SMARCA4 and Other SWItch/Sucrose NonFermentable Family Genomic Alterations in NSCLC: Clinicopathologic Characteristics and Outcomes to Immune Checkpoint Inhibition

Alessi, Joao; Ricciuti, Biagio; Spurr, Liam F.; Gupta, Hersh; Li, Yvonne Y.; Glass, Carolyn; Nishino, Mizuki; Cherniack, Andrew D.; Lindsay, James; Sharma, Bijaya; Felt, Kristen D.; Rodig, Scott J.; Cheng, Michael L.; Sholl, Lynette M.; Awad, Mark M.

doi:10.1016/j.jtho.2021.03.024

Cited by 57 publications

(64 citation statements)

References 53 publications

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“…As previously described, the co-mutation frequency of STK11 and KEAP1 significantly co-occurred [49,63,64]. Furthermore, STK11 and KEAP1 alterations frequently co-occur in 30% to 60% of SMARCA4-mutant NSCLCs [49,72].…”

Section: Stk11/lkb1 Alterations and Co-occurring Mutations: Prognosti...supporting

confidence: 67%

STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

Pons‐Tostivint

Lugat

Fontenau

et al. 2021

Cells

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The STK11/LKB1 gene codes for liver kinase B1 (STK11/LKB1), a highly conserved serine/threonine kinase involved in many energy-related cellular processes. The canonical tumor-suppressive role for STK11/LKB1 involves the activation of AMPK-related kinases, a master regulator of cell survival during stress conditions. In pre-clinical models, inactivation of STK11/LKB1 leads to the progression of lung cancer with the acquisition of metastatic properties. Moreover, preclinical and clinical data have shown that inactivation of STK11/LKB1 is associated with an inert tumor immune microenvironment, with a reduced density of infiltrating cytotoxic CD8+ T lymphocytes, a lower expression of PD-(L)1, and a neutrophil-enriched tumor microenvironment. In this review, we first describe the biological function of STK11/LKB1 and the role of its inactivation in cancer cells. We report descriptive epidemiology, co-occurring genomic alterations, and prognostic impact for lung cancer patients. Finally, we discuss recent data based on pre-clinical models and lung cancer cohorts analyzing the results of STK11/LKB1 alterations on the immune system and response or resistance to immune checkpoint inhibitors.

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Section: Stk11/lkb1 Alterations and Co-occurring Mutations: Prognosti...supporting

confidence: 67%

STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

Pons‐Tostivint

Lugat

Fontenau

et al. 2021

Cells

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“…On the other hand, a remarkable effect on ICI therapy received by patients with KRAS and TP53 mutation was seen that was compared to KRAS-SMARCA4 mutation or KRAS mutation alone, as this co-mutation facilitates T-cell infiltration and augments tumor immunogenicity, resulting in a high PD-L1 expression. This, in fact, further enhances the need to evaluate BRG1 IHC expression and molecular evaluation of co-mutations to predict the responders with NSCLC to immunotherapy [7,43,44].…”

Section: Prognostic and Predictive Management Issues In Smarca4-deficient Nsclcmentioning

confidence: 99%

“…The special relationship carried by KRAS-driven lung cancers with SMARCA4 loss was studied by some research groups [7,43,44]. As is already known, KRAS is a key oncogenic driver in lung adenocarcinomas, which is frequently observed in ever smokers and it is associated with a high TMB; hence, a subset of cases which carry other mutations may show a better response to ICI therapy.…”

Section: Prognostic and Predictive Management Issues In Smarca4-deficient Nsclcmentioning

confidence: 99%

“…However, the worse prognosis also holds true for NSCLCs with the presence of STK11 and/or KEAP1 mutation alone without SMARCA4 mutation or SMARCA4/STK11/KEAP1 wild-type in comparison to an independent SMARCA4-dNSCLC, despite the treatment with ICI or chemotherapy or both. It was also noted that although the pure SMARCA4 mutations benefit from ICI therapy, there is no significant difference in the efficacy of treatment with ICI found in NSCLC with SMARCA4 mutation or SMARCA4 wild-type, and if a resistance to treatment is recognized, the co-mutation status of STK11 and/or KEAP1 is a must to test [44,45].…”

