Intragenic EGFR::EGFR.E1E8 Fusion (EGFRvIII) in 4331 Solid Tumors

Abstract

Epidermal growth factor receptor variant III (EGFRvIII, the deletion of exons 2-7) is a recurrent intragenic EGFR::EGFR.E1E8 fusion that occurs in high-grade gliomas. The presence of EGFRvIII in other solid tumors has not been well characterized. We retrospectively reviewed advanced malignant solid tumor cases tested by a custom hybrid capture 610-gene next-generation sequencing platform from 2021 to 2022. EGFRvIII was identified in 17 of 4331 (0.4%) cases, including 16 of 238 (7%) brain tumors and 1/301 (0.3%) breast tumors. EGFRvIII-positive brain tumors were all glioblastoma IDH-wildtype, most with concurrent TERT promoter mutation (14 of 16), EGFR amplification (13 of 16), and EGFR mutation (8 of 16). The only EGFRvIII-positive breast lesion was a sarcomatoid neoplasm in a young female patient. A separate breast case tested outside our institution with reported EGFRvIII was noted in a young female patient with a malignant phyllodes tumor with stromal overgrowth. Microscopically, both EGFRvIII-positive breast tumors showed high-grade sarcomatoid morphology with brisk mitotic activity. In summary, EGFRvIII is rare, occurring primarily in glioblastoma and rarely in breast sarcomatoid neoplasm, with no instances identified in other tumor types in our series. This select group of patients may benefit from chemotherapy and/or targeted anti-EGFR therapy.

Keywords: EGFR::EGFR.E1E8 fusion; EGFRvIII; breast sarcomatoid neoplasm; glioblastoma; malignant phyllodes tumor.

Figure 1

Frequency of EGFRvIII among solid tumors. EGFR, epidermal growth factor.

Figure 2

Mutation profiles of EGFRvIII-positive brain and breast neoplasms and metaplastic carcinoma of breast. Tumor type, patient age, gender, and last follow-up status are listed at the top. Detected recurrent mutated genes are shown below for each corresponding tumor type. GBM, glioblastoma; SarBN, sarcomatoid breast neoplasm; MPT, malignant phyllodes tumor; MBC, metaplastic breast carcinoma; CN, copy number; DOD, deceased of disease; F/U, follow up; TMB, tumor mutational burden; MSS, microsatellite stable.

Figure 3

A case of IDH-wildtype glioblastoma with EGFRvIII and EGFR amplification. (A) A histological analysis shows a hypercellular lesion with microvascular proliferation (arrow in blue, 100×). (B) High power shows tumor cells with small-cell morphology (400×). (C) Immunohistochemical stain shows diffuse strong positivity for EGFR. The next-generation sequencing shows (D) two split sites within intron 1 of EGFR, (E) EGFR amplification, and (F) EGFR A289V mutation in extracellular domain.

Figure 4

Sarcomatoid neoplasm of the breast with EGFRvIII. (A) Histology shows a malignant high-grade sarcomatoid neoplasm (100×). (B) Analysis under high-power magnification reveals tumor cells with spindle and epithelioid morphology and numerous atypical mitotic figures (200×). Tumor cells show focal expression of (C) p63, (D) diffusely positive staining for TRPS1, (E) positive staining for GATA3, albeit rarely, and (F) patchy expression of Cam5.2. The next-generation sequencing shows (G) one split site within intron 1 of EGFR and (H) no detectable EGFR amplification.

Figure 5

Malignant phyllodes tumors of the breast with EGFRvIII. (A) Histology shows a poorly differentiated high-grade neoplasm (100×). (B) Analysis under high-power magnification reveals pleomorphic epithelioid tumor cells with a high nuclear-to-cytoplasm ratio and no identifiable definitive epithelial component (200×). (C) A focal area with leaf-like fronds was identified (40×). Tumor cells show diffuse expression of (D) TRPS1 and (E) GATA3 and (F) rare expression of cytokeratin.