Lung Cancer: Targets and Therapy最新文献

Purpose: Surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC), including ground-glass opacity (GGO)-type lung cancer. However, some patients are inoperable or refuse to undergo surgery. To explore whether proton beam therapy (PBT) can be an alternative to surgical resection in these patients, this study aimed to examine the retrospective treatment outcomes of patients with GGO-type lung cancer who underwent PBT.

Patients and methods: Patients with stage I NSCLC and GGOs who underwent PBT at the Medipolis Proton Therapy and Research Center (Kagoshima, Japan) between April 2011 and September 2015 were included. Patients were treated with a total dose of 66 GyE delivered in 10 fractions. Survival curves were calculated using the Kaplan-Meier method, and treatment-related adverse events (AEs) were assessed.

Results: A total of 48 patients (median age: 70.9 ± 9.2 years; men: 54.2%) were analyzed, among whom 53 tumors were observed. The 3-year overall survival rate after PBT was 91.7% (95% confidence interval [CI], 79.3-96.8%), the 3-year disease-free survival rate was 85.4% (95% CI: 71.8-92.8%), and the 3-year local control rate among 53 tumors was 92.5% (95% CI: 81.1-97.1%). During the 3-year follow-up period, 4 patients died, and 3 survived despite recurrence or metastasis. Common AEs were radiation pneumonitis (89.6%), rib fracture (27.1%), and cough (27.1%). None of the patients developed grade ≥3 treatment-related AEs.

Conclusion: The results of this study suggest that PBT may be a promising alternative for patients with GGO-type lung cancer when surgical resection is not feasible, with excellent survival outcomes and tolerable treatment-related AEs.

Mutations in the epidermal growth factor receptor (EGFR) are common amongst those with non-small cell lung cancer and represent a major factor in treatment decisions, most notably in the advanced stages. Small molecule tyrosine kinase inhibitors (TKIs) that target the EGFR, such as erlotinib, gefitinib, icotinib, afatinib, dacomitinib and osimertinib, have all shown to be effective in this setting. Osimertinib, a third-generation EGFR TKI, is a favorable option, but almost all patients develop resistance at some time point. There are no effective treatment options for patients who progress on osimertinib, but ongoing trials will hopefully address this unmet need. The aim of this review is to provide a comprehensive review of the data with EGFR TKIs, management of the toxicities and the ongoing trials with this class of agents.

Purpose: Although EGFR-mutated patients generally do not benefit from checkpoint inhibitors (ICIs), some patients in the KEYNOTE-001 study consistently benefited from this treatment. This study investigated immune microenvironment characteristics to identify the subgroup of patients that may benefit from ICIs.

Materials and methods: Using data from The Cancer Genome Atlas Program (TCGA) and Cancer Proteome Atlas, TMB and protein level of PD-L1 were explored in the patients with EGFR mutations and wild-type patients. Different patterns of EGFR mutations (according to EGFR co-mutation with different downstream pathway genesets) were used to group EGFR mutation population. Estimated infiltration analyses were used to explore changes in the immune microenvironment.

Results: This study analyzed somatic mutation data from 1287 patients from five cohorts (TCGA, Broad, The Tumour Sequencing Project, Memorial Sloan Kettering Cancer Center, Catalogue Of Somatic Mutations In Cancer database). The probability of EGFR mutation was approximately 14.30% (184/1287) and the co-mutation rate was 11.41% (21/184) in patients with EGFR mutations. Glycosaminoglycan-related pathways were significantly upregulated in the EGFR mutant group. EGFR-mutated patients had lower TMB and PD-L1 protein levels than those in wild-type patients. Increase immature DCs infiltration and decreased NK CD56dim, T gamma delta, cytotoxic, and Th2 cell infiltration were the main immune changes in EGFR-mutated patients. Patients with EGFR-MAPK co-mutations had higher levels of TMB and PD-L1 protein expression. Meanwhile, the co-mutated patients had a similar immune microenvironment as that in wild-type patients.

Conclusion: In this study, we defined a subgroup of patients with EGFR-MAPK co-mutations. These co-mutated patients may benefit from ICI treatment.

