin-Chao
BC
Wang
Xue-Ning
XN
Yang
Wen-Zhao
WZ
Zhong
Qiang
Q
Nie
Ri-Qiang
RQ
Liao
Tony S
TS
Mok
Yi-Long
YL
Wu
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000077547:Crizotinib; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D011905:Genes, ras; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010766:Phosphorylation; D011446:Prospective Studies; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D014178:Translocation, Genetic; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases