Expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed small cell lung cancer.

Background: The transformation of epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) into small cell lung cancer (SCLC) accounts for 3-14% of the resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). At present, there is no relevant research to explore the dynamic expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed SCLC/neuroendocrine carcinoma (NEC). Methods: Genetic analysis and protein level analysis by next-generation sequencing (NGS), Whole-exome sequencing (WES) and immunohistochemistry were performed to explore expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed SCLC. The research used three patient-derived organoids (PDOs) to explore the efficacy of combo [chemotherapy (chemo) plus TKI or bevacizumab] treatment. According to the subsequent treatment regimens after SCLC/NEC transformation, 35 patients were divided into chemo (n=21) and combo (n=14) groups. Results: EGFR L858R and EGFR E746-750 del protein expression by immunohistochemistry was 80.0% (4/5) and 100% (6/6), respectively (P=0.455) in initially-transformed tissues. Meanwhile, EGFR-mutant proteins were expressed in 85.7% (6/7) of dynamic rebiopsy tissues or effusion samples after the first transformation. Then, by the pathway enrichment analysis of tissue and plasma NGS, the EGFR-related pathways were still activated after SCLC/NEC transformation. Moreover, WES analysis revealed that transformed SCLC shared a common clonal origin from the baseline LUAD. The drug sensitivity of three PDOs demonstrated potent anti-cancer activity of EGFR-TKIs plus chemo, compared with chemo or TKI alone. There were significant differences in objective response rate (ORR) between the combo and chemo groups [42.9 % vs. 4.8%, P=0.010, 95% confidence interval (CI): 1.5-145.2]. Furthermore, the median post-transformation progression-free survival (pPFS) was significantly prolonged in the combo group, with 5.4 (95% CI: 3.4-7.4) versus 3.5 (95% CI: 2.7-4.3, P=0.012) months. Conclusions: EGFR 19del or L858R-mutant proteins could be constantly expressed, and EGFR pathway still existed in EGFR-mutant transformed SCLC/NEC with a common clonal origin from the baseline LUAD. Taking together, these molecular characteristics potentially favored clinical efficacy in transformed SCLC/NEC treated with the combo regimen.

Pathological characteristics and tumour immune microenvironment of lung malignancies with RET rearrangement.

BACKGROUND: For patients with lung malignancies with RET rearrangement, the efficacy of immune checkpoint inhibitors is limited. The characteristics of the tumour immune microenvironment (TIME) and molecular pathological features of these patients have not been well elucidated. We aimed to investigate their clinical outcomes and explore characteristics of TIME, using multiplex immunohistochemistry technology (mIHC). PATIENTS AND METHODS: The pathology and TIME characteristics of 29 patients with lung malignancies with RET rearrangement were retrospectively analysed, and their relationships with clinical efficacy and prognosis were investigated. Gene detection relied on high-throughput sequencing, and TIME detection was based on mIHC. RESULTS: Of 29 patients, 25(86%) had adenocarcinoma, and the acinar type accounted for the greatest percentage of patients, followed by the solid type, regardless of whether the disease was early or locally advanced and metastatic. In addition, we report a novel KIF5B-RET(k24:R8) rearrangement in pulmonary sarcoma. The density of CD8+ T cells in tumour stroma in early-stage patients was significantly higher than that in locally advanced and metastatic patients (P = 0.014). The proportion of M2 macrophages in tumour stroma was significantly higher than that in tumour parenchyma (P = 0.046). Although the difference was not statistically significant (P = 0.098), patients positive for M2 macrophage infiltration into the tumour parenchyma (≥5%) may have a better prognosis. Seven patients received immunotherapy and disease control rate was 85.7%. CONCLUSIONS: A novel KIF5B-RET rearrangement variant in pulmonary sarcoma shows similar TIME characteristics to lung cancer. amongst patients with lung malignancies with RET rearrangement, patients with M2 macrophage infiltration into the tumour parenchyma may have a better prognosis, but further studies with larger cohorts are needed.

Using patient-derived organoids to predict locally advanced or metastatic lung cancer tumor response: A real-world study.

