Icotinib in a lung adenocarcinoma patient with acquired EGFR 19del/C797S mutation-mediated resistance to osimertinib: a case report.

Based on the FLAURA and AURA III trials, compared to first- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), osimertinib provides a longer overall survival benefit for patients with untreated EGFR mutated non-small cell lung cancer. Similar to other EGFR-TKIs, drug resistance is, however, inevitable. The most common mechanism of acquired resistance to first-line osimertinib therapy is the C797S mutation, which accounts for 6% of cases. In view of the current challenges of the development of the next generation of EGFR inhibitors, the mechanism of third-generation targeted drug resistances and targeted strategies are key for further exploration. Our case report discusses a female patient with advanced lung adenocarcinoma carrying the EGFR exon19 E746_A750delinsIP mutation who received osimertinib as first-line therapy and acquired C797S resistance during treatment. The patient was then treated with icotinib for 8 months until the disease progressed. Icotinib may be effective in patients with the EGFR 19del-C797S resistant mutation acquired after osimertinib treatment.

Extensive Stage Small-Cell Lung Cancer with Cystic Brain Metastases: A Report of Two Cases.

Objective: Cystic brain metastases (BMs) are rare in small cell lung cancer (SCLC), and there are limited data on the treatment and prognosis of cystic BMs. Whole brain radiotherapy has been the mainstay for BMs since several years. Immune checkpoint inhibitors in extensive stage small cell lung cancer (ES-SCLC) have been shown to be suitable for patients who experienced better overall survival and progress-free survival and have been approved as the first-line treatment for ES-SCLC. In this report, we described two ES-SCLC patients developed cystic BMs after immunotherapy, after which the patients continued to treat the primary lesion with immune checkpoint inhibitors and the cystic BMs with radiotherapy. Case Description: Two male patients were diagnosed with ES-SCLC at the first admission and were subsequently treated with immunotherapy plus platinum therapy, during which cystic BMs developed. One patient received whole brain radiotherapy and the other received whole brain radiotherapy and Gamma knife radiosurgery (GKRS). Immunotherapy was continued after the brain lesions were controlled. It has been 33 months since the first patient was diagnosed and is now in stable condition. The other patient achieved an overall survival of 30 months. Conclusion: This report describes two patients with cystic brain metastases in ES-SCLC. Whole brain radiotherapy has a good effect on local control of cystic brain metastases in small cell lung cancer and can significantly improve the symptoms of patients. At the same time, we treat immunotherapy as the first-line treatment, and then perform cross-immunotherapy after disease progression, combined with anti-vascular targeting drugs. The patient did not develop severe iRAEs.

Single-cell RNA sequencing reveals the mechanism of PI3K/AKT/mTOR signaling pathway activation in lung adenocarcinoma by KRAS mutation.

BACKGROUND: Aberrant activation of the phosphatidlinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway has been shown to play an important role in lung adenocarcinoma (LUAD). The effect of KRAS mutations, one of the important signatures of LUAD, on the PI3K/AKT/mTOR pathway in LUAD remains unclear. METHODS: The Seurat package and principal component analysis were used for cell categorization of single-cell RNA sequencing data of LUAD. The AUCell score was used to assess the activity of the PI3K/AKT/mTOR pathway. Meanwhile, using the gene expression profiles and mutation profiles in the The Cancer Genome Atlas dataset, LUAD patients were categorized into KRAS-mutant (KRAS-MT) and KRAS-wild-types (KRAS-WT), and the corresponding enrichment scores were calculated using gene set enrichment analysis analysis. Finally, the subpopulation of cells with the highest pathway activity was identified, the copy number variation profile of this subpopulation was inscribed using the inferCNV package and the CMap database was utilized to make predictions for drugs targeting this subpopulation. RESULTS: There is higher PI3K/AKT/mTOR pathway activity in LUAD epithelial cells with KRAS mutations, and high expression of KRAS, PIK3CA, AKT1 and PDPK1. In particular, we found significantly higher levels of pathway activity and associated gene expression in KRAS-MT than in KRAS-WT. We identified the highest pathway activity on a subpopulation of GRB2+ epithelial cells and the presence of amplified genes within its pathway. Finally, drugs were able to target GRB2+ epithelial cell subpopulations, such as wortmannin, palbociclib and angiogenesis inhibitor. CONCLUSIONS: The present study provides a basic theory for the activation of the PI3K/AKT/mTOR signaling pathway as a result of KRAS mutations.

Prognostic factors, treatment, and outcomes in combined small cell lung cancer: a SEER survey from 2004 to 2015.