Purpose: The effects of immune checkpoint inhibitors have been reported to be linked with immune-related adverse events (irAEs). In patients with advanced non-small-cell lung cancer, who tested positive for programmed death-ligand 1 (PD-L1), pembrolizumab, an immune checkpoint inhibitor can be used as a treatment, and it was found to improve overall survival. However, there are only a few reports on the relationship between the therapeutic effects of pembrolizumab in patients with lung cancer and the irAEs of pembrolizumab. The purpose of this study was to determine the correlation between immune-related adverse events and the effects of pembrolizumab monotherapy in patients with non-small-cell lung cancer.

Patients and methods: From February 2017 to August 2019, we conducted a retrospective analysis of the effects of pembrolizumab treatment and immune-related adverse events in 94 patients with non-small-cell lung cancer treated with pembrolizumab only.

Results: In 63 cases, irAEs were observed. The most common irAE was rash. PD-L1 positivity ≥ 50% tended to cause irAEs. The median progression-free survival (PFS) rates with and without irAEs were 371 days (95% CI, 184-NR) and 67 days (95% CI, 51-87 days), respectively. In a multivariate analysis, irAEs and Eastern Cooperative Oncology Group performance status (PS) were the factors related to PFS.

Conclusion: In patients with lung cancer, who were treated with pembrolizumab monotherapy, the development of irAEs was likely indicative of the positive effects of pembrolizumab. This novel finding appears to be useful for clinicians who work with pembrolizumab for lung cancer treatment.

Neuroendocrine tumors (NETs) of the lung are well-differentiated neuroendocrine neoplasms (NENs) with a heterogeneous clinical behaviour. Unlike gastroenteropancreatic NENs where therapeutic armamentarium clearly increased over the last decade, everolimus represented the only clinical practical innovation for lung NET patients over the last years. Therefore, for lung NETs, a multidisciplinary discussion within a dedicated team remains critical for an adequate decision-making. Although the main regulatory authorities considered the everolimus-related evidence is enough to approve the drug in advanced lung NETs, several clinical features deserve to be discussed. In this review, we systemically and critically analysed the main clinical studies including patients with advanced lung NETs receiving everolimus. Furthermore, we reported the biological and clinical background of everolimus in lung NET setting. The purpose of this review is to help clinical community to contextualize evidence and experience for a personalised use of this drug in clinical practice in the context of advanced lung NET patients.

Background: ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.

Methods: Comprehensive genomic profiling (CGP) of DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.

Results: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events.

Conclusion: Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.

Lung cancer is the leading cause of death of all cancer entities and small-cell lung cancer (SCLC) is the most malignant subtype. Despite good initial response to chemotherapy, many patients relapse early and success of second line treatment remains poor. For years, no relevant improvement of second line treatment has been achieved in the field of SCLC. Lurbinectedin, a novel RNA-polymerase II inhibitor has shown promising results in pretreated SCLC patients as single agent and in combination with other chemotherapeutic drugs leading to an orphan drug designation from the FDA. This article reviews the current data on this emerging substance and its impact on the treatment of SCLC.

Background: The ROS1 gene is a member of the "sevenless" subfamily of tyrosine-kinase insulin-receptor genes. ROS1-fusion rearrangement causes constitutive downstream signal transduction, with an oncogenic role in non-small-cell lung carcinoma (NSCLC). Fortunately, crizotinib, an ALK1 tyrosine-kinase inhibitor, provides long-term disease control. The objective of this molecular epidemiological study was to estimate the frequency of ROS1 rearrangements and evaluate treatment outcomes with crizotinib therapy.

Methods: Patients with stage IV NSCLC adenocarcinoma histology were considered for this study. The study was conducted according to the ethical principles stated in the latest version of the Declaration of Helsinki and the applicable guidelines for good clinical practice. Clinical characteristics and treatment details were collected from patients' medical records.

