Characteristics and Outcomes of Patients with Lung Cancer Harboring Multiple Molecular Alterations: Results from the IFCT Study Biomarkers France

Guibert, Nicolas; Barlési, Fabrice; Descourt, R.; Léna, H.; Besse, Benjamin; Beau‐Faller, Michèle; Mosser, Jean; Pichon, Éric; Merlio, Jean-Philippe; Ouafik, L’Houcine; Guichard, F.; Mastroïanni, B.; Moreau, L.; Wdowik, A.; Sabourin, Jean‐Christophe; Lemoine, Antoinette; Missy, Pascale; Langlais, Alexandra; Moro-Sibilot, Denis; Mazières, Julien

doi:10.1016/j.jtho.2017.02.001

Cited by 59 publications

(61 citation statements)

References 28 publications

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“…Sensitivity of cells with KRAS/EGFR double mutations to tyrosine kinase inhibitors EGFR-TKI therapy [9,12,32]. Taken together, these reports indicate that EGFR-TKI therapy may represent an effective treatment strategy against NSCLC with EGFR/KRAS co-mutation.…”

Section: Plos Onementioning

confidence: 87%

“…In NSCLC, oncogenic driver mutations are typically mutually exclusive, although cases of mutations in multiple driver genes are increasingly reported [5,[7][8][9][10][11][12][13][14]. EGFR/KRAS co-mutation is likely to represent a certain proportion of cases of multiple mutations in NSCLC [12].…”

Section: Discussionmentioning

confidence: 99%

“…In the clinical setting, the limited prevalence of EGFR/KRAS co-mutated NSCLC means that its response to EGFR-TKI remains unclear. So far, several studies have reported the therapeutic effects of EGFR-TKI in patients with the co-mutations [9,12,32,33]. Zhang et al reported that EGFR/KRAS co-mutation was detected in 38 out of 2106 patients (1.8%), and that a larger proportion of patients with the co-mutation obtained a better objective response rate (38.9% vs. 9.5%) and longer progression-free survival (8.0 vs. 1.5 months) following EGFR-TKIs therapy compared with patients having a KRAS mutation alone.…”

Section: Discussionmentioning

confidence: 99%

“…In NSCLC prior to treatment, the majority of oncogenic driver mutations are mutually exclusive with other mutations [5,6]. However, recent studies have shown that additional driver mutations such as KRAS, ALK, and PI3K mutations co-exist with EGFR-mutations in a certain percentage of lung cancers [5,[7][8][9][10][11][12][13][14]. Of note, these driver mutations have been found not only in different cell populations in tumors, but also within the same cell population [15,16].…”

Section: Introductionmentioning

confidence: 99%

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Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line

2020

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In non-small cell lung cancer (NSCLC), oncogenic driver mutations including those in KRAS and EGFR are typically mutually exclusive. However, recent reports indicate that multiple driver mutations are found in a certain percentage of cancers, and that the therapeutic responses of such cases with co-mutations of driver genes are largely unclear. Here, using CRISPR-Cas9-mediated genome editing, we generated isogenic cell lines harboring one or two copies of an EGFR-activating mutation from the human NSCLC cell line A549, which is known to harbor a homozygous KRAS gene mutation. In comparison with parent cells with KRAS mutation alone, cells with concomitant EGFR mutation exhibited higher sensitivity to EGFR-tyrosine kinase inhibitors (TKIs) but not to conventional anti-cancer drugs. In particular, cells with two copies of EGFR mutation were markedly more sensitive to EGFR-TKIs compared with parent cells. Thus, the presence of concomitant EGFR mutation can affect the TKI response of KRAS-mutated cells, implying that EGFR-TKI may represent an effective treatment option against NSCLC with EGFR/KRAS co-mutation. OPEN ACCESSCitation: Tsukumo Y, Naito M, Suzuki T (2020) Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line. PLoS ONE 15(3): e0229712. https://doi.org/10.

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Section: Plos Onementioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line

2020

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“…However, with the advancement in molecular technology, multiple and coexisting EGFR mutations have been detected, without much exhaustive studies on their clinical significance. 6 …”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor receptor (EGFR), KRAS, and BRAF mutations in lung adenocarcinomas: A study from India

Singh

Guleria

Malik

et al. 2019

Current Problems in Cancer

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Mitogen-Activated Protein (MAP) Kinase pathway involves several oncogenic genes which can serve as potential targets for therapy. Therefore, aim of the present study is to analyze mutations in the MAP Kinase pathway in pulmonary adenocarcinoma (ADCA) of Indian patients along with clinico-pathologic correlation and determination of the survival status in patients receiving therapy. Blocks and slides of 125 pulmonary ADCA of last 5 years were retrieved. Histo-morphology and tumor content were determined. EGFR, KRAS, BRAF and MEK1 genes were analyzed using Sanger sequencing and Real-time polymerase chain reaction (PCR). Clinico-pathologic correlation and survival analysis were performed. Fifty-eight (46.4%) patients harbored genetic mutations of which 49 had single somatic mutations, 5 had multiple exonic and 4 showed coexisting EGFR and KRAS mutations. EGFR mutations were seen in 24.8%, KRAS in 19.2% and BRAF (non-V600E) in 2.4% cases. There was no difference in progression-free survival of wild- type/single mutations when compared with multiple/ coexisting mutations (P = 0.09). However, the P value may indicate borderline correlation. To conclude, EGFR and KRAS mutations may coexist in the same patient in lung ADCA. Multiple exonic mutations of KRAS gene formed substantial percentage of our cohort, requiring further exploration. Lung ADCA harbouring BRAF mutations are commonly non-V600E. Testing of all major genetic driver mutations of lung ADCA irrespective of histology and other demographic characteristics is necessary.

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Clinical features and therapeutic options in non‐small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

Zhuang

Zhao

et al. 2019

Cancer Medicine

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Background Although oncogenic driver mutations were thought to be mutually exclusive in non‐small cell lung cancer (NSCLC), certain tumors harbor co‐occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients. Methods This retrospective study included 3774 samples from patients diagnosed with NSCLC. All samples were screened for EGFR, ALK, ROS1, KRAS, and BRAF mutation using the amplification‐refractory mutation system. The relationship between concomitant driver mutations and clinicopathologic characteristics, and patient clinical outcomes were evaluated. Results Sixty‐three (1.7%) samples had more than one driver gene mutation. Among these, 43 were coalterations with an EGFR mutation, 20 with an ALK rearrangement, and eight with an ROS1 rearrangement. Except for ROS1 concomitant mutations that were more frequent in male patients (87.5%, P = 0.020), the clinicopathological features of the concomitant mutation patients were not significantly different from those harboring a single EGFR, ALK, or ROS1 mutation. Furthermore, first‐line EGFR‐TKI treatment did not significantly improve the progression‐free survival (PFS) of patients harboring EGFR concomitant mutation, compared to patients harboring a single EGFR mutation. However, for EGFR concomitant mutation patients, TKI therapy was more effective than chemotherapy (median PFS of 10.8 vs 5.2 months, P = 0.023). Lastly, KRAS mutations did not influence the EGFR‐TKI therapy treatment effect. Conclusion In this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR‐TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options.

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Characteristics and Outcomes of Patients with Lung Cancer Harboring Multiple Molecular Alterations: Results from the IFCT Study Biomarkers France

Cited by 59 publications

References 28 publications

Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line

Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line

Epidermal growth factor receptor (EGFR), KRAS, and BRAF mutations in lung adenocarcinomas: A study from India

Clinical features and therapeutic options in non‐small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

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