Posts Tagged ‘september’

High concordance between EGFR mutations from circulating-free tumor DNA and tumor tissue in non-small cell lung cancer

EGFR tyrosine kinase inhibitor (TKI) therapy is approved for EGFR activating mutation positive patients with advanced NSCLC, but the standard for determining mutation status is with DNA derived directly from tumor tissue, which can be limited or not available. A more abundant and less invasive source of tumor DNA may be cell free tumor DNA found circulating in the blood.

International researchers prospectively analyzed and compared tumor and matched plasma DNA for EGFR mutations from 1060 patients that were screened as part of a phase IV, open-label, single-arm, first-line gefitinib in EGFR mutation positive Caucasian patients. Also, when two plasma samples from the same patient were available the mutation status of each was compared.

The September issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer (IASLC), reports that the mutation status concordance between tumor and matched plasma for 652 patients that had results for both was 94% (95% CI 92-96) with a sensitivity of 66% (CI 56-75) and specificity of 100% (CI 99-100). The reproducibility between two plasma specimens from the same patient was also high with a mutation concordance of 97% (CI 94-99) for 224 matched specimens. Post-hoc analysis of the efficacy of first-line gefitinib revealed there was similar progression-free survival (PFS) for those with EGFR mutation positive tissue (9.7 months [CI 8.5-11.0]) versus both mutation positive tissue and plasma (10.2 months [CI 8.5-12.5]).

The authors acknowledge that “tumor tissue should be considered the preferred sample type when available, however, our encouraging results suggest that a single plasma-derived ctDNA sample may be considered appropriate for assessment of EGFR mutation status when tumor tissue is unavailable or exhausted.” “As there are no published guidelines for the use of ctDNA for EGFR mutation analysis in the absence of tumor tissue, these results may help address this current unmet need.” Dr. Douillard, lead author of the study, says his next steps are to “look for resistance mutations, like T790M, during treatment to better understand mechanisms of resistance and anticipate later line treatment at progression.” For future research he also suggests “searching for other resistance mutations along the EGFR pathway, as well as other related pathways, and improving the sensitivity by using more powerful testing methods, like next generation sequencers.”

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Deletion predicts survival in advanced non-small cell lung cancer

The BIM protein can activate the programmed cell death also known as the apoptotic pathway in cells. BIM deletion has been detected in 12.8% of the Asian population but is very rarely observed in the Caucasian population. All NSCLC patients treated with any therapy, targeted or chemotherapeutic, ultimately fail their therapy but at varying times.

Researchers at the National Taiwan University Hospital examined the impact of BIM deletion on the survival outcomes of 204 advanced NSCLC patients treated with either EGFR TKIs or chemotherapy.

Results reported in the September issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer (IASLC), showed that BIM deletion was an independent predictive factor for shorter PFS in EGFR TKI treated patients (hazard ratio=2.15, p=0.002) with median PFS of 4.6 months in BIM deletion versus 8.6 months in wild type patients. Similar results were observed in chemotherapy treated patients with a hazard ratio of 2.4 (p=0.016) and median PFS of 3.5 and 5.6 months in deletion versus wild type, respectively. Overall survival was also independently predicted by BIM deletion (hazard ratio=1.65, p=0.039)

Dr. James Chih-Hsin Yang, senior author and member of IASLC, notes “our findings suggest the BIM deletion polymorphism should be considered as a clinical trial stratification factor when systemic treatment is considered in Asian NSCLC patients.” Dr. Yang also says “since little is known about whether anti-apoptotic agents are able to overcome the resistance to EGFR TKIs resulting from BIM deletion, it may be warranted to explore anti-apoptotic agents, such as obatoclax, in future clinical trials.”

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Novel oncogenic RET mutation found in small cell lung cancer

SCLC is a highly malignant form of lung cancer representing 15% of all lung cancers and is strongly associated with tobacco smoking. NSCLC, representing 85% of lung cancer, has been extensively examined for genomic alterations and targeted therapies are approved for patients with certain mutations, however SCLC has not been examined with the same rigor and there are no approved targeted therapies for SCLC.

Investigators at Case Western University examined 6 SCLC tumors, 3 each from primary and metastatic tumors, for 238 somatic mutations across 19 oncogenes. RET wild type and mutant protein was then overexpressed in SCLC cell lines and these cell lines were examined for cell signaling, cell growth and responsiveness to two tyrosine kinase inhibitors of RET.

Results reported in the September issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer (IASLC), revealed the RET M918T mutation in a metastatic SCLC tumor and that overexpression of this mutant protein in SCLC cell lines resulted in increased ERK signaling, MYC expression and increased cell proliferation. Likewise, these cell lines overexpressing the RET protein became sensitive to ponatinib and vandetanib, tyrosine kinase inhibitors of RET. Decreased cell growth was the result of this inhibition of RET.

The authors say that their work “suggests that RET mutations play a potential role in some cases of SCLC as no other activating mutations were identified among the 19 oncogenes assayed in the tumor harboring the RET M918T mutation, potentially making M918T the driver mutation in this tumor.” However, the authors caution that “the role of oncogenic RET mutations cannot be judged fairly until a larger number of tumors are genomically analyzed, including metastatic tumors.”

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