The importance of enhancer methylation for epigenetic regulation of tumorigenesis in squamous lung cancer

Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell lung cancer (NSCLC). LUSC occurs at the bronchi, shows a squamous appearance, and often occurs in smokers. To determine the epigenetic regulatory mechanisms of tumorigenesis, we performed a genome-wide analysis of DNA methylation in tumor and adjacent normal tissues from LUSC patients. With the Infinium Methylation EPIC Array, > 850,000 CpG sites, including ~350,000 CpG sites for enhancer regions, were profiled, and the differentially methylated regions (DMRs) overlapping promoters (pDMRs) and enhancers (eDMRs) between tumor and normal tissues were identified. Dimension reduction based on DMR profiles revealed that eDMRs alone and not pDMRs alone can differentiate tumors from normal tissues with the equivalent performance of total DMRs. We observed a stronger negative correlation of LUSC-specific gene expression with methylation for enhancers than promoters. Target genes of eDMRs rather than pDMRs were found to be enriched for tumor-associated genes and pathways. Furthermore, DMR methylation associated with immune infiltration was more frequently observed among enhancers than promoters. Our results suggest that methylation of enhancer regions rather than promoters play more important roles in epigenetic regulation of tumorigenesis and immune infiltration in LUSC.

Case Report: Tumor Microenvironment Characteristics in a Patient With HER2 Mutant Lung Squamous Cell Carcinoma Harboring High PD-L1 Expression Who Presented Hyperprogressive Disease

BackgroundHigh PD-L1 expression in non-small cell lung cancer (NSCLC) is evident to predict elevated immunotherapy efficacy, to which NSCLC with onco-driver gene mutations is probed with poor responsiveness. Thus, it is of great interest to investigate how effective immune monotherapy is in the presence of concurrent high PD-L1 expression and driving gene mutation.Patients and methodsWe present a case of squamous lung cancer with high PD-L1 expression and HER2 exon 20 insertion (20Ins) who presented hyperprogressive disease (HPD) after being treated with PD-1 inhibitor.ResultsA 71-year-old female was diagnosed with advanced squamous lung cancer with 98% tumor proportion score of PD-1 and 20ins. She benefited from first-line docetaxel cisplatin followed by 2 months second-line afatinib. Third-line pembrolizumab monotherapy was then given. Unfortunately, she rapidly progressed with dramatically enlarged primary site as well as mediastinal lymph nodes and pleural effusion only 2 weeks later, presenting severe dyspnea and dysphagia. Re-biopsy was conducted, and we found that compared with the baseline, CD8+ T cells were largely recruited only in tumor stroma but not in tumor parenchyma. Tumor-associated macrophages were notably increased in both tumor stroma and parenchyma. Concomitantly, CD56dim NK cells in tumor parenchyma were decreased.ConclusionsApplication of immune monotherapy in patients with positive driver genes demands extreme caution, even harboring high PD-L1 expression. Abnormality of tumor microenvironment might be critically involved in immune checkpoint inhibitor-induced HPD. Further study in greater depth is required.

Case Report: Abscopal Effect of Microwave Ablation in a Patient With Advanced Squamous NSCLC and Resistance to Immunotherapy

Currently, immunotherapy has been a backbone in the treatment of advanced non-small cell lung cancer (NSCLC) without driver gene mutations. However, only a small proportion of NSCLC patients respond to immune checkpoint inhibitors, and majority of patients with initial response will develop acquired resistance at 5 years, which usually manifests as oligo-progression or oligo-metastases. Evidence from multiple clinical trials indicates that local consolidative therapies could improve the prognosis of oligometastatic NSCLC patients. Herein, we reported a case of advanced squamous lung cancer which showed a durable abscopal effect from microwave ablation after acquired resistance of immunotherapy.

