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Actionable Mutations in Lung Cancer

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 30634

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Special Issue Editors

Dr. Jianjun Zhang

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Guest Editor

1. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: cancer genomics; cancer immunology; tumor heterogeneity

Dr. Xiuning Le

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Guest Editor

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: oncogene-driven lung cancer; therapy resistance and response; novel therapy

Dr. Yasir Elamin

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Guest Editor

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: targeted therapy; oncogene-driven lung cancer; local consolidation therapy

Special Issue Information

Dear Colleagues,

Targeted therapy has revolutionized the therapeutic paradigm for non-small cell lung cancer (NSCLC). As of 2021, nine targetable genomic alterations have been defined in NSCLC with FDA-approved targeted therapies. With emerging new therapeutic options, we are facing new challenges and questions. For example, with most targetable mutations having more than one targeted agent, how can we best choose and sequence treatments in the context of cytotoxic chemotherapy and immunotherapy? What are the resistance mechanisms for those novel targeted therapies, and which are common and which unique? For each oncogene-defined subtype of NSCLC, how do co-mutations and other tumor features contribute to the heterogeneity of each subtype of lung cancer? For immune-inert oncogene-driven lung cancers, such as EGFR-mutant NSCLC, can we modulate the tumor immune microenvironment to make the tumor immune-responsive? How can we best combine targeted therapy with other therapeutic approaches to achieve even greater benefit for patients? In this Special Issue of Cancers, we aim to present research articles and timely reviews on those topics of high interest in the field of oncogene-driven lung cancers.

Dr. Jianjun Jay Zhang
Dr. Xiuning Le
Dr. Yasir Elamin
Guest Editors

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Keywords

oncogene
lung cancer
actionable mutation
targeted therapy
resistance mechanisms
tumor heterogeneity
cancer genomics

Published Papers (13 papers)

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Editorial

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4 pages, 191 KiB

Open AccessEditorial

New Actions on Actionable Mutations in Lung Cancers

by Xiuning Le, Yasir Y. Elamin and Jianjun Zhang

Cancers 2023, 15(11), 2917; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15112917 - 26 May 2023

Cited by 3 | Viewed by 1100

Abstract

Actionable mutations refer to DNA alterations that, if detected, would be expected to affect patients’ response to treatments [...] Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

Research

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17 pages, 2313 KiB

Open AccessEditor’s ChoiceArticle

TP53 Co-Mutation Status Association with Clinical Outcomes in Patients with EGFR-Mutant Non-Small Cell Lung Cancer

by Xiuning Le, Cliff Molife, Mark S. Leusch, Maria Teresa Rizzo, Patrick M. Peterson, Nicola Caria, Yongmei Chen, Elena Gonzalez Gugel and Carla Visseren-Grul

Cancers 2022, 14(24), 6127; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246127 - 12 Dec 2022

Cited by 8 | Viewed by 1811

Abstract

TP53 co-mutations have shown association with poor prognosis in various solid tumors. For EGFR-mutated advanced non-small cell lung cancer (aNSCLC), conflicting results exist regarding its impact on survival. Clinical outcomes and genomic data were obtained retrospectively from the real-world (rw) de-identified clinicogenomic database. Patients who initiated therapy for EGFR-mutated aNSCLC between January 2014 and December 2020 were identified. Clinical outcomes were evaluated by TP53-mutational status. In 356 eligible EGFR-mutated aNSCLC patients (median age 68 years), 210 (59.0%) had TP53 co-mutation and 146 (41.0%) had TP53 wild-type tumor. Unadjusted analysis showed significantly shorter survival in patients with TP53 co-mutation versus TP53 wild-type (rw progression-free survival [rwPFS]: HR = 1.4, 95% CI 1.1–1.9, p = 0.0196; overall survival [OS]: HR = 1.6, 95% CI 1.1–2.2, p = 0.0088). Multivariable analysis confirmed independent association between TP53 co-mutation and worse rwPFS (HR = 1.4, 95% CI 1.0–0.9, p = 0.0280) and OS (HR = 1.4, 95% CI 1.0–2.0, p = 0.0345). Directionally consistent findings were observed for response rates, and subgroups by EGFR-activating mutation and first-line (1 L) therapy, with more pronounced negative effect in 1 L EGFR-TKI subgroup. TP53 co-mutations negatively affected survival in patients with EGFR-mutated aNSCLC receiving standard 1 L therapy in real-world practice. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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12 pages, 3078 KiB

