Case Report: Coexpression of somatic EGFR, BRCA1, and BRCA2 mutations in metastatic non-small cell lung cancer

Treatment of non-small cell lung cancer (NSCLC) has evolved dramatically over the past decade with the advent of widespread genetic testing, immunotherapy, and targeted therapies. Treatments directed against epidermal growth factor receptor (EGFR) and other driver mutations have reduced toxicity and improved efficacy for selected patients.

We present a 59-year-old man with metastatic NSCLC harboring coexisting EGFR, BRCA1, and RNA-binding motif protein 10 (RBM10) mutations and high programmed death-ligand 1 (PD-L1) expression. A BRCA2 mutation was later detected on peripheral blood testing. The patient presented with a debilitating stroke that included dysphagia and hemiparesis. During his course of care, he received osimertinib, after which EGFR and RBM10 variant allele frequencies (VAFs) increased on peripheral blood testing. He also received immunotherapy and olaparib. Despite high response rates reported in the literature, he did not respond to these agents. He had a response to chemotherapy but tolerated it poorly. Ultimately, given the lack of durable response and his inability to tolerate chemotherapy, the patient opted for palliative care.

Patients with actionable targets such as EGFR, BRCA1/2, or elevated PD-L1 generally have superior outcomes with targeted and combination therapy compared with patients who lack targetable options. However, coexisting mutations can interact and provide escape mechanisms. The lack of response in our patient is consistent with studies showing reduced efficacy of EGFR-directed therapy in the presence of RBM10 loss-of-function (LOF) alterations. Further research in patients with multiple concurrent mutations is needed to improve treatment options for this group.