Cancer Res Treat.  2023 Oct;55(4):1087-1095. 10.4143/crt.2023.682.

Clinicopathological Characteristics of NRG1 Fusion–Positive Solid Tumors in Korean Patients

• Cha YJ
• Lee C
• Joo B
• Kim KA
• Lee Ck
• Shim HS

• KMID: 2547783
• DOI: http://doi.org/10.4143/crt.2023.682

Abstract

Purpose
Neuregulin 1 (NRG1) gene fusion is a potentially actionable oncogenic driver. The oncoprotein binds to ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic approach for inhibiting ERBB3/ERBB2. However, the frequency and clinicopathological features of solid tumors harboring NRG1 fusions in Korean patients remain largely unknown.
Materials and Methods
We reviewed archival data from next-generation sequencing panel tests conducted at a single institution, specifically selecting patients with in-frame fusions that preserved the functional domain. The clinicopathological characteristics of patients harboring NRG1 fusions were retrospectively reviewed.
Results
Out of 8,148 patients, NRG1 fusions were identified in 22 patients (0.27%). The average age of the patients was 59 years (range, 32 to 78 years), and the male-to-female ratio was 1:1.2. The lung was the most frequently observed primary site (n=13), followed by the pancreaticobiliary tract (n=3), gastrointestinal tract (n=2, stomach and rectum each), ovary (n=2), breast (n=1), and soft tissue (n=1). Histologically, all tumors demonstrated adenocarcinoma histology, with the exception of one case of sarcoma. CD74 (n=8) and SLC3A2 (n=4) were the most frequently identified fusion partners. Dominant features included the presence of fewer than three co-occurring genetic alterations, a low tumor mutation burden, and low programmed death-ligand 1 expression. Various clinical responses were observed in patients with NRG1 fusions.
Conclusion
Despite the rarity of NRG1 fusions in Korean patients with solid tumors, identification through next-generation sequencing enables the possibility of new targeted therapies.

Keyword

fusion; Solid tumor; Pathology; Genomics; Targeted therapy

Figure

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  Fig. 1 Pie chart with the prevalence of primary site of neuregulin 1 (NRG1) fusion–positive tumor.

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  Fig. 2 Detection rate of neuregulin 1 (NRG1) fusion in all patients and in different primary sites. Etc (n=170) includes thyroid (n=50), thymus (n=38), lymphoma (n=28), malignancy of unknown primary (n=21), skin (n=17), testis (n=13), and adrenal gland (n=3).

• 

  Fig. 3 Histologic features of neuregulin 1 (NRG1) fusion–positive tumors. (A) Typical histology of invasive mucinous adenocarcinoma (H&E, ×200). (B) Columnar tumor cells with intraluminal necrosis (H&E, ×200). (C) Columnar tumor cells in papillary architecture (H&E, ×200). (D) Micropapillary tumor clusters floating in the extracellular mucin pool (H&E, ×200). (E) Adenocarcinoma with tubular formation (H&E, ×200).

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  Fig. 4 Summary of co-occurring genomic alterations. CNV, copy number variation; GI, gastrointestinal; INDEL, insertion and deletion; NA, not available; PB, pancreaticobiliary; SNV, single-nucleotide variant; TTF-1, thyroid transcription factor-1.

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  Fig. 5 Swimmer plot displaying treatment sequence and survival of patients with neuregulin 1 (NRG1) fusion. Swimmer plot showing treatment sequences (first-line and up to fourth-line of systemic treatment) with survival from diagnosis of recurrence/metastasis until the last follow-up. NRG1 fusion partner genes and primary tumor sites are shown. The duration of NRG1 targeting treatment is also shown. Four patients with lung cancer (P02, P10, P20, and P21) are undergoing NRG1 targeting treatment at the cut-off date with a durable response. GI, gastrointestinal tract; PB, pancreaticobiliary tract.

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