Given their good antitumor effects, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-sensitive mutations, including exon 19 deletions and exon 21 L858R mutations. EGFR fusion mutations and EGFR amplification are very rare in non-small cell lung cancer (NSCLC). We describe 2 patients with NSCLC harboring EGFR fusion mutations (EGFR-MACF1 and EGFR-GNAT3) combined with EGFR amplification. Both patients received EGFR-TKI treatment, and 1 of them showed an antitumor response.

EGFR mutations are among the most common driver mutations in lung adenocarcinoma. Rare alterations, such as the EGFR-RAD51 fusion, respond to treatment with EGFR tyrosine kinase inhibitors but can be missed by limited genomic sequencing panels. Here, we report a case of metastatic lung adenocarcinoma in a never-smoker patient who initially did not have a targetable alteration identified on two different sequencing panels. The initial response to combination chemoimmunotherapy was short-lived. A rare EGFR-RAD51 fusion was then identified using a more in-depth sequencing panel. The patient experienced a dramatic and durable response to osimertinib. This case highlights the rarity of EGFR-RAD51 fusions, the efficacy of EGFR tyrosine kinase inhibitors, and the importance of a thorough search for targetable alterations in never-smokers with lung adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) fusions are rare genomic events in non-small-cell lung cancer (NSCLC). Clinical support and evidence to guide management are absent for NSCLC patients harboring EGFR fusion.
METHODS: In this case report, we describe a 69-year-old female who received right lobectomy and was diagnosed with pathological stage IIIA lung adenocarcinoma harboring EGFR L858R. Twenty months later he had recurrent disease in the liver, lung, and bone, and was treated with icotinib. A novel vesicular overexpressed in cancer pro-survival protein 1 (VOPP1)-EGFR fusion gene coexistent with T790M were identified by next-generation sequencing using pericardial effusion and blood samples after icotinib treatment, which led to progression after icotinib six months and suggested a potential resistance mechanism. Subsequently, the patient was switched to osimertinib treatment, which resulted in a progression-free survival interval of more than 11 months.
CONCLUSIONS: The present results suggested that acquired VOPP1-EGFR fusion gene with T790M potentially serve an additional resistance mechanism to first-generation EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. And the present case increases the evidence supporting use of osimertinib for treatment of NSCLC patients harboring EGFR fusion.

EGFR fusions are rare genomic events in non-small cell lung cancer (NSCLC), and a total of nine types have been previously reported in lung adenocarcinoma: EGFR-RAD51, EGFR-PURB, EGFR-ANXA2, EGFR-ZNF713, EGFR-YAP1, USP42-EGFR, EGFR-SEPTIN14, EGFR-TNS3, and EGFR-ZCCHC6. EGFR fusion mutations combined with EGFR amplification are even rarer in NSCLC. The EGFR-intergenic region (IGR) fusion mutation is unreported, and thus, there are no studies targeting this fusion together with EGFR amplification in lung adenocarcinoma. Our brief study provides clinical evidence that combined targeted therapy with gefitinib and cetuximab could result in a significant antitumor response in patients with the EGFR-IGR fusion and EGFR amplification. KEY POINTS: EGFR fusion mutations are rare, and EGFR fusion mutations combined with EGFR amplification are even rarer in non-small cell lung cancer (NSCLC). To the authors\' knowledge, there is no previous report on the coexistence of the EGFR-intergenic region (IGR) fusion and EGFR amplification. This is the first report of a patient with NSCLC with the EGFR-IGR fusion and EGFR amplification who achieved a significant antitumor response from treatment with gefitinib combined with cetuximab.

Epidermal growth factor receptor (EGFR) fusions are rare genomic events in non-small-cell lung cancer (NSCLC). With advances in detection technology, some uncommon genomic mutation events, including EGFR fusions, have been detected. There are no standard treatment options for NSCLC patients harboring EGFR fusion. Herein, we report a case of KIF5B-EGFR fusion in NSCLC responding to tyrosine kinase inhibitors (TKIs). A 50-year-old male underwent left upper lobectomy followed by adjuvant chemotherapy for pathological stage IA3 lung adenocarcinoma. The tumor tissue was subjected to next-generation sequencing (NGS) and showed a KIF5B-EGFR fusion. When cancer recurrence occurred thirteen months later, the patient received afatinib (40 mg qd) as second-line treatment, and a partial response was observed, which resulted in an 11-month progression-free survival (PFS). This case provides valuable information on the response to afatinib in an NSCLC patient with a novel KIF5B-EGFR fusion. The NGS assay provides a powerful tool for identifying rare or atypical EGFR gene mutations in patients with NSCLC, which should be encouraged in clinical practice.

Here, we report a case of a 36-year-old female patient with metastatic non-small cell lung cancer (NSCLC) harboring EGFR-ANXA2 and EGFR-RAD51 double fusion mutations with BRCA2 (nonsense mutation of exon 11) and ATR mutations (Exon 44 variable shear mutation) identified by next generation sequencing (NGS). The efficacy was significantly improved after lobaplatin combined with pemetrexed, temozolomide and bevacizumab. This is the first report of a novel mutation type EGFR-ANXA2, as well as double EGFR fusion mutations in advanced lung adenocarcinoma. Furthermore, platinum-based chemotherapy plus bevacizumab rather than targeted therapy showed favorable effects in this patient, providing a novel therapeutic conception for patients, even with multidriver mutations.

Multiple oncogene fusions beyond ALK receptor tyrosine kinase (ALK), RET, and ROS1 fusion has been described in lung cancer, especially in lung adenocarcinomas without common oncogenic mutations. Molecular inhibitors have been developed and proved effective for patients whose tumors harbor these novel alterations.
A consecutive series of surgically resected lung adenocarcinomas were collected and profiled using an enrichment strategy to detect nine common oncogenic driver mutations and fusions concerning EGFR, KRAS, HER2, BRAF, MET, ALK, RET, ROS1, and FGFR. Driver-negative cases were further analyzed by a comprehensive RNA-based next-generation sequencing (NGS) fusion assay for novel fusions.
In total, we profiled 1681 lung adenocarcinomas, among which 255 cases were common driver-negative. One hundred seventy-seven cases had sufficient tissue for NGS fusions screening, which identified eight novel fusions. NRG1 fusions occurred in 0.36% of all lung adenocarcinoma cases (6 of 1681 cases), including 4 CD74-NRG1-positive cases, 1 RBPMS-NRG1-positive case, and 1 novel ITGB1-NRG1-positive case. Furthermore, another 2 novel fusions were also detected, including 1 EGFR-SHC1 fusion and 1 CD47-MET fusion, both of which were in-frame and retained the functional domain of the corresponding kinases. No fusion event was detected for NTRK, KRAS, BRAF or HER2 genes in this cohort. Detailed clinicopathologic data showed that invasive mucous adenocarcinoma (three of eight cases) and acinar-predominant adenocarcinoma (three of eight cases) were the most prevalent pathologic subtypes among novel fusions.
Fusions affecting NRG1, EGFR, and MET were detected in 0.48% of unselected lung adenocarcinomas, and NRG1 fusions ranked the most prevalent fusions in common driver-negative lung adenocarcinomas from Chinese population. RNA-based NGS fusion assay was an optional method for screening actionable fusions in common driver-negative cases.