Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients

Abstract

Purpose: To investigate the prognostic role of genomic gain for MET and epidermal growth factor receptor (EGFR) genes in surgically resected non-small-cell lung cancer (NSCLC).

Patients and methods: This retrospective study included 447 NSCLC patients with available tumor tissue from primary lung tumor and survival data. EGFR and MET status was evaluated by fluorescent in situ hybridization (FISH) in tissue microarray sections.

Results: EGFR FISH results were obtained in 376 cases. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 10.4% and 32.4% of cases, respectively. EGFR FISH-positive patients had a nonsignificant shorter survival than EGFR FISH-negative patients (P = .4). Activating EGFR mutations were detected in 9.7% of 144 stage I-II disease with no impact on survival. MET FISH analysis was performed in 435 cases. High MET gene copy number (mean > or = 5 copies/cell) was observed in 48 cases (MET+, 11.1%), including 18 cases with true gene amplification (4.1%). MET+ status was associated with advanced stage (P = .01), with grade 3 (P = .016) and with EGFR FISH+ result (P < .0001). No patient with activating EGFR mutation resulted MET+. In the whole population, MET-positive patients had shorter survival than MET-negative patients (P = .005). Multivariable model confirmed that MET-negative patients had a significant reduction in the risk of death than MET-positive patients (hazard ratio, 0.66; P = .04).

Conclusion: MET increased gene copy number is an independent negative prognostic factor in surgically resected NSCLC. EGFR gene gain does not impact survival after resection.

Fig 1.

(A) A total of 215 patients were epidermal growth factor receptor (EGFR) fluorescent in situ hybridization (FISH) negative (57.2%), and 161 were EGFR FISH positive (42.8%), including 122 with EGFR high polysomy (32.4%) and 39 with EGFR gene amplification (10.4%). Median survival was 48.3 months for the low polysomic group, 40.7 months for high polysomic, and 30.7 months for patients with gene amplification. (B) Patients with high polysomy or gene amplification (EGFR FISH+) had a median survival of 40.7 months, while patients with low polysomy (EGFR FISH−) had a median survival of 48.3 months. The difference was not statistically significant (P = .4).

Fig 2.

(A) Survival outcome of patients with a mean of ≥ 5 copies of MET/cell was similar to the outcome of patients with a mean of ≥ 6 copies of MET/cell, and shorter than survival of patients with less than 5 copies of MET/cell. Based on these results, mean of ≥ 5 copies of MET/cell qualified the result as MET+. Median survival was 22.3 months for the 10 patients with mean MET copy number less than 2; 44.4 months in 129 individuals with mean MET copy number ≥ 2 and less than 3; 38.6 months for 149 patients with mean MET copy number ≥ 3 and less than 4; not reached for 95 patients with mean MET copy number ≥ 4 and less than 5; 28.1 months for 28 individuals with MET copy number ≥ 5 and less than 6; 21.4 months for 20 patients with mean copy number ≥ 6. (B) Patients MET fluorescent in situ hybridization (FISH)+ (n = 48) had a median survival of 25.8 months versus 47.5 months in MET FISH− (n = 383). This difference was statistically significant (P = .0045).

Fig 3.

Survival of MET fluorescent in situ hybridization (FISH)+ and MET FISH− according to stage, grade, and epidermal growth factor receptor (EGFR) FISH. (A) In stage I-II disease, 20 patients were MET FISH+ and 233 were MET FISH−. Median survival was not reached in MET FISH− and was 33.0 months in MET FISH+. This difference was statistically significant (P = .032). (B) In stage III-IV disease, MET FISH+ patients (n = 28) had shorter survival (20.8 v 22.8 months) than MET FISH− (n = 150). This difference was not statistically significant (P = .3). (C) In grade 1-2 disease, MET FISH+ (n = 23) had shorter survival (28.1 v 48.8 months) than MET FISH− (n = 250). The difference did not reach the statistical significance (P = .1). (D) In grade 3 disease, MET FISH+ (n = 25) had significantly shorter survival (20.8 v 38.1 months) than MET FISH− (n = 131). The difference was statistically significant (P = .03). (E) EGFR FISH negative/MET FISH− (n = 197) had significantly longer survival (55.9 v 22.6 months; P = .0001) than EGFR FISH−/MET FISH+ (n = 15). (F) Among patients EGFR FISH+, survival was longer in MET FISH− (n = 128) than in the 31 patients MET FISH+ (median survival, 42.6 v 28.9 months) even if the difference was not statistically significant (P = .2).

Fig A1.

Survival outcome based on the average MET gene copy number in the three tissue microarray cores. Survival of patients with a mean of ≥ 5 copies of MET/cell was similar to the outcome of patients with a mean of ≥ 6 copies of MET/cell, and shorter than survival of patients with < 5 copies of MET/cell. Based on these results, mean of ≥ 5 copies of MET/cell qualified the result as MET fluorescent in situ hybridization positive. Median survival was 40.4 months for the 17 patients with mean MET copy number < 2; 44.9 months in 163 individuals with mean MET copy number ≥ 2 and < 3; 40.7 months for 153 patients with mean MET copy number ≥ 3 and < 4; not reached for 75 patients with mean MET copy number ≥ 4 and < 5; 28.1 months for nine individuals with MET copy number ≥ 5 and < 6; and 21.4 months for 17 patients with mean copy number ≥ 6.

Fig A2.

Survival outcome based on the average MET gene copy number in the three tissue microarray cores. Patients who were MET fluorescent in situ hybridization (FISH) positive (n = 26) had a median survival of 24.1 v 46.5 months in those who were MET FISH negative (n = 409). This difference was statistically significant (P = .015).

Fig A3.

MET fluorescent in situ hybridization negative (low copy number, left) and positive high copy number by polysomy (center) and gene amplification (right).

Fig A4.

Section from a patient with non–small-cell lung cancer showing epidermal growth factor receptor fluorescent in situ hybridization (FISH) high polysomy (left) and MET FISH high polysomy (right).

Fig A5.

Section from a patient with non–small-cell lung cancer showing epidermal growth factor receptor fluorescent in situ hybridization (FISH) gene amplification (left) and MET FISH gene amplification (right).