Relationship between loss-of-function mutation of the stromal antigen 2 gene and treatment in non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20509-e20509
Author(s):  
Minglei Zhuo ◽  
Xin Liu ◽  
Rongrong Chen ◽  
Xiong Xu ◽  
Bin Ni
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Systemic Treatment ◽  
Genetic Alterations ◽  
Small Cell ◽  
Age At Diagnosis ◽  
Loss Of Function ◽  
Small Cell Lung ◽  
The Impact

e20509 Background: The protein encoded by Stromal Antigen 2 ( STAG2) gene is a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Loss-of-function (LOF) mutations of STAG2 gene are commonly detected in different tumors including non-small-cell lung cancer. However, there is no relevant research on the impact of STAG2 alterations on lung cancer treatment. Here we explored the correlation between the LOF of STAG2 and clinical features, concomitant genetic alterations and treatment in NSCLC pts. Methods: A total of 2882 NSCLC pts were enrolled. All the tissue samples were detected by DNA based next generation sequencing (NGS) with a 1021 gene panel. Clinical information was obtained synchronously from physicians and surgeons. According to whether LOF of STAG2 is detected, pts were divided into LOF subgroup and wild type (WT) group. Results: All pts enrolled are Chinese, and median age at diagnosis of them is 63±11.21. Compared to the WT subgroup, a higher average TMB was observed in the LOF group (12.64muts/Mb vs. 6.66mut/Mb, P＜0.05). Between the LOF group and the WT group, there were no significantly difference in all clinical baseline characteristics including age at diagnosis, gender, tumor stage and pathological type. At the time of sample collection, there was no significant difference between the two groups of pts whether they had received systemic treatment (chemotherapy, targeted therapy or immunotherapy) and systemic treatment, and the number of systemic treatment lines received. Neither significant differences in driver gene alteration and other accompanying mutations were observed in the two groups. Conclusions: In NSCLC pts, LOF of STAG2 is not a change after drug resistance, but it may lead to an increase in TMB, which indicates that these pts may have more benefits from immunotherapy. But the influence on prognosis of NSCLC pts needs further research to clarify.

scholarly journals Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 690 ◽  
Author(s):  
Arik Bernard Schulze ◽  
Georg Evers ◽  
Andrea Kerkhoff ◽  
Michael Mohr ◽  
Christoph Schliemann ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Molecular Pathways ◽  
Loss Of Function ◽  
Small Cell Lung ◽  
Therapeutic Concept ◽  
Platinum Based Chemotherapy

Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13). Apart from these factors, the application of so-called ‘poly-(ADP)-ribose polymerases’ (PARP) inhibitors can influence tumor repair mechanisms and thus offer new perspectives for future treatment. Another promising therapeutic concept is the inhibition of ‘enhancer of zeste homolog 2’ (EZH2) in the loss of function of tumor suppressors or amplification of (proto-) oncogenes. Considering the poor prognosis of SCLC patients, new molecular pathways require further investigation to augment our therapeutic armamentarium in the future.

scholarly journals The impact of EGFR mutation status and single brain metastasis on the survival of non-small-cell lung cancer patients with brain metastases

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Yuya Fujita ◽  
Manabu Kinoshita ◽  
Tomohiko Ozaki ◽  
Koji Takano ◽  
Kei Kunimasa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Egfr Mutation ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutation Status ◽  
The Impact

Abstract Background Molecular and genetic alterations of non-small-cell lung cancer (NSCLC) now play a vital role in patient care of this neoplasm. The authors focused on the impact of epidermal growth factor receptor mutation (EGFR-mt) status on the survival of patients after brain metastases (BMs) from NSCLC. The purpose of the study was to understand the most desirable management of BMs from NSCLC. Methods This was a retrospective observational study analyzing 647 patients with NSCLC, including 266 patients with BMs, diagnosed at our institute between January 2008 and December 2015. EGFR mutation status, overall survival (OS) following diagnosis, OS following BMs, duration from diagnosis to BMs, and other factors related to OS and survival after BMs were measured. Results Among 647 patients, 252 (38.8%) had EGFR mutations. The rate and frequency of developing BMs were higher in EGFR-mt patients compared with EGFR wildtype (EGFR-wt) patients. EGFR-mt patients showed longer median OS (22 vs 11 months, P < .001) and a higher frequency of BMs. Univariate and multivariate analyses revealed that good performance status, presence of EGFR-mt, single BM, and receiving local therapies were significantly associated with favorable prognosis following BM diagnosis. Single metastasis, compared with multiple metastases, exhibited a positive impact on patient survival after BMs in EGFR-mt patients, but not in EGFR-wt NSCLC patients. Conclusions Single BM with EGFR-mt performed better than other groups. Furthermore, effective local therapies were recommended to achieve better outcomes.