BACKGROUND: The epidemiological characteristics of combined small cell lung cancer (C-SCLC) are still unclear. Therefore, in this study, we aimed to investigate the prognostic factors and treatment modalities for C-SCLC. METHODS: The clinical data from patients with primary C-SCLC from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Next, we applied the 8th edition of the TNM classification. A Cox regression model was used to identify the relevant variables and treatment modalities which affected the overall survival (OS) and cancer-specific survival (CSS). RESULTS: In total, 1,010 patients were included in the analysis. The median OS and median CSS were 9 months and 10 months, respectively. Individuals aged 65 and younger, female, and classified as being in an earlier stage were independent predictors of an improved OS and CSS. For patients with stage I, surgery alone significantly improved the OS (HR, 0.371; 95% CI, 0.180-0.769) and CSS (HR, 0.367; 95% CI, 0.162-0.892). For patients with stage II, surgery combined with radiotherapy significantly improved the OS (HR, 0.237; 95% CI, 0.063-0.890). For patients with stage III, radiotherapy alone was an independent predictor of OS (HR, 0.464; 95% CI, 0.316-0.618) and CSS (HR, 0.452; 95% CI, 0.305-0.670). For patients with stage IV, surgery combined with radiotherapy significantly improved OS (HR, 0.315; 95% CI, 0.181-0.547) and CSS (HR, 0.329; 95% CI, 0.189-0.573), and surgery alone also improved OS (HR, 0.257; 95% CI, 0.144-0.461) and CSS (HR, 0.280; 95% CI, 0.156-0.501). Undergoing chemotherapy was also an independent predictor of an improved OS (HR, 0.619; 95% CI, 0.419-0.915) in patients with stage III, and OS (HR, 0.283; 95% CI, 0.228-0.350) and CSS (HR, 0.289; 95% CI, 0.232-0.259) of patients with stage IV. CONCLUSIONS: These findings may help to determine possible treatment choices and aid further research on this rare disease.

Surgery for small cell lung cancer: A Surveillance, Epidemiology, and End Results (SEER) Survey from 2010 to 2015.

The role of surgery in small cell lung cancer (SCLC) is controversial. This study explored whether surgery offered a survival benefits for patients with SCLC.Patients diagnosed with SCLC between 2010 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. The tumor, node, and metastasis (TNM) stage of SCLC in these patients was reclassified according to the 8th edition of the TNM classification for lung cancer. Overall survival (OS) was separately compared according to TNM stage between patients who underwent surgery and those who did not using Kaplan-Meier method. A Cox regression model was used to identify relevant variables affecting survival. Additional Kaplan-Meier curves were created to compare different types of surgery. Cox regression models and Forest plots were used to identify the predictors of survival in the surgery cohort.A total of 26,659 patients with SCLC were included, among which 627 (2.4%) patients underwent surgery. Surgery was associated with longer survival in patients with stage IA (45.0 vs 20.0 months, P < .001), stage IB (47.0 vs 19.0 months, P = .001), stage IIA (16.0 m vs NR, P = .007), stage III (18.0 vs 12.0 months, P < .001), and stage IV (9.0 vs 5.0 months, P < .001) disease, although the difference was not statistically significant for patients with stage IIB disease. Multivariate analysis identified surgery as an independent predictor of improved survival for all cohorts divided by stages except for stage IIB. Lobectomy was the most commonly performed procedure. Multivariate analysis in patients who underwent surgery identified lobectomy (hazard ratio [HR], 0.544; 95% confidence interval [CI], 0.341-0.869; P = .011) and chemotherapy (HR, 0.634; 95% CI, 0.487-0.827; P < .001) as independent predictors of improved survival in the surgery cohort.In a national analysis, surgery was performed in some patients for both early and advanced-stage SCLC. Surgery for SCLC was associated with improved survival except for patients with stage IIB disease. These results support an increased role of surgery in multimodal therapy for SCLC.

Trastuzumab monotherapy for bone marrow metastasis of breast cancer: A case report.

The current study presents the case of a 41-year-old female patient who received modified radical mastectomy and adjuvant chemotherapy and radiotherapy for infiltrating ductal cancer of the left breast. The pathological stage of the disease was IIA. In addition, the patient was negative for the estrogen and progesterone receptors, and human epidermal growth factor receptor-2 gene amplification was identified. At one year following surgery, the patient presented with severe pancytopenia and pain at multiple sites all over the body. Furthermore, the patient's Eastern Cooperative Oncology Group performance status score was 3 and numeric rating scale pain score was 8. The bone marrow puncture indicated bone marrow metastatic cancer, and the positron emission tomography/computed tomography (CT) indicated multiple internal organ metastases and osseous metastasis. Chemotherapy treatment posed great risks due to the patient's poor performance status and severe bone marrow suppression. Therefore, trastuzumab monotherapy was administered at a loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg every three weeks. Following four doses of trastuzumab treatment, the patient's performance status significantly improved and the peripheral blood cell counts had returned to within the normal ranges. Taxol was added to the trastuzumab treatment and seven cycles were completed. No metastatic cancer cells were found in the subsequent bone marrow smear test; however, CT showed metastatic foci in the left lung. Furthermore, the enlarged lymph nodes had subsided and the tumor in the right appendix region had decreased in size by 50%. The patient's disease condition was maintained stable for 11 months.