Dual EGFR L858R and KRAS G12A Mutations in Lung Adenocarcinoma: A Rare Case Report and Literature Review

Abstract

Background: KRAS mutations are typically mutually exclusive in non-small cell lung cancer (NSCLC), with the G12C mutation being the most common subtype. The coexistence of KRAS and EGFR mutations is exceedingly rare and is typically emerges as a secondary event following acquired resistance to EGFR-targeted therapies. We presented a case of a newly diagnosed NSCLC patient harboring concurrent EGFR L858R and KRAS G12A mutations.

Case presentation: A 64-year-old male with a 30-pack-year smoking history presented with a 3-month history of progressive shortness of breath and chest tightness. Contrast-enhanced chest CT revealed a 5 cm spiculated mass in the right upper lobe, abutting the mediastinum, along with bronchial obstruction, right middle lobe atelectasis, and pleural effusion. A CT-guided transthoracic needle biopsy confirmed lung adenocarcinoma. Next-generation sequencing (NGS) identified a c.2573T>G (p.L858R) mutation in exon 21 of the EGFR gene and a c.35G>C (p.G12A) mutation in exon 2 of the KRAS gene. The patient started first-line therapy with osimertinib combined with pemetrexed/nedaplatin, resulting in a transient partial response, significant resolution of pleural effusion, and partial regression of the primary tumor. However, disease progression occurred within 6 months, marked by the appearance of a new cerebellar metastasis, confirmed by MRI. The patient continued osimertinib maintenance therapy and underwent stereotactic radiotherapy for the brain lesion. Despite initial stabilization, pulmonary progression was observed 11 months after the start of treatment. Due to declining performance status and personal preferences, the patient declined further treatment and was lost to follow-up.

Conclusion: We report a rare case of treatment-naïve lung adenocarcinoma harboring concurrent KRAS G12A and EGFR L858R mutations. The patient achieved only transient disease control following treatment with a third-generation EGFR TKI combined with chemoradiotherapy. Further research to explore optimal therapeutic strategies for such complex molecular profiles is needed.

Keywords: EGFR; KRAS; concurrent mutation; non-small cell lung cancer.

Figure 1

Initial imaging findings of the patient. (A and B) Chest CT: A well-defined, heterogeneously enhancing mass (5.0 × 3.5 cm²) was observed in the anterior segment of the right upper lobe, abutting the mediastinum. The lesion demonstrated bronchial obstruction with secondary involvement of the superior mediastinum and adjacent right lung parenchyma. Associated findings included segmental atelectasis of the right middle lobe, moderate right pleural effusion, and partial collapse of the right lower lung. (C and D) Cranial and Abdominal MRI: No evidence of metastatic neoplastic lesions was identified in the brain or abdominal viscera. The lesions are indicated by the red arrows.

Figure 2

Pathological findings. (A) Hematoxylin-eosin (HE) staining shows complete disruption of native alveolar architecture, replaced by infiltrating tumor cells with nuclear enlargement and prominent eosinophilic nucleoli (×100 magnification). (B–E) Immunohistochemical analysis revealed the neoplastic cells were strong and diffuse positivity for CK7 (B), TTF-1 (C), NapsinA (D), and EGFR (E); Ki67 positivity was around 10% (F) at ×200 magnification.

Figure 3

Genetic testing results. NGS analysis identified a c.2573T>G (p.L858R) mutation in exon 21 of the EGFR gene and a c.35G>C (p.G12A) mutation in exon 2 of the KRAS gene.

Figure 4

Imaging findings after two courses of radiotherapy. (A) Chest CT after two treatment cycles shows a decrease in right-sided pleural effusion volume; the mass in the right upper lobe has reduced to approximately 3.4×2.1 cm². (B) Radiotherapy targeting pulmonary carcinoma lesions and adjacent lymph nodes. (C) Contrast-enhanced head MRI shows nodular abnormal enhancement in the left cerebellar hemisphere. (D) Radiotherapy targeting cerebellar metastatic lesions. The lesion is indicated by the red arrow.