Open AccessArticle

Fatty Acid Synthase Mutations Predict Favorable Immune Checkpoint Inhibitor Outcome and Response in Melanoma and Non-Small Cell Lung Cancer Patients

by Qinghua Wang, Na Tian, Wenjing Zhang, Zhijuan Lin, Fuyan Shi, Yujia Kong, Yanfeng Ren, Juncheng Lyu, Hao Qin and Hongqing Liu

Cancers 2022, 14(22), 5638; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14225638 - 17 Nov 2022

Cited by 7 | Viewed by 1414

Abstract

Fatty acid synthase (FASN) acts as the central member in fatty acid synthesis and metabolism processes, which regulate oncogenic signals and tumor immunogenicity. To date, no studies have reported the connection of FASN mutations with ICI efficacy. In this study, from 631 melanoma and 109 NSCLC patients who received ICI treatments, we retrospectively curated multiomics profiles and ICI treatment data. We also explored the potential molecular biological mechanisms behind FASN alterations. In melanoma patients, FASN mutations were observed to associate with a preferable immunotherapeutic prognosis and response rate (both p < 0.01). These connections were further corroborated by the NSCLC patients (both p < 0.01). Further analyses showed that a favorable tumor immunogenicity and immune microenvironment were involved in FASN mutations. This work confirms the clinical immunotherapy implications of FASN mutation-mediated fatty acid metabolism and provides a possible indicator for immunotherapy prognosis prediction. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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18 pages, 4359 KiB

Open AccessArticle

Radiogenomic System for Non-Invasive Identification of Multiple Actionable Mutations and PD-L1 Expression in Non-Small Cell Lung Cancer Based on CT Images

by Jun Shao, Jiechao Ma, Shu Zhang, Jingwei Li, Hesen Dai, Shufan Liang, Yizhou Yu, Weimin Li and Chengdi Wang

Cancers 2022, 14(19), 4823; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194823 - 02 Oct 2022

Cited by 9 | Viewed by 2685

Abstract

Purpose: Personalized treatments such as targeted therapy and immunotherapy have revolutionized the predominantly therapeutic paradigm for non-small cell lung cancer (NSCLC). However, these treatment decisions require the determination of targetable genomic and molecular alterations through invasive genetic or immunohistochemistry (IHC) tests. Numerous previous studies have demonstrated that artificial intelligence can accurately predict the single-gene status of tumors based on radiologic imaging, but few studies have achieved the simultaneous evaluation of multiple genes to reflect more realistic clinical scenarios. Methods: We proposed a multi-label multi-task deep learning (MMDL) system for non-invasively predicting actionable NSCLC mutations and PD-L1 expression utilizing routinely acquired computed tomography (CT) images. This radiogenomic system integrated transformer-based deep learning features and radiomic features of CT volumes from 1096 NSCLC patients based on next-generation sequencing (NGS) and IHC tests. Results: For each task cohort, we randomly split the corresponding dataset into training (80%), validation (10%), and testing (10%) subsets. The area under the receiver operating characteristic curves (AUCs) of the MMDL system achieved 0.862 (95% confidence interval (CI), 0.758–0.969) for discrimination of a panel of 8 mutated genes, including EGFR, ALK, ERBB2, BRAF, MET, ROS1, RET and KRAS, 0.856 (95% CI, 0.663–0.948) for identification of a 10-molecular status panel (previous 8 genes plus TP53 and PD-L1); and 0.868 (95% CI, 0.641–0.972) for classifying EGFR / PD-L1 subtype, respectively. Conclusions: To the best of our knowledge, this study is the first deep learning system to simultaneously analyze 10 molecular expressions, which might be utilized as an assistive tool in conjunction with or in lieu of ancillary testing to support precision treatment options. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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14 pages, 5858 KiB

Open AccessArticle

A Machine Learning-Based Predictive Model of Epidermal Growth Factor Mutations in Lung Adenocarcinomas

by Ruimin He, Xiaohua Yang, Tengxiang Li, Yaolin He, Xiaoxue Xie, Qilei Chen, Zijian Zhang and Tingting Cheng

Cancers 2022, 14(19), 4664; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194664 - 25 Sep 2022

