EGFR mutation heterogeneity and the mixed response to EGFR tyrosine kinase inhibitors of lung adenocarcinomas

Abstract

Background: Non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations have mixed responses to tyrosine kinase inhibitors (TKIs). Intertumor heterogeneity in EGFR mutations is one potential explanation for this phenomenon.

Methods: We performed direct sequencing to identify EGFR mutations in 180 pairs of lung adenocarcinoma samples (from 3,071 patients). The high-resolution melting method was used in discordant cases to confirm EGFR mutation status. Matching samples were divided into four groups: primary lesions detected at different times, primary tumors with matched metastatic lymph nodes, multiple pulmonary nodules, and primary tumors with matched distant metastases. Multivariate analyses were performed to evaluate correlations between heterogeneity and patient characteristics.

Results: In the study population, the discordance rate was 13.9% (25 of 180). The multiple pulmonary nodules group had the highest discordance rate of 24.4% (10 of 41; odds ratio for heterogeneity in primary lesions detected at different times, 6.37; 95% confidence interval, 1.71-23.72; p = .006). Discordance rates in the metachronous and synchronous settings were 15.7% (22 of 140) and 7.5% (three of 40), respectively. In the 34 patients who developed EGFR TKI resistance, 10 (29.4%) cases exhibited heterogeneity and five (14.7%) patients exhibited a mixed response to the drug. Three (8.8%) of the patients with a mixed response also exhibited discordant EGFR mutations.

Conclusions: The overall discordance rate of EGFR mutation heterogeneity in Asian patients with pulmonary adenocarcinoma is relatively low, but the rate in patients with multiple pulmonary nodules is significantly higher. This observation may explain the mixed tumor response to EGFR TKIs.

Figure 1.

Enrollment and outcomes. Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; SCLC, small cell lung cancer.

Figure 2.

EGFR mutation heterogeneity in different spatial and treatment groups. (A): Spatial group and heterogeneity. (B): Treatment group and heterogeneity. Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Figure 3.

Heterogeneity and mixed responses. Mixed response indicates shrinkage of the primary tumor but progression of the metastasis (or vice versa). (A): A 46-year-old male (patient 5 in Table 3). PET-CT showed a round mass with a high SUV in the left upper lobe with multiple bone metastases. No suspected lesions were found in the adrenal gland or the retroperitoneal space. A deletion in exon 19 of EGFR was detected in tumor tissue biopsied from the left upper lobe. After 4 months of first-line erlotinib therapy, a second PET-CT scan showed that the SUV and diameter of the primary tumor located in the left upper lobe had decreased significantly, whereas an aggressive novel neoplasm emerged in the retroperitoneal space and adrenal gland. Wild-type EGFR was identified in a tumor retrieved from the retroperitoneal space by laparoscopy, whereas an exon 19 deletion plus a T790M mutation in exon 20 of EGFR was observed in tissue biopsied from the adrenal gland. A third PET-CT scan was conducted after erlotinib plus cetuximab was continued for two cycles. Moderate left upper lobe enlargement was observed, but the EGFR exon 19 deletion was still present in rebiopsied tissue. Additionally, the retroperitoneal lymph node lesion was significantly smaller, but the adrenal gland lesion had grown aggressively. (B): The pie chart illustrates the frequencies of the various mechanisms of EGFR TKI resistance in 34 patients with NSCLC. Pre- and post-treatment images were evaluated to define the role of mixed responses to EGFR TKIs. The mixed-response cases accounted for 14.7% of TKI-resistant cases and include two subsets: mixed response combined with heterogeneity (8.8%) and mixed response combined with uncertain EGFR status (5.9%). Abbreviations: EGFR, epidermal growth factor receptor; NA, not available; NSCLC, non-small cell lung cancer; PD, progressive disease; PET–CT, positron emission tomography–computed tomography; PR, partial response; SUV, standardized uptake value; TKI, tyrosine kinase inhibitor; WT, wild-type.