Synchronous Double Primary Lung Adenocarcinomas With EGFR L858R Point Mutation and MET Exon 14 Skipping Mutation

Various driver mutations and the corresponding molecular-targeted drugs have been detected and developed in non-small cell lung cancer. There were many cases in which surgical specimens had happened to find double primary cancers. However, to our knowledge, our case was the first report of synchronous double primary lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) L858R and mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations. A 75-year-old Japanese woman with chronic heart and renal failures was referred to our department because of a growing nodule in the right upper lung field on chest X-ray films. Chest computed tomography (CT) detected a nodule in the right S₁ and another nodule in the left S₁₊₂. Bronchoscopic biopsy diagnosed the right S₁ nodule as moderately differentiated adenocarcinoma. Oncomine Dx Target Test Multi-CDx system of the right S₁ adenocarcinoma detected EGFR L858R mutation. The 18^F-fluorodeoxyglucose positron emission tomography/CT showed abnormal uptakes both in the right S₁ and the left S₁₊₂ nodules, and in the bilateral inferior paratracheal lymph nodes. We made a diagnosis of c-stage IIIA (cT_1bN₂M₀) of adenocarcinoma in the right S₁ and suspected another primary lung cancer in the left S₁₊₂. Considering her general conditions, comorbidities and wishes, we started osimertinib. The right S₁ cancer achieved partial response (PR), while the left S₁₊₂ nodule and lymph nodes enlarged. Aspiration cytology from the left supraclavicular lymph node showed adenocarcinoma. The FoundationOne^® Liquid CDx tumor profiling test detected not only EGFR L858R, but also MET exon 14 skipping mutation. We made a diagnosis of another primary adenocarcinoma from the left S₁₊₂ nodule (cT_1bN₃M₀, c-stage IIIB) with MET mutation, and changed osimertinib to capmatinib. Although the left S₁₊₂ cancer achieved and maintained PR by capmatinib, the right S₁ cancer increased, and several new metastases appeared. The subsequent switch from capmatinib to osimertinib could not control cancers. In this case, we tried to switch monotherapies from osimertinib to capmatinib for double primary adenocarcinomas harboring different two driver mutations, according to each cancer progression. The temporal and spatial heterogeneity reinforces the need for primary tissue biopsy if dual primaries are suspected. Temporally distinct liquid biopsies, not standard at present, may be considered.