Cited by 7 | Viewed by 1621

Abstract

Data from 758 patients with lung adenocarcinoma were retrospectively collected. All patients had undergone computed tomography imaging and EGFR gene testing. Radiomic features were extracted using the medical imaging tool 3D-Slicer and were combined with the clinical features to build a machine learning prediction model. The high-dimensional feature set was screened for optimal feature subsets using principal component analysis (PCA) and the least absolute shrinkage and selection operator (LASSO). Model prediction of EGFR mutation status in the validation group was evaluated using multiple classifiers. We showed that six clinical features and 622 radiomic features were initially collected. Thirty-one radiomic features with non-zero correlation coefficients were obtained by LASSO regression, and 24 features correlated with label values were obtained by PCA. The shared radiomic features determined by these two methods were selected and combined with the clinical features of the respective patient to form a subset of features related to EGFR mutations. The full dataset was partitioned into training and test sets at a ratio of 7:3 using 10-fold cross-validation. The area under the curve (AUC) of the four classifiers with cross-validations was: (1) K-nearest neighbor (AUCmean = 0.83, Acc = 81%); (2) random forest (AUCmean = 0.91, Acc = 83%); (3) LGBM (AUCmean = 0.94, Acc = 88%); and (4) support vector machine (AUCmean = 0.79, Acc = 83%). In summary, the subset of radiographic and clinical features selected by feature engineering effectively predicted the EGFR mutation status of this NSCLC patient cohort. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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14 pages, 1911 KiB

Open AccessArticle

LncRNA H19 Promotes Lung Adenocarcinoma Progression via Binding to Mutant p53 R175H

by Yaodong Zhou and Qing Xia

Cancers 2022, 14(18), 4486; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14184486 - 16 Sep 2022

Cited by 2 | Viewed by 1291

Abstract

Background: Accumulating data suggest that long non-coding RNA (lncRNA) H19 and p53are closely related to the prognosis of lung cancer. This study aims to analyze the association and interaction betweenH19 and mutant p53 R175H in lung adenocarcinoma (LAC). Methods: Mutant-type (Mt) p53 R175H was assessed by using RT-PCR in LAC cells and 100 cases of LAC tissue samples for association with H19 expression. Western blot, RNA-pull down, immunoprecipitation-Western blot and animal experiments were used to evaluate the interaction between H19 and mtp53. Results: Mtp53 R175H and H19 were over-expressed in LAC tissues and cells, while H19 over-expression extended the p53 half-life and enhanced transcriptional activity. Combined with anti-p53, ShH19 can significantly inhibit tumor growth in vivo. Conclusions: H19 over-expression may induce the elevated expression of mtp53 and interact with mtp53, leading to LAC progression. In addition, the high expression of mtp53 R175H is associated with poor overall survival inpatients. The simultaneous inhibition of H19 and mtp53 may provide a novel strategy for the effective control of LAC clinically. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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11 pages, 2375 KiB

Open AccessArticle

Oncogenic EFNA4 Amplification Promotes Lung Adenocarcinoma Lymph Node Metastasis

by Xiangyu Zhao, Yuxing Chen, Xiaoqin Sun, Zaoke He, Tao Wu, Chenxu Wu, Jing Chen, Jinyu Wang, Kaixuan Diao and Xue-Song Liu

Cancers 2022, 14(17), 4226; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174226 - 30 Aug 2022

Cited by 5 | Viewed by 2061

Abstract

Lymph nodes metastases are common in patients with lung cancer. Additionally, those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. Somatic DNA alterations are key drivers of cancer, and copy number alterations (CNAs) are major types of DNA alteration that promote lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung-cancer-metastasis-related gene, EFNA4. The EFNA4 genome locus was significantly amplified, and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 overexpression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis, and suggests EFNA4 as a potential target in metastatic lung cancer therapy. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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14 pages, 3039 KiB

Open AccessArticle

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

by Wenjing Zhang, Zhijuan Lin, Fuyan Shi, Qiang Wang, Yujia Kong, Yanfeng Ren, Juncheng Lyu, Chao Sheng, Yuting Li, Hao Qin, Suzhen Wang and Qinghua Wang

Cancers 2022, 14(14), 3495; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143495 - 19 Jul 2022