Patho-genomic feature of PI3K / AKT / mTOR pathway mutations in Chinese patients with non-small cell lung cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21049-e21049
Author(s):  
Weiwei Li ◽  
Yuan Qiu ◽  
Hanzhang Chen ◽  
Haihong Yang ◽  
Qiuhua Deng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Mtor Pathway ◽  
Chinese Patients ◽  
Genomic Feature ◽  
Loss Of Function ◽  
Small Cell Lung

e21049 Background: Inhibition of PI3K/AKT/mTOR pathway has emerged as a promising anticancer strategy. Measuring genetic alterations in PI3K/AKT/mTOR pathway are critical for clinical decision making for patients with lung cancer. This study aims to analyze PI3K/AKT/mTOR pathway-related gene mutations in non-small cell lung cancer (NSCLC) in a consecutive cohort. Methods: 536 surgically resected tumor tissues were collected. Target region capture sequencing for 508 cancer-related genes was conducted on MGI-seq 2000 platform. Results: PI3K/AKT/mTOR pathway genes were mutated in 120 samples (22.4%). Female or older patients displayed higher mutation incidence of PI3K/AKT/mTOR pathway (P = 0.06 for female, P = 0.05 for patients ≥60 y). In NSCLC samples, mutations mainly occurred in NF1/2(18/499), PTEN (7/499), MTOR (4/499), TSC1/2(18/499), PIK3CA (26/499), PDK1 (2/499), AKT1/2/3 (5/499) and KRAS (49/499) genes. Genetic alterations of AKT2 (p = 0.003), mTOR (P = 0.03), PTEN (P = 0.005) and PIK3CA (P < 0.001) are preferred to occur in squamous NSCLC. PIK3CA variants (p.E542K, p.E545K, p.Q546K) were more enriched in non-squamous NSCLC, while amplification of PIK3CA was more prevalent in squamous NSCLC (P = 0.038). Histologically, TSC1/2 mutations were more correlate with micro-invasion subtype in non-squamous NSCLC (P = 0.002). Meanwhile, PIK3CA alterations, especially, amplification occurred more often in keratinizing squamous NSCLC (P < 0.001). In addition, four patients with biallelic NF1 loss of function mutations were exclusively found in non-squamous NSCLC without co-occurrence of mutation in known driver genes like EGFR or TP53, which indicated biallelic loss of function of NF1 might be sufficient to drive oncogenesis of non-squamous NSCLC. Conclusions: PI3K/AKT/mTOR pathway alterations present a heterogenous distribution across various types of lung malignancies especially in NSCLC. As more small molecule inhibitors developed to target PI3K/AKT/mTOR pathway, this study might shed light on further clinical investigation of these lately developed therapeutic approaches. [Table: see text]

Do we Need Maintenance Chemotherapy in Advanced NSCLC in the Era of Immune and Targeted Therapy?

2019 ◽  
Vol 15 (1) ◽  
pp. 50-55
Author(s):  
Ahmed Nagy ◽  
Omar Abdel Rahman ◽  
Heba Abdullah ◽  
Ahmed Negida
Keyword(s):  
Lung Cancer ◽  
Maintenance Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Statistical Significance ◽  
Small Cell ◽  
Maintenance Chemotherapy ◽  
Small Cell Lung ◽  
The Impact

Background: Although well established for the effective management of hematologic cancers, maintenance chemotherapy has only been recently incorportated as a treatment paradigm for advanced non–small-cell lung cancer. Maintenance chemotherapy aims to prolong a clinically favorable response state achieved after finishing induction therapy which is usually predefined in number before startng treatment. There are 2 modalities for maintenance therapy; continuation maintenance (involving a non-platinum component which was a part of the induction protocol or a targeted agent) and switch maintenance therapy (utilizing a new agent which was not a part of the induction regimen). Methods: The purpose of this article is to review the role of maintenance therapy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC) and provide a brief overview about induction chemotherapy in NSCLC to address the basis of maintenance therapy as a treatment option. We will also compare the impact of maintenance chemotherapy with the now evolving role of immunotherapy in NSCLC. Results: There have been 4 maintenance studies to date showing prolonged PFS and OS with statistical significance. However, Three out of the four studies (ECOG4599, JMEN, and PARAMOUNT) did not report tumor molecular analysis. As regard Immunotherapy, current data is in favour of strongly an increasing role for immunotherapy in NSCLC. Conclusion: Maintenance therapy in NSCLC continues to be an important therapeutic line to improve outcome in patients with metastatic and recurrent disease.

Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

2020 ◽  
Vol 16 (1) ◽  
pp. 5-10
Author(s):  
Adrien Costantini ◽  
Theodoros Katsikas ◽  
Clementine Bostantzoglou
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
Small Cell ◽  
Extensive Literature ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Mutational Status

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

scholarly journals 479P The impact of initial symptoms on survival time in advanced non-small cell lung cancer

2016 ◽  
Vol 27 ◽  
pp. ix153-ix154
Author(s):  
T. Miyawaki ◽  
S. Yagishita ◽  
R. Ko ◽  
Y. Suzuki ◽  
N. Matsumoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Survival Time ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Initial Symptoms ◽  
The Impact

scholarly journals Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

2021 ◽  
Vol 9 (4) ◽  
pp. e002421
Author(s):  
Alessio Cortellini ◽  
Massimo Di Maio ◽  
Olga Nigro ◽  
Alessandro Leonetti ◽  
Diego L Cortinovis ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Multivariable Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
First Line ◽  
Metastatic Nsclc ◽  
The Impact

BackgroundSome concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.MethodsWe present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.Results950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.ConclusionIn this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

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