Precision Medicine In Lung Cancer Research Articles

RNF8-mediated regulation of Akt promotes lung cancer cell survival and resistance to DNA damage.

Despite the tremendous success of targeted and conventional therapies for lung cancer, therapeutic resistance is a common and major clinical challenge. RNF8 is a ubiquitin E3 ligase that plays essential roles in the DNA damage response; however, its role in the pathogenesis of lung cancer is unclear. Here, we report that RNF8 is overexpressed in lung cancer and positively correlates with the expression of p-Akt and poor survival of patients with non-small-cell lung cancer. In addition, we identify RNF8 as the E3 ligase for regulating the activation of Akt by K63-linked ubiquitination under physiological and genotoxic conditions, which leads to lung cancer cell proliferation and resistance to chemotherapy. Together, our study suggests that RNF8 could be a very promising target in precision medicine for lung cancer.

PSY1-2 Expanding the reach of precision medicine in lung cancer

PSY1-2 Expanding the reach of precision medicine in lung cancer

An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance.

Implementation of precision medicine in lung cancer has benefited from intense research in the past years, developing subsequently an improved quality of life and increased overall survival of the patients. Targeted therapy has become one of the most important therapeutic innovations for the non-small cell lung cancer category with anaplastic lymphoma kinase (ALK) gene rearrangement. The aim of this review is to provide a thorough overview of the main molecules of ALK tyrosine kinase inhibitors (TKI) with their general and particular mechanisms of resistance, the main methods of ALK gene detection, each with advantages and limits, and the future perspectives currently under research which try to overcome the mechanisms of resistance. We have used two of the most reliable medical databases EMBASE and PubMed to properly select the latest and the most relevant articles for this topic. Encouraged by the promising results, the clinical practice was enriched by the approval of TKI molecules, three generations being developed, each one with more powerful agents than the previous ones. Unfortunately, the resistance to TKI eventually occurs and it may be induced by several mechanisms, either known or unknown. Crizotinib was the most intensely studied TKI, becoming the first molecule approved into clinical practice and although four other drugs have been broadly used (alectinib, ceritinib, brigatinib, and lorlatinib) it seems that even the most recently developed one remains imperfect due to the resistance mutations that developed. There are two types of resistance generally described for the entire class and for the particular drugs, but half of them remain unknown.

The evolving paradigm of precision medicine in lung cancer.

In this review, we report a complete and updated summary of the most recent treatment advances in the fields of oncogene-addicted disease and provide expert perspectives on the evolving paradigm of precision medicine in lung cancer patients. The advent of innovative genome sequencing technologies is rapidly increasing the number of targetable molecular alterations in advanced nonsmall cell lung cancer (NSCLC), leading to the introduction of novel selective inhibitors into the clinical arena, showing unprecedent tumor responses against rare and elusive NSCLC targets. The results of the ADAURA trial suggested that targeting EGFR pathway in the adjuvant setting is a feasible and effective strategy. The routine use of next-generation sequencing (NGS) is currently recommended as new standard approach to profile advanced NSCLC samples while recent findings suggest the potential application of a plasma-based first approach for tumor genotyping. Innovative umbrella trials provide the right infrastructure to investigate the role of precision medicine in advanced NSCLC, but failed to show clinical benefit. Implementing NGS-based molecular screening, increasing patients' access to biomarker driven-clinical trials, ensuring equal access to molecular testing and innovative treatments, overcoming disparities and preserve health systems' financial sustainability represents the main challenges of precision medicine worldwide.

1) Development of East-Asian Genomic Screening Platform (LC-SCRUM-Asia) to Establish Precision Medicine in Lung Cancer

1) Development of East-Asian Genomic Screening Platform (LC-SCRUM-Asia) to Establish Precision Medicine in Lung Cancer

Application of Radiomics and Artificial Intelligence for Lung Cancer Precision Medicine.