Cited by 6 | Viewed by 1940

Abstract

Immune checkpoint inhibitors (ICIs) markedly promote the survival outcome of advanced melanoma and non-small cell lung cancer (NSCLC). Clinically, favorable ICI treatment efficacy is noticed only in a smaller proportion of patients. Heparan sulfate proteoglycan 2 (HSPG2) frequently mutates in both tumors. Herein, we aim to investigate the immunotherapeutic and immunological roles of HSPG2 mutations in melanoma and NSCLC. A total of 631 melanoma samples and 109 NSCLC samples with both somatic mutational profiles and clinical immunotherapy data were curated. In addition, by using The Cancer Genome Atlas data, genomic and immunological traits behind HSPG2 mutations were elucidated. Melanoma patients with HSPG2 mutations had a markedly extended ICI outcome than other patients. An association between HSPG2 mutations and the improved outcome was further confirmed in NSCLC. In addition, an elevated ICI response rate was presented in HSPG2-mutated NSCLC patients (81.8% vs. 29.7%, p = 0.002). Subsequent analyses revealed that HSPG2-mutated patients had a favorable abundance of response immunocytes, an inferior abundance of suppression immunocytes, enhanced mutational burden, and interferon response-relevant signaling pathways. We uncovered that HSPG2 mutations were predictive of a better ICI response and associated with preferable immunogenicity, which may be considered as a genomic determinant to customize biotherapy strategies. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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13 pages, 1119 KiB

Open AccessArticle

Limited Benefit from the Addition of Immunotherapy to Chemotherapy in TKI-Refractory EGFR-Mutant Lung Adenocarcinoma

by Lingzhi Hong, Whitney E. Lewis, Monique Nilsson, Sonia Patel, Susan Varghese, Melvin J. Rivera, Robyn R. Du, Pingjun Chen, Haley N. Kemp, Waree Rinsurongkawong, Simon Heeke, Amy R. Spelman, Yasir Y. Elamin, Marcelo V. Negrao, Boris Sepesi, Don L. Gibbons, J. Jack Lee, Jia Wu, Natalie I. Vokes, John V. Heymach, Jianjun Zhang and Xiuning Le Show full author list Hide full author list

Cancers 2022, 14(14), 3473; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143473 - 17 Jul 2022

Cited by 4 | Viewed by 2676

Abstract

Background: The benefit of chemotherapy combined with immunotherapy in EGFR-mutant lung adenocarcinoma (LUAD) patients whose tumor developed resistance to EGFR tyrosine kinase inhibitors (TKIs) is not thoroughly investigated. The goal of this retrospective cohort study is to assess the clinical efficiency of immunotherapy alone or in combination with chemotherapy in a real-world setting. Methods: This retrospective cohort study enrolled LUAD patients with EGFR sensitive mutations whose tumor had acquired resistance to EGFR TKIs and received systemic treatment with chemotherapy (chemo; n = 84), chemotherapy combined with immunotherapy (chemoIO; n = 30), chemotherapy plus bevacizumab with or without IO (withBev; n = 42), and IO monotherapy (IO-mono; n = 22). Clinical progression-free survival (PFS) and overall survival (OS) were evaluated. Associations of clinical characteristics with outcomes were assessed using univariable and multi-covariate Cox Proportional Hazards regression models. Results: A total of 178 patients (median age = 63.3; 57.9% females) with a median follow-up time of 42.0 (Interquartile range: 22.9–67.8) months were enrolled. There was no significant difference in PFS between chemoIO vs. chemo groups (5.3 vs. 4.8 months, p = 0.8). Compared to the chemo group, patients who received withBev therapy trended towards better PFS (6.1 months vs. 4.8; p = 0.3; HR 0.79; 95% CI: 0.52–1.20), while patients treated with IO-mono had inferior PFS (2.2 months; p = 0.001; HR 2.22; 95% CI: 1.37–3.59). Furthermore, PD-L1 level was not associated with PFS benefit in the chemoIO group. Patients with EGFR-mutant LUAD with high PD-L1 (≥50%) had shorter PFS (5.8 months) than non-EGFR/ALK LUAD patients who received chemoIO (12.8 months, p = 0.002; HR 0.22; 95% CI: 0.08–0.56) as first-line treatment. Chemotherapy-based therapy rendered similar benefit to patients with either EGFR exon19 deletion vs. L858R in the LUAD. Conclusions: This retrospective analysis revealed that immunotherapy provided limited additional benefit to chemotherapy in TKI-refractory EGFR-mutant LUAD. Chemotherapy alone or combined with bevacizumab remain good choices for patients with actionable EGFR mutations. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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19 pages, 3155 KiB