Predicting the clinical response to chemotherapeutic or targeted treatment in patients with locally advanced or metastatic lung cancer requires an accurate and affordable tool. Tumor organoids are a potential approach in precision medicine for predicting the clinical response to treatment. However, their clinical application in lung cancer has rarely been reported because of the difficulty in generating pure tumor organoids. In this study, we have generated 214 cancer organoids from 107 patients, of which 212 are lung cancer organoids (LCOs), primarily derived from malignant serous effusions. LCO-based drug sensitivity tests (LCO-DSTs) for chemotherapy and targeted therapy have been performed in a real-world study to predict the clinical response to the respective treatment. LCO-DSTs accurately predict the clinical response to treatment in this cohort of patients with advanced lung cancer. In conclusion, LCO-DST is a promising precision medicine tool in treating of advanced lung cancer.

A potential treatment option for transformed small-cell lung cancer on PD-L1 inhibitor-based combination therapy improved survival.

OBJECTIVES: Transformed small-cell lung cancer (T-SCLC) has an extremely poor prognosis, and no remedies based on immunotherapy have been evaluated among T-SCLC patients. We retrospectively analysed the efficacy and safety of combining atezolizumab with chemotherapy for T-SCLC. METHODS: Forty-seven patients harbouring EGFR mutations who developed T-SCLC were enrolled. Eleven patients who used immunotherapy were defined as the I/O group, and the remaining 36 were defined as the Non-I/O group. Clinical characteristics, pathological data, and survival outcomes were collected. RNA sequencing and whole-exome sequencing (WES) were performed for in-depth analysis. RESULTS: All patients received at least one line of EGFR-TKI before rebiopsy to confirm T-SCLC. Nine patients received atezolizumab-bevacizumab-carboplatin-paclitaxel (albumin-bound) (ABCP), and the remaining 2 received atezolizumab-etoposide-carboplatin (ECT) in the I/O group. The objective response rate was 73 % (8/11). The median progression-free survival (mPFS) of T-SCLC on post-transformation therapy with I/O group and Non-I/O group was 5.1 m and 4.1 m, respectively. The median post-T-SCLC overall survival of the I/O group was significantly longer than that Non-I/O group (20.2 m vs 7.9 m, P ＜ 0.01). T-SCLC harbouring EGFR L858R tended to be longer than EGFR 19del (mPFS: not reached vs 3.7 m, P = 0.11). Positive PD-L1 status was also associated with PFS benefits (mPFS: 6.0 m vs 3.7 m, P = 0.20). Furthermore, RNA sequencing revealed that expression of SFTPA1 is significantly higher in the durable clinical benefit group. WES showed that STC2 mutation is more frequently observed at the time-point immunotherapy acquired resistance. Combination therapy based on a PD-L1 inhibitor was well tolerated, and the safety profile was consistent with previously reported studies. CONCLUSION: Our study first demonstrated that a PD-L1 inhibitor combined with chemotherapy ± bevacizumab could be a potential safe option for specific SCLC-transformed patients. Subsequent studies with more patients are essential to verify the efficacy and potential biomarkers.

Response to Icotinib Plus Chemotherapy in Pulmonary Atypical Carcinoid Harboring the EGFR L858R Mutation: A Brief Report.

INTRODUCTION: Pulmonary atypical carcinoid (PAC) is a rare subtype of pulmonary neuroendocrine neoplasm. Although EML4-ALK fusion has been detected in PAC, EGFR mutations have not been reported before. METHODS: We performed hematoxylin and eosin staining, immunohistochemistry, and next-generation sequencing on tissues at baseline and after surgery. RESULTS: The patient was diagnosed with having advanced PAC harboring the EGFR L858R mutation and then received a combination of icotinib and irinotecan plus cisplatin chemotherapy, achieving a partial response before the operation. Postoperative histology results revealed SCLC harboring the EGFR L858R mutation. Surprisingly, both the KRAS amplification and the RB1 deletion disappeared. CONCLUSIONS: EGFR tyrosine inhibitors plus irinotecan plus cisplatin chemotherapy might be a potential treatment option for advanced pulmonary neuroendocrine neoplasms harboring EGFR mutations.