Medical imaging is the standard-of-care for early detection, diagnosis, treatment planning, monitoring, and image-guided interventions of lung cancer patients. Most medical images are stored digitally in a standardized Digital Imaging and Communications in Medicine format that can be readily accessed and used for qualitative and quantitative analysis. Over the several last decades, medical images have been shown to contain complementary and interchangeable data orthogonal to other sources such as pathology, hematology, genomics, and/or proteomics. As such, "radiomics" has emerged as a field of research that involves the process of converting standard-of-care images into quantitative image-based data that can be merged with other data sources and subsequently analyzed using conventional biostatistics or artificial intelligence (AI) methods. As radiomic features capture biological and pathophysiological information, these quantitative radiomic features have shown to provide rapid and accurate noninvasive biomarkers for lung cancer risk prediction, diagnostics, prognosis, treatment response monitoring, and tumor biology. In this review, radiomics and emerging AI methods in lung cancer research are highlighted and discussed including advantages, challenges, and pitfalls.

Application of Organoids in Lung Cancer Precision Medicine

肺癌的全程管理需要依靠精准医学来完成。肿瘤类器官（patient-derived organoids, PDO）模型的提出，在肺癌现有的以病理和基因等多组学检测结果为基础的精准医学决策体系之外，增加了从体外功能学模型角度出发的“黑箱”决策体系，未来有望填补分子病理指导下的难治性肺癌的治疗方案的空缺。将PDO应用于临床决策，需要验证肺癌PDO与原始癌灶多维度的一致性，更需要验证与临床试验中患者对治疗反应与PDO药敏结果的一致性。本文将对PDO模型作一简介，并在现有的肺癌精准治疗背景下，对PDO的应用场景进行综述。

Feasibility and utility of transbronchial cryobiopsy in precision medicine for lung cancer: Prospective single-arm study.

Cryoprobe is a novel transbronchial biopsy (TBB) tool that yields larger tissue samples than forceps. Pathological diagnosis and biomarker analysis, such as genetic alterations and programmed death‐ligand 1 (PD‐L1) expression, are paramount for precision medicine against lung cancer. We evaluated the safety and usefulness of cryoprobe TBB for lung cancer diagnosis and biomarker analysis. In this single‐center, prospective single‐arm study, patients suspected of having or diagnosed with primary lung cancer underwent cryoprobe TBB using flexible bronchoscopy after conventional forceps TBB from the same lesion. Cryoprobe TBB was performed in 121 patients. The incidence rate of severe bleeding and serious adverse events (4% [90% confidence interval: 2%‐9%]) was significantly lower than the expected rate (20% with 30% threshold, P < 0.01). Combining both central and peripheral lesions, the diagnostic yield rate of cryoprobe samples was 76% and that of forceps samples was 84%. Compared with forceps TBB samples, cryoprobe TBB samples were larger (cryoprobe 15 mm2 vs forceps 2 mm2) and resulted in a larger proportion of definite histomorphological diagnosis (cryoprobe 86% vs forceps 74%, P < 0.01), larger amounts of DNA extracted from samples (median: cryoprobe, 1.60 µg vs forceps, 0.58 µg, P = 0.02) and RNA (median: cryoprobe, 0.62 µg vs forceps, 0.17 µg, P < 0.01) extracted from samples, and tended to yield greater rates of PD‐L1 expression >1% (51% vs 42%). In conclusion, cryoprobe is a safe and useful tool for obtaining lung cancer tissue samples of adequate size and quality, which allow morphological diagnosis and biomarker analysis for precision medicine against lung cancer.

2) Development of East-Asian Genomic Screening Platform (LC-SCRUM-Asia) to Establish Precision Medicine in Lung Cancer

2) Development of East-Asian Genomic Screening Platform (LC-SCRUM-Asia) to Establish Precision Medicine in Lung Cancer

Precision Medicine in Lung Cancer

Precision Medicine in Lung Cancer

497P - Real-word efficacy of osimertinib in patients with metastatic EGFRm NSCLC: An interim analysis from a multi-center study in China