Open AccessArticle

TP53 and LRP1B Co-Wild Predicts Improved Survival for Patients with LUSC Receiving Anti-PD-L1 Immunotherapy

by Jiangyong Yu, Zaiwen Fan, Zhipeng Zhou, Ping Zhang, Jing Bai, Xu Li, Min Tang, Nannan Fan, Xiaonan Wu, Xin Nie, Xiaoyan Chen, Di Ma, Xi Chen, Liang Cui, Xuefeng Xia, Ling Yang, Xin Yi and Lin Li

Cancers 2022, 14(14), 3382; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143382 - 12 Jul 2022

Cited by 6 | Viewed by 2107

Abstract

Immunotherapy brought long-term benefits for partial patients with lung squamous cell carcinoma (LUSC). The predictor of anti-PD-L1 therapy was controversial and limited in LUSC. We aimed to explore novel biomarker for LUSC immunotherapy and the potential mechanism. Five hundred and twenty-five Chinese patients (Geneplus cohort) with LUSC underwent targeted sequencing and were involved to explore the genomic profiling. TP53 and LRP1B were the most frequently recurrent genes and correlated to higher tumor mutational burden (TMB). We observed that LUSC patients with TP53 and LRP1B co-wild (co-wild type) were associated with better survival of anti-PD-L1 therapy compared with TP53 mutant or LRP1B mutant (mutant type) in POPAR/OAK cohort. Copy-number variation (CNV) and whole genome doubling (WGD) data from TCGA LUSC cohort were obtained to assess the CNV events. There were fewer CNV alterations and lower chromosome instability in patients with TP53/LRP1B co-wild compared with those with TP53/LRP1B mutant. RNA expression data from the TCGA LUSC cohort were collected to explore the differences in RNA expression and tumor immune microenvironment (TIME) between mutant and co-wild groups. The TP53/LRP1B co-wild type had a significantly increased proportion of multiple tumor-infiltrating lymphocytes (TILs), including activated CD8 T cell, activated dendritic cell (DC), and effector memory CD8 T cell. Immune-related gene sets including checkpoint, chemokine, immunostimulatory, MHC and receptors were enriched in the co-wild type. In conclusion, TP53/LRP1B co-wild LUSC conferred an elevated response rate in anti-PD-L1 therapy and improved survival, which was associated with a chromosome-stable phenotype and an activated immune microenvironment. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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12 pages, 1043 KiB

Open AccessArticle

Oncogenic Alterations in Histologically Negative Lymph Nodes Are Associated with Prognosis of Patients with Stage I Lung Adenocarcinoma

by Yiping Tian, Qian Lai, Yuansi Zheng, Lisha Ying, Canming Wang, Jiaoyue Jin, Minran Huang, Yingxue Wu, Huizhang Li, Jianjun Zhang and Dan Su

Cancers 2022, 14(3), 824; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030824 - 06 Feb 2022

Cited by 2 | Viewed by 1696

Abstract

Background: Survival of patients with stage I non-small cell lung cancer (NSCLC) varies greatly. We sought to explore whether presence of oncogenic alterations in histologically-negative lymph nodes (LNs) can be of prognostic significance in stage I lung adenocarcinoma (LUAD). Methods: Genomic analysis of oncogenic alterations was applied to 123 stage I LUAD tumors. The same genomic variants identified in primary tumors were examined in corresponding histologically-negative LNs. Results: A total of 102 (82.9%) patients had at least one canonical oncogenic alteration detected in primary tumors, and 57 LNs from 12 patients (11.8%) were found to carry the identical oncogenic alterations detected in the corresponding primary tumor tissues, including EGFR mutations (six cases), KRAS mutations (three cases), ALK fusion (one case), BRAF mutation (one case) and HER2 & NRAS co-mutations (one case). None of these LNs was found to have occult tumor cells by routine pathological assessment or immunohistochemistry staining using antibodies against pan-cytokeratins (AE1/AE3) and the epithelial marker Ber-EP4. The detection rate of oncogenenic alterations in LN was significantly higher in RAS-mutant tumors than EGFR mutant tumors (36.36% verse 7.41%, p = 0.017). Patients with oncogenic alterations in LN showed inferior disease-free survival (DFS, p = 0.025) and overall survival (OS, p = 0.027). Furthermore, patients with RAS-mutations detected in LN had the worst DFS and OS (p = 0.001). Among the 11 patients with RAS mutation in primary tumors, DFS and OS in the four patients with mutations detected in LN were significantly shorter than the remaining seven patients without mutations LN (DFS, p = 0.001, OS, p = 0.002). Conclusions: Genomic analysis has the potential to detect oncogenic alterations in regional LNs for localized LUAD and presence of oncogenic alterations in regional LN may be associated with inferior clinical outcome of stage I LUAD, particularly for certain molecular subgroups. ClinicalTrials.gov ID NCT04266691 Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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Review