Section: Prognostic and Predictive Management Issues In Smarca4-deficient Nsclcmentioning

confidence: 99%

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Perspectives and Issues in the Assessment of SMARCA4 Deficiency in the Management of Lung Cancer Patients

Armon

Hofman

Ilié

2021

Cells

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Lung cancers are ranked third among the cancer incidence in France in the year 2020, with adenocarcinomas being the commonest sub-type out of ~85% of non-small cell lung carcinomas. The constant evolution of molecular genotyping, which is used for the management of lung adenocarcinomas, has led to the current focus on tumor suppressor genes, specifically the loss of function mutation in the SMARCA4 gene. SMARCA4-deficient adenocarcinomas are preponderant in younger aged male smokers with a predominant solid morphology. The importance of identifying SMARCA4-deficient adenocarcinomas has gained interest for lung cancer management due to its aggressive behavior at diagnosis with vascular invasion and metastasis to the pleura seen upon presentation in most cases. These patients have poor clinical outcome with short overall survival rates, regardless of the stage of disease. The detection of SMARCA4 deficiency is possible in most pathology labs with the advent of sensitive and specific immunohistochemical antibodies. The gene mutations can be detected together with other established lung cancer molecular markers based on the current next generation sequencing panels. Sequencing will also allow the identification of associated gene mutations, notably KRAS, KEAP1, and STK11, which have an impact on the overall survival and progression-free survival of the patients. Predictive data on the treatment with anti-PD-L1 are currently uncertain in this high tumor mutational burden cancer, which warrants more groundwork. Identification of target drugs is also still in pre-clinical testing. Thus, it is paramount to identify the SMARCA4-deficient adenocarcinoma, as it carries worse repercussions on patient survival, despite having an exceptionally low prevalence. Herein, we discuss the pathophysiology of SMARCA4, the clinicopathological consequences, and different detection methods, highlighting the perspectives and challenges in the assessment of SMARCA4 deficiency for the management of non-small cell lung cancer patients. This is imperative, as the contemporary shift on identifying biomarkers associated with tumor suppressor genes such as SMARCA4 are trending; hence, awareness of pathologists and clinicians is needed for the SMARCA4-dNSCLC entity with close follow-up on new management strategies to overcome the poor possibilities of survival in such patients.

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“…A few therapeutic molecules targeting these genomic alterations are under development, most are being tested in vitro but some are also being evaluated in clinical trials. ICIs have been found to be efficacious in patients with SMARCA4 mutated or rearranged tumors 138,139 . However, cases of hyper progression after administration of ICIs have also been reported in these tumors 139 .…”

Section: Other Gene Fusions In Nsclcmentioning

confidence: 99%

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

Kazdal

Hofman

Christopoulos

et al. 2022

Genes Chromosomes & Cancer

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Based on superior efficacy and tolerability, targeted therapy is currently preferred over chemotherapy and/or immunotherapy for actionable gene fusions that occur in late‐stage non‐small cell lung carcinoma (NSCLC). Consequently, current clinical practice guidelines mandate testing for ALK, ROS1, NTRK, and RET gene fusions in all patients with newly diagnosed advanced non‐squamous NSCLC (NS‐NSCLC). Gene fusions can be detected using different approaches, but today RNA next‐generation sequencing (NGS) or combined DNA/RNA NGS is the method of choice. The discovery of other gene fusions (involving, eg, NRG1, NUT, FGFR1, FGFR2, MET, BRAF, EGFR, SMARC fusions) and their partners has increased progressively in recent years, leading to the development of new and promising therapies and mandating the development and implementation of comprehensive detection methods. The purpose of this review is to focus on recent data concerning the main gene fusions identified in NSCLC, followed by the discussion of major challenges in this domain.

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SMARCA4 and Other SWItch/Sucrose NonFermentable Family Genomic Alterations in NSCLC: Clinicopathologic Characteristics and Outcomes to Immune Checkpoint Inhibition

Cited by 57 publications

References 53 publications

STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

Perspectives and Issues in the Assessment of SMARCA4 Deficiency in the Management of Lung Cancer Patients

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

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