BackgroundThe EGFRm rate in metastatic NSCLC is 30%∼40% in China. Osimertinib, 3rd generation EGFR-TKI, is approved as the 1st line treatment for patients with advanced EGFRm NSCLC and 2nd line treatment for patients with EGFR T790M positive advanced NSCLC globally, and only is approved as the 2nd line treatment in China by now. This study is to investigate the efficacy of Osimertinib in patients with metastatic EGFRm NSCLC in the real word clinical setting in China. MethodsThis multi-center study was conducted in 13 medical centers in China from April 2017 to May 2019 (Clinical trial ID: 1800019903). Patients with metastatic EGFRm NSCLC received by Osimertinib were enrolled into this study. All data were collected and analyzed on China Multi-center Lung Cancer Precision Medicine Registry RWE Box. ResultsA total of 346 patients with metastatic EGFRm NSCLC were enrolled in this study (female: 56.5%, male: 43.5%). 95.1% patients were adenocarcinoma, 2.3% patients were squamous carcinoma and 1.7% patients were adenosquamous carcinoma. The percentage of Osimertinib as 1st line, 2nd line, 3rd line, and more than 3rd line therapy was 10.4%, 55.8%, 21.4% and 12.6%, respectively. 42.5% patients were identified as the secondary T790M (+)after failure of the 1st line EGFR-TKI. For patients (N = 145) with T790M (+) metastatic NSCLC treated by Osimertinib as 2nd line therapy, the ORR was 75.1%, the mPFS was 276 days. Subgroup analysis showed that for those with both T790M (+) and CNS metastasis (N = 146), the mPFS was 280 days and CNS ORR was 67.2%. Interestingly, the CNS ORR was 34.4% for those with T790M (-) of CNS metastasis. In patients (N = 193) who had progressed after 2nd line Osimertinib, 78.9% received chemotherapy, 13.4% received bevacizumab combined with chemotherapy, and 7.7% received immunotherapy, respectively. ConclusionsOsimertinib was generally used as 2nd line treatment in patients who were resistance to the 1st line EGFR-TKI in China. Real-word data further demonstrated and validated the similar efficacy of Osimertinib as 2nd line therapy in China as that previously reported clinical trials. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Abstract 4840: Characterization of URST1 as a biomarker and therapeutic target for precision medicine of lung cancer

Abstract This study aims to identify novel biomarkers and therapeutic targets for lung cancer. We initially screened genes that overexpressed in the majority of lung cancers by using our original gene expression profile database. During this process, we identified up-regulated in solid tumor 1 (URST1) as a candidate. Immunohistochemical staining showed that URST1 was expressed in 231 (64.5%) of 358 non-small cell lung cancer (NSCLC) that had undergone curative surgery. Strong URST1 expression was associated with poor prognosis for NSCLC patients (P = 0.0003 by log-rank test). In addition, multivariate analysis showed that strong URST1 expression was an independent prognostic factor for NSCLC patients. Reduction of URST1 expression by siRNA or treatment with selective URST1 inhibitor significantly suppressed cancer cell growth partly through cell cycle arrest at G2/M phase and mitotic cell death as detected by flow cytometric analysis and live cell imaging. Our findings suggest that URST1 could be a potential biomarker and therapeutic target for developing precision medicine of lung cancer. Note: This abstract was not presented at the meeting. Citation Format: Atsushi Takano, Yohei Miyagi, Yataro Daigo. Characterization of URST1 as a biomarker and therapeutic target for precision medicine of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4840.

Abstract 391: Serine/threonine kinase LASK2 as a biomarker and therapeutic target for lung cancer

Abstract Since the number of lung cancer patients responding well to standard chemotherapies is still small, further development of new anti-cancer drugs with minimum risk of adverse effects and highly sensitive cancer biomarkers for precision medicine is eagerly required. We have been developing new molecular therapies targeting oncogenic proteins with their companion diagnostics by screening system as follows; i) To identify overexpressed genes in 120 lung cancers by our original gene expression profile database, ii) To confirm the candidate genes for their low expression in 23 normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering hundreds of non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the growth/invasion of cancer cells by siRNAs. During this process, we selected dozens of druggable oncoproteins with various enzymatic activities, and detected higher expression of serine/threonine kinase LASK2 (lung cancer-associated kinase 2) in the majority of various types of lung cancers, but scarce expression in normal tissues except testis. We further observed much higher expression patterns of LASK2 in brain metastasis as well as advanced primary lung tumors, compared to those in earlier-stage primary lung tumors. Immunohistochemical analysis using tissue microarray showed that strong LASK2 positivity was an independent prognostic factor for NSCLC (P&amp;lt;0.0001). Suppression of LASK2 expression with its siRNAs inhibited growth of lung cancer cells, whereas enhanced cellular proliferation by exogenous expression of LASK2 in mammalian cells also supported its oncogenic function in vitro and in mice model. Invasion of mammalian cells transfected with LASK2-expression vector through Matrigel was significantly enhanced, compared to the control cells transfected with mock or LASK2-kinase dead vector, suggesting that LASK2 could also contribute to the highly malignant phenotype of lung-cancer cells. Induction of LASK2 appeared to activate oncogenic signals for lung cancer such as phosphorylation of MAPK and PCNA. Our data indicate that LASK2 is a promising diagnostic biomarker and therapeutic target for developing precision medicine of lung cancer. Note: This abstract was not presented at the meeting. Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Serine/threonine kinase LASK2 as a biomarker and therapeutic target for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 391.

