Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer

Abstract

Background: The discovery of distinct subsets of nonsmall cell lung cancer (NSCLC) characterized by activation of driver oncogenes has greatly affected personalized therapy. It is hypothesized that the dominant oncogene in NSCLC would be associated with distinct patterns of metastatic spread in NSCLC at the time of diagnosis.

Methods: A total of 209 consecutive patients with stage IV nonsquamous NSCLC with an EGFR (epidermal growth factor receptor) mutation (N = 39), KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation (N = 49), ALK (anaplastic lymphoma receptor tyrosine kinase) gene rearrangement (N = 41), or wild-type for all 3 (triple negative, N = 80) were included. The percentage of patients with metastatic disease at a given site was compared between each molecular cohort (EGFR, KRAS, or ALK) and the triple negative cohort.

Results: ALK gene rearrangement was significantly associated with pericardial disease (odds ratio [OR] = 4.61; 95% confidence interval [CI] = 1.30, 16.37; P = .02) and pleural disease (OR = 4.80; 95% CI = 2.10, 10.97; P < .001). Patients with ALK gene rearrangements (OR = 5.50; 95% CI = 1.76, 17.18; P = .003) and patients with EGFR mutations (OR = 5.17; 95% CI = 1.63, 16.43; P = .006) were predisposed to liver metastasis compared to the triple negative cohort. No molecular cohort had a predisposition to pulmonary nodules, or adrenal, bone, or brain metastasis compared to the triple negative cohort. The mean number of metastatic disease sites in patients within the ALK rearranged cohort was significantly greater than that of the triple negative cohort (mean = 3.6 sites vs 2.5 sites, P < .0001).

Conclusions: The results support the hypothesis that the dominant molecular oncogenes in NSCLC are associated with different biological behaviors manifesting as distinct patterns of metastatic spread at the time of diagnosis.

Figure 1. Metastases to Serous Membranes

The percentage of patients with the presence of metastatic disease in the pericardium (A) or pleura (C) is shown by molecular cohort. Absolute numbers of patients with or without metastases in each cohort is provided below. Panel B depicts axial (left) or coronal (right) CT scan slices showing a pericardial effusion in a 42 year old female patient with an ALK gene rearrangement.

Figure 2. Metastases to Lymph Nodes

The percentage of patients with the presence of metastatic disease in the intrathoracic (A) or extrathoracic (B) lymph nodes is shown by molecular cohort. Absolute numbers of patients with or without metastases in each cohort is provided below.

Figure 3. Metastases to the Liver

The percentage of patients with the presence of metastatic disease in the liver is shown by molecular cohort. Absolute numbers of patients with or without metastases in each cohort is provided below.

Figure 4

Positive predictive value (PPV) and the contribution of EGFR (open) and ALK (filled) are shown in the bar graph. Also displayed are the specificity and likelihood ratio (LR) for the presence of an actionable gene alteration in EGFR or ALK given known metastases to the pericardium, pleura or liver.

Figure 5. Metastases to other Distant Sites

The percentage of patients with the presence of metastatic disease in the bone (A), pulmonary nodules (B), adrenal gland(s) (C), and brain (D) is shown by molecular cohort. Absolute numbers of patients with or without metastases in each cohort is provided below.

Figure 6. Number of Metastatic Sites at Presentation

The mean numbers of metastatic sites of disease, including intra- and extra-thoracic lymph node(s), for each molecular cohort is displayed. One-way ANOVA was used to compare each cohort to the triple negative cohort. Error bars represent standard error.