scholarly journals The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures

2021 ◽  
Vol 11 ◽  
Author(s):  
Miriam Grazia Ferrara ◽  
Alessio Stefani ◽  
Sara Pilotto ◽  
Carmine Carbone ◽  
Emanuele Vita ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Molecular Characteristics ◽  
Specific Substrate ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Molecular Alterations

Non-small cell lung cancer (NSCLC) represents the perfect paradigm of ‘precision medicine’ due to its complex intratumoral heterogeneity. It is truly characterized by a range of molecular alterations that can deeply influence the natural history of this disease. Several molecular alterations have been found over time, paving the road to biomarker-driven therapy and radically changing the prognosis of ‘oncogene addicted’ NSCLC patients. Kirsten rat sarcoma (KRAS) mutations are present in up to 30% of NSCLC (especially in adenocarcinoma histotype) and have been identified decades ago. Since its discovery, its molecular characteristics and its marked affinity to a specific substrate have led to define KRAS as an undruggable alteration. Despite that, many attempts have been made to develop drugs capable of targeting KRAS signaling but, until a few years ago, these efforts have been unsuccessful. Comprehensive genomic profiling and wide-spectrum analysis of genetic alterations have only recently allowed to identify different types of KRAS mutations. This tricky step has finally opened new frontiers in the treatment approach of KRAS-mutant patients and might hopefully increase their prognosis and quality of life. In this review, we aim to highlight the most interesting aspects of (epi)genetic KRAS features, hoping to light the way to the state of art of targeting KRAS in NSCLC.

Therapeutic impact of mutation subtypes and concomitant STK11 mutations in KRAS–mutated non-small cell lung cancer (NSCLC): A result of nationwide genomic screening project (LC-SCRUM-Japan).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9589-9589 ◽  
Author(s):  
Yutaro Tamiya ◽  
Yoshitaka Zenke ◽  
Shingo Matsumoto ◽  
Naoki Furuya ◽  
Tomohiro Sakamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kras Mutation ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Genomic Screening

9589 Background: KRAS mutations are one of the common oncogene drivers in non-small cell lung cancer (NSCLC), and the development of several targeted drugs for KRAS-mutated NSCLC is now ongoing. However, the clinical impact of KRAS mutation subtypes or concomitant other gene mutations in NSCLC patients (pts) remains unclear. Methods: In a nationwide genomic screening project (LC-SCRUM-Japan), we have prospectively analyzed lung cancer pts for genetic alterations and tumor mutation burden (TMB) by next-generation sequencing system, and for PD-L1 expression by immunohistochemistry (22C3 antibody). The therapeutic efficacy and survival of KRAS-mutated non-squamous (non-sq) NSCLC pts were evaluated using a clinico-genomic database of the LC-SCRUM-Japan. Results: A total of 5166 non-sq NSCLC pts enrolled from 2015 to 2019. KRAS mutations were detected in 794 pts (15%; G12C/G12D/G12V/G12A/G13X/others = 232/186/165/66/61/84). Among the 794 pts, TMB and PD-L1 expression were analyzed in 128 and 79, respectively, and 218 received PD-1/PD-L1 inhibitors (IO) after 1st-line chemotherapy. The median age was 66 years (range, 29-89). 142 pts (65%) were male and 172 (78%) were smokers. Concomitant STK11 mutations were detected in 33 pts (15%) with no difference in the mutation frequency among KRAS mutation subtypes. KRAS G12C was significantly associated with high TMB (≥ 10 mut/Mb) (p = 0.03), and KRAS G12C or G12V with high PD-L1 expression (≥ 50%) (p = 0.02). In pts who received IO, median progression-free survival (mPFS) was significantly longer in pts with KRAS G12C or G12V than in those with other KRAS mutations (4.7 vs 2.0 months, hazard ratio (HR) 0.58 [95%CI 0.43-0.78], p < 0.01). Among pts with KRAS G12C or G12V, mPFS of IO was significantly shorter in pts with concomitant STK11 mutations than in those without (1.8 vs. 5.7 months, HR 1.97 [95%CI 1.06-3.41], p = 0.02). These correlations were not observed in platinum-containing chemotherapy (Plt-CTx). There were also no significant differences in IO and Plt-CTx efficacies between with and without other concomitant mutations, such as TP53, RB1, CDKN2A and PTEN mutations. Conclusions: Non-sq NSCLC pts with KRAS G12C/V were more sensitive to IO therapies than those with other KRAS mutations, but KRAS G12C/V-positive pts with concomitant STK11 mutations were less sensitive than those without. These results could be highly informative in the development of novel targeted therapies for KRAS-mutated NSCLC.