Study Progress of Radiomics in Precision Medicine for Lung Cancer

精准医疗，影像先行。影像组学作为人工智能中机器学习的一种方法，通过肿瘤感兴趣区进行定量分析，提供有价值的诊断、预后或预测信息，以支持个性化的临床决策和改善个体化的治疗选择，为实现精准医疗的目标打下了坚实基础。本文将综述影像组学在肺癌精准诊断和治疗的最新研究进展。

Targeted Therapies in Non-small-Cell Lung Cancer.

The treatment landscape for non-small-cell lung cancer (NSCLC) has dramatically shifted over the past two decades. Targeted or precision medicine has primarily been responsible for this shift. Older paradigms of treating metastatic NSCLC with cytotoxic chemotherapy, while still important, have given way to evaluating tumor tissues for specific driver mutations that can be treated with targeted agents. Patients treated with targeted agents frequently have improved progression-free survival and overall survival compared to patients without a targetable driver mutation, highlighting the clinical benefit of precision medicine. In this chapter, we explore the historic landmark trials, the current state of the field, and potential future targets under investigation, in this exciting, rapidly evolving discipline of precision medicine in lung cancer.

Race, Poverty, and Initial Implementation of Precision Medicine for Lung Cancer.

Data are limited regarding whether the availability of biomarker-directed therapy for lung cancer exacerbates racial and socioeconomic disparities. Patients diagnosed with stage IV lung adenocarcinoma from 2008 to 2013 were identified using Surveillance, Epidemiology, and End Results Program-Medicare. The primary outcome was a Medicare claim for molecular testing within 60 days of diagnosis, analyzed using multivariable logistic regression; the secondary outcome was overall survival, analyzed using multivariable Cox proportional hazards models. All statistical tests were two-sided. Of 5556 patients, 1437 (25.9%) had molecular testing. Testing rates were 14.1% among black, 26.2% among white, and 32.8% among patients of Asian/other descent (adjusted P < .001); 20.6% among patients with Medicaid eligibility vs 28.4% among those without (adjusted P = .01); and 19.9% among patients in the highest census tract-level poverty rate quintile vs 30.7% among patients in the lowest quintile (for all quintiles, adjusted P = .18). Median survival from 60 days was 8.2 months among patients with molecular testing within 60 days of diagnosis and 6.1 months among those without (hazard ratio = 0.92, 95% confidence interval = 0.86 to 0.99; adjusted P = .02). Equitable precision medicine requires concerted implementation efforts.

AJS-4 - Current Situation of Precision Medicine in Lung Cancer

Since the finding of EGFR gene mutation in non-small cell lung cancer (NSCLC) 15 years ago, remarkable progress of precision medicine has been observed in this field. Due to the different ratio of EGFR-mutation positive patients among races, lots of important evidence regarding EGFR-mutation positive NSCLC has been built in East Asia studies. In addition, various driver oncogenes such as ALK and ROS1 were then identified and corresponding molecular-targeted drugs for these mutations have been developed. Best sequence of treatment by using these drugs is now being investigated. Furthermore, immune checkpoint inhibitors (ICI) were approved for the treatment of NSCLC. The results of clinical trials by monotherapy of ICI as well as Chemo/ICI combo have made us consider appropriate biomarkers for optimizing selection of NSCLC patients, especially those without driver oncogene mutation. Currently NSCLC is leading the way in the development of precision medicine in solid tumors and novel clinical questions are emerging day by day. In this symposium, we discuss the development of precision medicine in NSCLC from the point of Japanese view and introduce our challenge to establish new evidence.

Contribution of nationwide genome screening in Japan (LC-SCRUM-Japan) to the development of precision medicine for non-small cell lung cancer.