Pre- and post-surgery change of EGFR mutation status in a lung squamous cell cancer patient

BackgroundThe percentage of epidermal growth factor receptor (EGFR) mutations in squamous lung cancer was relatively low. The dynamic changes of EGFR mutation in peripheral blood before and after surgical resection in epidermal growth factor receptor (EGFR) has been rarely reported.Case presentationWe report a 73-year-old woman with squamous lung cancer of the left upper lobe and EGFR exon 19 deletion (19del) was identified in biopsy and peripheral plasma separately before a surgical operation. The mass regressed remarkably after three cycles of platinum-based neoadjuvant chemotherapy and then the patient was administered curative-intent surgery. Postoperative pathology supported the diagnosis of left upper lobe squamous cell carcinoma and EGFR 19del mutation. At the time of 40 days after surgery, EGFR 19del mutation in peripheral blood was undetectable using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and next-generation sequencing (NGS) method.ConclusionsWe report, for the first time, the perioperational dynamics of EGFR mutation in a LSCC patient. EGFR 19del mutation was eliminated after surgical operation. The genetic mutation status from peripheral blood could be converted through the operation.

Different pathologic responses to neoadjuvant anti-PD-1 in primary squamous lung cancer and regional lymph nodes

Neoadjuvant immunotherapy provides a unique opportunity for understanding therapeutic responses. We analyzed pathologic responses in surgical specimens obtained from 31 squamous non-small cell lung cancer (NSCLC) patients receiving neoadjuvant anti-PD-1 treatment. Fifteen (48.4%) patients achieved pathologic complete response (pCR) or major pathologic response (MPR). Among them, seven (46.7%) were assessed as radiological partial response and eight (53.3%) as stable disease. Among 20 patients with pathologically identified tumor beds in lymph nodes (LNs), 10 and six patients achieved pCR/MPR in primary tumors and paired LNs, respectively. pCR was achieved in 6/19 N1 nodes and 1/7 N2 nodes. Residual viable tumor (RVT) cells in 8/9 MPR specimens had 100% immune-activated phenotype, while a median of 80% of RVT cells in pathologic nonresponse specimens presented immune-excluded/desert phenotype. These findings demonstrated that assessment of pathologic responses in both primary tumor and LNs may be important as a surrogate for assessing neoadjuvant immunotherapeutic efficacy.

Case Report: Pathologic Complete Response to Pembrolizumab in Combination With Neoadjuvant Chemotherapy in a Patient With Stage IIB Squamous Lung Cancer

The emergence of PD-1 antibodies has radically changed the therapeutic profiles of lung cancer, which has the highest incidence and mortality rate among all cancers worldwide. Pembrolizumab, an anti-PD-1 antibody, has been proven to have strong anti-tumor activity in a variety of clinical studies. Here, we described a patient with stage IIB squamous lung cancer who has benefited from a preoperative pembrolizumab plus chemotherapy regimen. The addition of pembrolizumab to neoadjuvant chemotherapy before surgery led to a pathologic complete response and the avoidance of left pneumonectomy. This case highlights the effect of neoadjuvant pembrolizumab plus chemotherapy on non-small cell lung cancer patients and has provided a promising choice in future clinical practice.

Possibilities of differential diagnostics of histologicalforms of primary lung cancer with multi-spiral computed tomography based on artificial intelligence

The problem of lung cancer, visualized including spherical formation of the lung, is becoming increasingly important every year. In the structure of the oncological morbidity of the Russian population among men in 2018, this pathology occupied the leading position 16.9% (in women 4.0%). When analyzing the distribution of patients with lung cancer of various age groups depending on the histotype of the tumor, it was found that in most cases it is adenocarcinoma and squamous lung cancer 85%. MSCT was performed in 342 patients with spherical formation of the lung aged 45 to 80 years using computed tomographs Aquillion 64 and Asteion 4 (Toshiba Medical Systems). Digital analysis of scans was performed using the X-ray + program (Russia, Barnaul), which allows direct sampling of average pixel densities in a tabular form in selected areas of interest from DICOM files for subsequent analysis and statistical processing. The obtained densitometric indicators were received at the inputs of an artificial neural network. The effectiveness of differential diagnosis of histological forms: sensitivity 35.7 + 2.6%, specificity 40.6 + 2.6%, accuracy 76.3 + 2.3%.