Incidence of inconsistent driver mutations between multiple lung ground-glass nodules in patients with non-small cell lung cancer.

Abstract Background KRAS is the most frequently mutated oncogene in cancer, however efforts to develop targeted therapies have been largely unsuccessful. Recently, two small-molecule inhibitors, AMG 510 and MRTX849, have shown promising activity in KRAS G12C-mutant solid tumors. The current study aims to assess the molecular profile of KRAS G12C in colorectal (CRC) and non-small-cell lung cancer (NSCLC) tested in a clinical certified laboratory. Methods CRC and NSCLC samples submitted for KRAS testing between 2017 and 2019 were reviewed. CRC samples were tested for KRAS and NRAS by pyrosequencing, while NSCLC samples were submitted to next generation sequencing of KRAS, NRAS, EGFR, and BRAF. Results The dataset comprised 4897 CRC and 4686 NSCLC samples. Among CRC samples, KRAS was mutated in 2354 (48.1%). Most frequent codon 12 mutations were G12D in 731 samples (14.9%) and G12V in 522 (10.7%), followed by G12C in 167 (3.4%). KRAS mutations were more frequent in females than males (p = 0.003), however this difference was exclusive of non-G12C mutants (p < 0.001). KRAS mutation frequency was lower in the South and North regions (p = 0.003), but again KRAS G12C did not differ significantly (p = 0.80). In NSCLC, KRAS mutations were found in 1004 samples (21.4%). As opposed to CRC samples, G12C was the most common mutation in KRAS, in 346 cases (7.4%). The frequency of KRAS G12C was higher in the South and Southeast regions (p = 0.012), and lower in patients younger than 50 years (p < 0.001). KRAS G12C mutations were largely mutually exclusive with other driver mutations; only 11 NSCLC (3.2%) and 1 CRC (0.6%) cases had relevant co-mutations. Conclusions KRAS G12C presents in frequencies higher than several other driver mutations, and may represent a large volume of patients in absolute numbers. KRAS testing should be considered in all CRC and NSCLC patients, independently of clinical or demographic characteristics.

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Molecular profile of KRAS G12C-mutant colorectal and non-small-cell lung cancer

10.21203/rs.3.rs-108171/v1 ◽

2020 ◽

Author(s):

Luiz H. Araujo ◽

Bianca Souza ◽

Laura Leite ◽

Sabrina Parma ◽

Natália Lopes ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Driver Mutations ◽

Molecular Profile ◽

Common Mutation ◽

Small Cell Lung ◽

The South ◽

Kras Mutations

Abstract Background: KRAS is the most frequently mutated oncogene in cancer, however efforts to develop targeted therapies have been largely unsuccessful. Recently, two small-molecule inhibitors, AMG 510 and MRTX849, have shown promising activity in KRAS G12C-mutant solid tumors. The current study aims to assess the molecular profile of KRAS G12C in colorectal (CRC) and non-small-cell lung cancer (NSCLC) tested in a clinical certified laboratory.Methods: CRC and NSCLC samples submitted for KRAS testing between 2017 and 2019 were reviewed. CRC samples were tested for KRAS and NRAS by pyrosequencing, while NSCLC samples were submitted to next generation sequencing of KRAS, NRAS, EGFR, and BRAF. Results: The dataset comprised 4,897 CRC and 4,686 NSCLC samples. Among CRC samples, KRAS was mutated in 2,354 (48.1%). Most frequent codon 12 mutations were G12D in 731 samples (15.2%) and G12V in 462 (9.6%), followed by G12C in 167 (3.4%). KRAS mutations were more frequent in females than males (p=0.003), however this difference was exclusive of non-G12C mutants (p<0.001). KRAS mutation frequency was lower in the South and North regions (p=0.003), but again KRAS G12C did not differ significantly (p=0.80). In NSCLC, KRAS mutations were found in 1,004 samples (21.4%). As opposed to CRC samples, G12C was the most common mutation in KRAS, in 346 cases (7.4%). The frequency of KRAS G12C was higher in the South and Southeast regions (p=0.012), and lower in patients younger than 50 years (p<0.001). KRAS G12C mutations were largely mutually exclusive with other driver mutations; only 11 NSCLC (3.2%) and 3 CRC (1.8%) cases had relevant co-mutations. Conclusions: KRAS G12C presents in frequencies higher than several other driver mutations, represent a large volume of patients in absolute numbers. KRAS testing should be considered in all CRC and NSCLC patients, independently of clinical or demographic characteristics.

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Paradigm shift in the management of metastatic Non-small Cell Lung Cancer

10.22541/au.161358458.83540275/v1 ◽

2021 ◽

Author(s):

Ruby Gupta ◽

Melanie Smalley ◽

Nwabundo Anusim ◽

Vishal Jindal ◽

Mandeep Singh Rahi ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Paradigm Shift ◽

Survival Rates ◽

Small Cell ◽

Driver Mutations ◽

Small Cell Lung ◽

Cancer Management ◽

Chemotherapeutic Approach

Background: Lung cancer is one of the leading causes of cancer mortality in the US. The use of precision medicine in the past 10 years has significantly changed the therapeutic landscape of lung cancer. Management of advanced non-small cell lung cancer (NSCLC) has transitioned from a chemotherapeutic approach to targeted treatments and immunotherapeutic agents. Several tyrosine kinase inhibitors (TKIs) have been approved for patients with targeted mutations while patients who do not have driver mutations; immunotherapy has been recently approved as frontline therapy, which has resulted in marked improvement in overall survival and added a new tool in our armamentarium. Aims: The purpose of this review is to highlight recent advancements in diagnostic approach and management strategies in patients with metastatic NSCLC. Materials and methods: Published studies included in Medline (via PubMed) and National Comprehensive Cancer Network Guidelines were reviewed for data gathering. Conclusion: The use of next generation sequencing has significantly changed our understanding of molecular oncogenic mechanisms of lung cancer. These advancements have created a paradigm shift in the treatment strategies of metastatic lung cancer from primarily chemotherapeutic approach to increasing use of targeted therapies and immune check point inhibitors (ICI) leading to better survival rates and lesser toxicity.

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Systemic and Radiation Therapy Approaches for Locally Advanced Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.21.01707 ◽

2022 ◽

Author(s):

Kristin A. Higgins ◽

Sonam Puri ◽

Jhanelle E. Gray

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Locally Advanced ◽

Standard Of Care ◽

Circulating Tumor Dna ◽

Small Cell ◽

Concurrent Chemoradiation ◽

Driver Mutations ◽

Small Cell Lung

The treatment for locally advanced non–small-cell lung cancer has changed dramatically over the past several years, with consolidative immunotherapy after concurrent chemoradiation becoming the new standard of care. Five-year survival outcomes have substantially improved with this approach. Despite these advances, further improvements are needed as the majority of patients ultimately develop progression of disease. The next-generation immunotherapy trials are currently being conducted that include approaches such as concurrent immunotherapy and addition of other therapeutic agents in the concurrent and consolidative settings. Specific unmet needs continue to exist for patients who develop disease progression after concurrent chemoradiation and immunotherapy, as well as defining the best treatment for patients with driver mutations. Future directions also include refinement of radiation techniques to reduce toxicities as much as possible, as well as the use of circulating tumor DNA in the surveillance setting. The current scientific landscape shows promising approaches that may further improve outcomes for patients with locally advanced non–small-cell lung cancer.

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