9085 Background: A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of lung cancer precision medicine. Methods: Since 2013, non-squamous non-small lung cancer patients have been screened for ALK/ROS1/RET fusions using RT-PCR and FISH, and since 2015, they have also analyzed for 143 gene alterations using a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. Based on the molecular screening and the monitoring of clinical course and patient survival, a large-scale integrative clinico-genomic database has been established. Results: As of December, 2017, 251 institutions were participating and 4371 patients had been enrolled. The success rates of RT-PCR and NGS were 95% and 92%, respectively. Of 3919 available samples, a total of 1568 actionable gene alterations (382 KRAS mut, 193 ERBB2 mut/amp, 142 ROS1 fus, 100 RET fus, 98 MET skip/amp, 97 BRAF mut, 97 ALK fus, 96 PIK3CA mut, 54 FGFR1 amp, 13 NRAS mut, 6 AKT1 mut, 6 FGFR2/3 fus, 4 NRG1 fus, 2 NTRK3 fus and others) were detected in 1505 samples (38%). The concordance rates of the results in ALK, ROS1 and RET fusion detection between NGS and the corresponding RT-PCR were 0.98, 0.99 and 0.99, respectively. Through this screening, a total of 793 genotype-matched patients to molecular-targeted clinical trials were identified, and 136 of them (17%) were enrolled into the trials. Of the 2345 patients analyzed by NGS, the survival data were available in 1298 (55%). The patients with actionable gene alterations who were treated with targeted agents (n = 136) had significantly longer overall survivals than those not treated with targeted agents (n = 401) or the patients without actionable gene alterations (n = 761) (median survival [95%CI], 4.2 [2.4-8.2.] vs. 3.4 [2.3-5.8] vs. 2.3 [1.9-2.8] years, respectively; p = 0.01). Conclusions: LC-SCRUM-Japan contributes to the development of precision medicine, especially for ROS1, RET, ERBB2, BRAF and MET-positive lung cancers. In addition to the tissue-based molecular screening, a NGS assay with liquid biopsy was started in December 2017 and is now ongoing in the LC-SCRUM-Japan.

Lung Disease and Genomics.

Research and application of genomic medicine in lung disease during the past century has clarified our understanding and focus on specific phenotypes, helping clinicians tailor treatment for individual patients. Cystic fibrosis and lung cancer have been researched extensively; specific genotypes have been instrumental in precision medicine to treat these lung diseases. Asthma and chronic obstructive pulmonary disease are more complex and heterogeneous in their pathogenesis, genotypic profile, and phenotypic expression, making treatment more difficult with increasing disease severity. This article focuses on the evolving state of the science of precision medicine in lung cancer, chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The body of knowledge in lung disease is growing related to pharmacogenomics, clinical guidelines, genome editing, and approaches to genomic health that will guide clinical treatment options, reduce risk, and promote health.

Estado da Arte dos Doentes com Cancro do Pulmão de Não Pequenas Células: Doença Avançada e Mutação EGFR Positiva

O aparecimento de terapêuticas dirigidas, trouxe na última década uma enorme esperança para os doentes com cancro do pulmão. Os inibidores dos recetores do fator de crescimento epidérmico (EGFR), erlotinib e gefitinib (inibidores de tirosina quinase TKI), estiveram na vanguarda das mudanças da prática de tratamento para doença avançada do cancro do pulmão de não pequenas células (CPNPC), nos últimos 10 anos, com a descoberta de mutações EGFR que conferem sensibilidade a inibidores da tirosina quinase no CPNPC.&#x0D; O ano de 2004, marcou o início da era da medicina de precisão para o cancro do pulmão. Os estudos randomizados de fase III investigaram o papel de dois inibidores de EGFR-TKI, gefitinib e erlotinib, como tratamento de primeira linha em comparação com a quimioterapia à base de platina, em doentes com CPNPC doença avançada com mutações de ativação do EGFR.&#x0D; Um TKI de segunda geração (afatinib) encontra-se já aprovado pela EMA com a mesma indicação após resultados dos clínicos do Lux Lung 3 e 6. No entanto, os doentes com mutação EGFR positiva, regra geral, progridem após 10-12 meses de tratamento, necessitando de novas opções terapêuticas. Inibidores de 3ª geração entretanto desenvolvidos (dirigidos à mutação de resistência do T790M, e outras, após rebiópsia), demostraram uma notável eficácia, em doentes já tratados e com um perfil de toxicidade ainda menor que os TKI de 1ª e 2ª geração.&#x0D; Recebido: 30/05/2016 - Aceite: 03/06/2016