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16 pages, 693 KiB

Open AccessReview

HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies

by Natalie F. Uy, Cristina M. Merkhofer and Christina S. Baik

Cancers 2022, 14(17), 4155; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174155 - 27 Aug 2022

Cited by 19 | Viewed by 6560

Abstract

Human epidermal growth factor receptor 2 (HER2), a member of the ERBB family of tyrosine kinase receptors, has emerged as a therapeutic target of interest for non-small cell lung cancer (NSCLC) in recent years. Activating HER2 alterations in NSCLC include gene mutations, gene amplifications, and protein overexpression. In particular, the HER2 exon 20 mutation is now a well clinically validated biomarker. Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations. This remains an unmet clinical need, as HER2 alterations are present in 7–27% of de novo NSCLC and may serve as a resistance mechanism in up to 10% of EGFR mutated NSCLC. There has been an influx of research on antibody–drug conjugates (ADCs), monoclonal antibodies, and tyrosine kinase inhibitors (TKIs) with mixed results. The most promising therapies are ADCs (trastuzumab-deruxtecan) and novel TKIs targeting exon 20 mutations (poziotinib, mobocertinib and pyrotinib); both have resulted in meaningful anti-tumor efficacy in HER2 mutated NSCLC. Future studies on HER2 targeted therapy will need to define the specific HER2 alteration to better select patients who will benefit, particularly for HER2 amplification and overexpression. Given the variety of HER2 targeted drugs, sequencing of these agents and optimizing combination therapies will depend on more mature efficacy data from clinical trials and toxicity profiles. This review highlights the challenges of diagnosing HER2 alterations, summarizes recent progress in novel HER2-targeted agents, and projects next steps in advancing treatment for the thousands of patients with HER2 altered NSCLC. Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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Other

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18 pages, 2286 KiB

Open AccessSystematic Review

Efficacy and Safety of Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Combination Therapy as First-Line Treatment for Patients with Advanced EGFR-Mutated, Non-Small Cell Lung Cancer: A Systematic Review and Bayesian Network Meta-Analysis

by Jianchao Xue, Bowen Li, Yadong Wang, Zhicheng Huang, Xinyu Liu, Chao Guo, Zhibo Zheng, Naixin Liang, Xiuning Le and Shanqing Li

Cancers 2022, 14(19), 4894; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194894 - 06 Oct 2022

Cited by 2 | Viewed by 2139

Abstract

(1) Background: Several randomized controlled trials (RCTs) have been conducted in combination with Efficacy and Safety of Epidermal Growth Factor Receptor(EGFR)-Tyrosine Kinase Inhibitor (TKI) for the first-line treatment of patients with advanced non-small cell lung cancer; however, head-to-head comparisons of combination therapies are still lacking. Therefore, this study aims to compare the efficacy and safety of various combination treatments. (2) Methods: We conducted a systematic review and Bayesian network meta-analysis by searching MEDLINE, EMBASE, and COCHRANE for relevant RCTs. (3) Results: TKI combined with antiangiogenic therapy, chemotherapy, or radiation achieved a significant benefit compared with TKI alone for progression free survival (PFS). A combination with radiation yielded better benefits in PFS than any other treatment. In terms of overall survival (OS), only the combination with pemetrexed and carboplatin (HR = 0.63, 95% credible interval 0.43–0.86)/radiation (0.44, 0.23–0.83) was superior to TKI alone. All of the combination therapies may increase the incidence of ≥Grade 3 AEs, as the pooled RRs are over 1; different toxicity spectrums were revealed for individual treatments. (4) Conclusions: The TKI combination of radiation/pemetrexed and carboplatin could provide the best antitumor effects among the first generation TKI-based treatments. Considering safety, ramucirumab and bevacizumab may be the ideal additions to TKIs (systematic review registration: PROSPERO CRD42022350474). Full article

(This article belongs to the Special Issue Actionable Mutations in Lung Cancer)

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