BackgroundDiagnosing and treating patients with multiple primary lung cancers (MPLCs) bring challenges to the clinic, and the preliminary evidence has revealed unsatisfying outcomes after targeted therapy and immunotherapy. Therefore, we surveyed genomic profiles of MPLCs and their possible associations with tumor mutation burden (TMB), programmed death-ligand 1 (PD-L1), and the immune cell infiltration landscape.Materials and methodsA total of 112 patients with MPLCs with surgically resected 294 tumors were eligible, and 255 tumors were sequenced using a 1021-gene panel. Immunohistochemistry staining was performed to evaluate the levels of PD-L1 and the density of CD3+/CD8+ tumor-infiltrating lymphocytes (TILs), and CD68+/CD163+ tumor-associated macrophages (TAMs) at the central tumor and invasive margin, and immunotypes were generated based on those variables.ResultsMPLCs often occur simultaneously in non-smoker women younger than 60 years and manifest as ground-glass opacities, adenocarcinoma, and stage I lung lesions. The most frequently mutated genes in the 255 tumors were EGFR (56%), ERBB2 (12%), TP53 (12%), BRAF (11%), RBM10 (11%), and KRAS (9%). We found 87 (77.7%) patients with diverse genomic profiles, and 61 (54.5%) who shared at least one putative driver gene between different tumors presented more aggressive tumors. The median TMB was 1.92 mutations/Mb, and high-TMB (≥3) lesions often harbored EGFRL858R/KRASG12C/RBM10/TP53/LRP1B mutations or wild-type ERBB2. Only 8.1% of patients and 3.9% of lesions were positive for PD-L1 on tumor cells, and this positivity was more frequent in LRP1B/TP53-mutant tumors. EGFRL858R/RBM10/TP53 mutations were positively associated with specific immune cells and an inflamed immunotype, but ERBB2 mutations were negatively correlated. TMB, CD3+TILs, and CD68+/CD163+ TAMs presented with significant heterogeneity among paired tumors (all kappa <0.2), but PD-L1 and CD8 +TILs were more uniformly present in tumor pairs.ConclusionMPLCs are driven by different molecular events and often exhibit low TMB, low PD-L1, and a heterogeneous immune infiltration landscape. Specific genomic profiles are associated with TMB and the tumor immune microenvironmental landscape in MPLCs. Our findings can help to guide MPLCs diagnoses and to identify patient populations that may benefit from immunotherapy and targeted therapy.

Primary pulmonary enteric adenocarcinoma (PEAC) is a rare invasive adenocarcinoma clinically similar to metastatic colorectal adenocarcinoma (MCRC). Although many studies have addressed the differential diagnosis of PEAC, few have described the treatment of PEAC, especially using immunotherapy. This report describes a 61-year-old man who presented initially with pain in the ribs. Pathological analysis of biopsy samples shows malignant tumors of the right pleura, and next-generation sequencing of 26 genes showed a KRAS gene mutation. Positron emission tomography-computed tomography (PET-CT) found no evidence of gastrointestinal malignancy. Due to multiple metastases, the patient could not undergo radical surgery. The patient was treated with a combination chemotherapy regimen of paclitaxel plus carboplatin, along with sindilizumab immunotherapy, but, after one cycle of treatment, the tumor showed a hyperprogressive state. The patient is still being monitored regularly. These findings indicate that chemotherapy combined with immunotherapy may be ineffective in the treatment of primary PEAC with positive driver genes.

e18074 Background: Epidermal growth factor receptor (EGFR) mutation is most commonly oncogenic driver in lung adenocarcinoma with 50% incidence in Asians.Osimertinib is the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which has been widely used in metastatic EGFR-mutant non-small cell lung cancer (NSCLC) and has significantly improved outcomes. At present, the treatment of HNSCC mainly relies on surgery or chemoradiotherapy. EGFR is overexpressed in more than 90% of head and neck squamous cell carcinoma (HNSCC). Targeted therapy for HNSCC is mainly monoclonal antibodies, while the application of small molecule inhibitors is limited. The EGFR-TKI can only be applied in subsequent-line, when disease progression on or after platinum therapy. However, the efficacy of EGFR-TKI in patients with both NSCLC and HNSCC remains unclear. Methods: We searched all patients with EGFR-mutation metastatic non-small cell lung cancer and HNSCC who used EGFR-TKI in the Second Xiangya Hospital. Tumor sections were assessed immunohistochemically using PD-L1 and EGFR expression. EGFR amplification was detected by fluorescence in situ hybridization (FISH). We collected clinical characteristics and treatment histories for all patients including time to progression on EGFR-TKI. Time to progression on EGFR-TKI was defined as time from start of EGFR-TKI to time of radiographic RECIST progression. The efficacy and prognosis were evaluated based on the RECIST (version 1.1). Results: We found an advanced lung adenocarcinoma patient who harbored an EGFR-mutation and concurrently had tongue squamous cell carcinoma with EGFR wild-type.The tongue tumor tissue sample for EGFR expression was positive by immunohistochemistry and EGFR amplification was negative by FISH. NGS showed inactive mutation of patched1 (PTCH1) and EGFR wild-type.PET-CT scans demonstrated a partial response (PR) of the lung tumor and tongue cancer after two months of treatment of osimertinib. The lung tumor maintian partial response until now (nearly 30 months). And the tongue tumor reached the first progression- free survival (PFS) at 21 months. Conclusions: The patient with NSCLC and tongue cancer who exhibited objective response to EGFR-TKI, osimertinib monotherapy. The result indicates a clear response of tongue cancer to osimertinib and the potential for the use of osimertinib in tongue cancer. However, with the specific mechanism largely unknown, it is necessary to study further the effect of osimertinib on HNSCC.