Identification of actionable mutations in surgically resected tumor specimens from Japanese patients with non-small cell lung cancer by ultra-deep targeted sequencing.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7572-7572 ◽  
Author(s):  
Yasuhiro Koh ◽  
Hirotsugu Kenmotsu ◽  
Masakuni Serizawa ◽  
Mitsuhiro Isaka ◽  
Keita Mori ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Targeted Sequencing ◽  
Cancer Center ◽  
Molecular Characteristics ◽  
Small Cell Lung ◽  
Wide Range

7572 Background: Detection of tumor genetic alterations is critically needed for lung cancer clinic as well as for the development of molecular targeted therapeutics. Here we report the results of a broad spectrum of genetic alterations identified in Japanese non-small cell lung cancer (NSCLC) patients by ultra-deep targeted sequencing. Methods: Highly multiplexed amplicon sequencing was performed using genomic DNA extracted from snap-frozen tumor specimens. TruSeq amplicon cancer panel was used for the detection of somatic mutations in 48 cancer related genes followed by ultra-deep sequencing (Illumina) at an average coverage of approximately 2800x. ALK, ROS1 and RET traslocations and EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications were also detected by multiplex RT-PCR and quantitative PCR, respectively. Results: The demographics of 204 consecutive patients enrolled in this prospective study at Shizuoka Cancer Center between July 2011 and November 2012: median age 69 years (range: 38-92); male 66%; never smoker 25.5%; histology: adenocarcinoma 68.6%, squamous cell carcinoma (SQ) 27.0%, others 4.4%; tumor stage: I 53.9%, II 28.4%, III 12.7%, IV 4.9%. TP53 mutation was most frequently detected (44.4%) in all patients, particularly in SQ (67.9%). Mutations in genes such as MLH1 (4.9%), STK11 (6.3%), CTNNB1 (5.6%), SMAD4 (1.4%), VHL1 (1.4%), PTPN11 (0.7%) and GNAS (0.7%) were detected besides major mutations in genes such as EGFR (43.0%), KRAS (17.6%) and PIK3CA (14.1%) in adenocarcinoma. PIK3CA (21.4%), MLH1 (5.4%), APC (3.6%), STK11 (3.6%), FGFR2 (1.8%) and VHL (1.8%) mutations were identified in SQ and notably, 48.2% of SQ patients harbored simultaneous gene mutations, suggesting the genetic complexity of this histology. FGFR1 amplification was found in 8.9 % of SQ, suggesting lower frequency in Asian population than in Caucasian population. Conclusions: We managed to detect a wide range of genetic alterations and identified additional actionable mutations besides popular driver mutations. This approach may facilitate elucidation of detailed molecular characteristics of NSCLC, thereby implementing personalized cancer medicine.

scholarly journals Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2446
Author(s):  
Zoi Kanaki ◽  
Alexandra Voutsina ◽  
Athina Markou ◽  
Ioannis S. Pateras ◽  
Konstantinos Potaris ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Tumor Cells ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Intratumor Heterogeneity ◽  
Molecular Characteristics ◽  
Tumor Evolution ◽  
Small Cell Lung

