Unique Genetic Characteristics and Clinical Prognosis of Female Patients with Lung Cancer Harboring RET Fusion Gene

Abstract

Objectives: Since no report on the genetic characteristics of RET fusions in female patients with lung cancer is available, this study revealed the genetic and prognostic characteristics of female patients with lung cancer harboring RET fusion gene for the first time.

Materials and methods: The molecular portfolios of 1,652 patients with lung cancer who underwent targeted next-generation sequencing for screening candidate oncogenic drivers in their histological specimens from January 2016 to December 2018 were investigated in this study.

Results: RET fusions were identified in 23 cases, 15 females [2.2% (15/685)] and eight males [0.9% (8/902)]. The most common fusions were KIF5B-RET in females [80% (12/15)] and CCDC6-RET in males [50% (4/8)], along with some rare RET fusions, including SLC39A8-RET, ITIH2-RET, FYCO1-RET and SLC25A36-RET in females, and MIR3924-RET, ZBTB41-RET and ITGA8-RET in males. Interestingly, the highly positive, moderate positive, and negative rates of PD-L1 staining in females were 33.3%, 8.3% and 58.3%, respectively; whereas those in males were 0%, 57.1% and 42.9%. Additionally, the progression-free survival (PFS) of stage IV patients was comparatively shorter in females, shown by the medians of 4.0 months in females and 6.0 months in males (P = 0.029). A 43-year-old female patient with metastatic lung adenocarcinoma, who harbored KIF5B-RET fusion and had highly positive PD-L1 staining, received nivolumab as second-line treatment. A partial response was achieved and remained for more than five months.

Conclusion: Unique genetic characteristics and poor prognosis are found in female patients with lung cancer harboring RET fusion gene. Immune checkpoint inhibitors are a potential option for patients with high expression of PD-L1.

Figure 1

Patient screening flowchart.

Figure 2

Gender ratios of RET gene fusions. Among the 1,587 patients, RET fusions were identified in 23 cases, 15 females and 8 males. The most common fusions were KIF5B–RET in females (P = 0.023) and CCDC6–RET in males (P = 0.131).

Figure 3

Positive rates of PD–L1 in females and males. In females, the highly positive (≥50%), moderate positive (1–49%), and negative (0%) rates of PD–L1 staining were 33.3%, 8.3% and 58.3%, respectively, whereas those in males were 0%, 57.1% and 42.9%.

Figure 4

Progression free survivals in stage IV patients and patients only receiving chemotherapy. In stage IV patients, the median PFSs were 4.0 months in females and 6.0 months in males (P = 0.029). The median PFSs of patients only receiving chemotherapy were 4.0 months in females and 13.0 months in males (P = 0.017).

Figure 5

IHC staining of HE and PD-L1. HE staining, B. IHC staining demonstrated PD–L1 (+, positive rate of about 65%), magnification ×200.

Figure 6

Imaging changes in a patient treated with nivolumab. A 43-year-old female nonsmoker was diagnosed with stage IV poorly differentiated adenocarcinoma of the lung. Targeted NGS revealed a KIF5B–RET fusion. Her disease progressed after 4.2 months of platinum-based chemotherapy, and then became partially respond to second-line treatment with nivolumab. However, new lesions of her disease were detected after 5.5 month.