Results: A total of 709 stage IV NSCLC adenocarcinoma patients were included in the study. There were 457 (64.46%) men and 252 (35.54%) women, with a median age of 60 years. ROS1-gene rearrangement was positive in 20 (2.82%) cases, 13 using Fluorescent In-Situ Hybridization (FISH), and two and five cases, respectively, using immunohistochemistry (IHC) and next-generation sequencing (NGS), followed by confirmation with FISH. Fourteen of the 20 patients with ROS1-gene rearrangement received crizotinib therapy, with an objective response rate of 64.28%. At a median follow-up of 6 months, the study had not achieved the end points of median progression free survival and overall survival.

Conclusion: ROS1-gene rearrangement was present at a relatively higher frequency of 2.8% in north Indian patients with lung adenocarcinoma and was successfully targeted by crizotinib therapy. Although the only US Food and Drug Administration and Conformité Européenne approved method for testing ROS1 rearrangement is NGS, FISH alone or IHC with D4D6 antibody as initial screen with subsequent confirmation of IHC-positive cases by FISH are cost-effective methods in institutions lacking NGS facilities.

Central nervous system (CNS) metastasis carries a significant morbidity and mortality in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Next-generation ALK tyrosine kinase inhibitors (TKIs) are highly CNS-penetrant and have demonstrated remarkable intracranial activity across clinical studies, and yet radiation remains the mainstay of treatment modality against CNS metastasis. We have previously reported alectinib can induce CNS radiation necrosis even after a remote history of radiation (7 years post-radiation). Lorlatinib is another potent next-generation ALK TKI that can overcome many ALK resistance mutations and has been shown to have excellent activity in patients with baseline CNS metastasis. Here we report two ALK-rearranged NSCLC patients who developed radiation necrosis shortly after initiating lorlatinib following progression on the sequential treatment of crizotinib, alectinib, and brigatinib. In both cases, radiation necrosis is evidenced by serial MRI images and histological examination of the resected CNS metastasis that had previously been radiated. Our cases highlight the importance of recognizing CNS radiation necrosis that may mimic disease progression in ALK-rearranged NSCLC treated with and potentially precipated by next-generation ALK TKIs.

Asbestos is a naturally occurring mineral consisting of extremely fine fibres that can become trapped in the lungs after inhalation. Occupational and environmental exposures to asbestos are linked to development of lung cancer and malignant mesothelioma, a cancer of the lining surrounding the lung. This review discusses the factors that are making asbestos-induced lung cancer a continuing problem, including the extensive historic use of asbestos and decades long latency between exposure and disease development. Genomic mutations of DNA nucleotides and gene rearrangements driving lung cancer are well-studied, with biomarkers and targeted therapies already in clinical use for some of these mutations. The genes involved in these mutation biomarkers and targeted therapies are also involved in epigenetic mechanisms and are discussed in this review as it is hoped that identification of epigenetic aberrations in these genes will enable the same gene biomarkers and targeted therapies to be used. Currently, understanding of how asbestos fibres trapped in the lungs leads to epigenetic changes and lung cancer is incomplete. It has been shown that oxidoreduction reactions on fibre surfaces generate reactive oxygen species (ROS) which in turn damage DNA, leading to genetic and epigenetic alterations that reduce the activity of tumour suppressor genes. Epigenetic DNA methylation changes associated with lung cancer are summarised in this review, and some of these changes will be due to asbestos exposure. So far, little research has been carried out to separate the asbestos driven epigenetic changes from those due to non-asbestos causes of lung cancer. Asbestos-associated lung cancers exhibit less methylation variability than lung cancers in general, and in a large proportion of samples variability has been found to be restricted to promoter regions. Epigenetic aberrations in cancer are proving to be promising biomarkers for diagnosing cancers. It is hoped that further understanding of epigenetic changes in lung cancer can result in useful asbestos-associated lung cancer biomarkers to guide treatment. Research is ongoing into the detection of lung cancer epigenetic alterations using non-invasive samples of blood and sputum. These efforts hold the promise of non-invasive cancer diagnosis in the future. Efforts to reverse epigenetic aberrations in lung cancer by epigenetic therapies are ongoing but have not yet yielded success.