Recent advances in sequencing technologies have allowed the in-depth molecular study of tumors, even at the single cell level. Sequencing efforts have uncovered a previously unappreciated heterogeneity among tumor cells, which has been postulated to be the driving force of tumor evolution and to facilitate recurrence, metastasis, and drug resistance. In the current study, focused on early-stage operable non-small cell lung cancer, we used tumor growth in patient-derived xenograft (PDX) models in mice as a fast-forward tumor evolution process to investigate the molecular characteristics of tumor cells that grow in mice, as well as the parameters that affect the grafting efficiency. We found that squamous cell carcinomas grafted significantly more efficiently compared with adenocarcinomas. Advanced stage, patient age and primary tumor size were positively correlated with grafting. Additionally, we isolated and characterized circulating tumor cells (CTC) from patients’ peripheral blood and found that the presence of CTCs expressing epithelial-to-mesenchymal (EMT) markers correlated with the grafting potential. Interestingly, exome sequencing of the PDX tumor identified genetic alterations in DNA repair and genome integrity genes that were under-represented in the human primary counterpart. In conclusion, through the generation of a PDX biobank of NSCLC, we identified the clinical and molecular properties of tumors that affected growth in mice.

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.

Improvements in access to cancer clinical trials facilitated by comprehensive genomic profiling in non-small cell lung cancer.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 59-59
Author(s):  
Woojung Lee ◽  
Scott Spencer ◽  
Josh John Carlson ◽  
Tam Dinh ◽  
Victoria Dayer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Genomic Profiling ◽  
Small Cell Lung ◽  
Eligibility Criteria ◽  
Comprehensive Genomic Profiling

59 Background: The use of comprehensive genomic profiling (CGP) in cancer patients could lead to additional enrollment in clinical trials that study novel genetic biomarkers, potentially reducing treatment costs for payers and improving health outcomes for patients. Our objective was to estimate the number of additional clinical trials in which patients with non-small cell lung cancer (NSCLC) could potentially enroll due to the use of CGP vs. a comparator panel of 50 genes or less. Methods: Clinical trials in NSCLC that started between 2015 - 2020 were identified from the Aggregate Analysis of ClinicalTrials.gov (AACT) database. Trials with unknown status or study sites outside the United States only were excluded. We abstracted information on required genetic alterations based on the study eligibility criteria. We calculated the incremental number of trials available to patients due to results generated by CGP (FoundationOne CDx, 324 genes) vs. a commercially available comparator panel that was 50 genes or less (Oncomine Dx Target Test, 23 genes) by phase and calendar year. The additional trials were characterized by disease severity, type of therapy, and setting. Results: Enrollment eligibility was dependent on genetic variant status in 35% (250/709) of all identified NSCLC trials. There were 29 (248 vs. 219) additional clinical trials available to patients through the use of CGP, 12% of all gene-specific trials for NSCLC. We identified 45 uses of genetic markers in the 29 additional clinical trials. The most frequent genetic marker in the incremental trials was microsatellite instability, accounting for 44% of all identified markers (20/45). The incremental number of trials available to patients due to the use of CGP did not vary significantly over time but varied by phase – most of the additional clinical trials were in phase 1 or 2 (28/29, 97%). Most of the incremental trials were in metastatic disease (22/29, 76%) and were conducted in academic or advanced community settings (18/29, 62%). The most frequently studied type of intervention in these studies was targeted monotherapy (8/29, 28%), followed by immuno-monotherapy (7/29, 24%). Conclusions: Clinical trials in NSCLC initiated over the past 5 years have consistently included CGP-specific genes or markers in eligibility criteria. Patients with NSCLC have the potential to benefit from the use of CGP as compared to smaller gene panels through improved access to clinical trials.[Table: see text]

scholarly journals Efficacy of nivolumab in pre-treated non-small-cell lung cancer patients harbouring KRAS mutations

2018 ◽  
Vol 120 (1) ◽  
pp. 57-62 ◽  
Author(s):  
Francesco Passiglia ◽  
Federico Cappuzzo ◽  
Oscar Alabiso ◽  
Anna Cecilia Bettini ◽  
Paolo Bidoli ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Lung Cancer Patients
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