Prognostic and predictive effects of TP53 co-mutation in patients with EGFR -mutated non-small cell lung cancer (NSCLC)

Labbé, Catherine; Cabanero, Michael; Korpanty, Grzegorz; Tomasini, Pascale; Doherty, Mark; Mascaux, Céline; Jao, Kevin; Pitcher, Bethany; Wang, Rick; Pintilie, Melania; Leighl, Natasha B.; Feld, Ronald; Liu, Geoffrey; Bradbury, Penelope Ann; Kamel‐Reid, Suzanne; Tsao, Ming‐Sound; Shepherd, Frances A.

doi:10.1016/j.lungcan.2017.06.014

Cited by 173 publications

(168 citation statements)

References 36 publications

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“…In addition to intrinsic resistance caused by specific EGFR TKI‐resistant mutations, many other mechanisms might potentially affect the efficacy of TKI treatment, and combination therapies may be need in certain situations. According to the study by Labbé et al, dual TP53 and EGFR mutation was found in 41% of lung ADCs . Moreover, these patients had marginally shorter PFS under EGFR TKI treatment.…”

Section: Discussionmentioning

confidence: 96%

Mutation Profile of ResectedEGFR-Mutated Lung Adenocarcinoma by Next-Generation Sequencing

Zhao

Lin

et al. 2019

The Oncologist

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Background The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co‐mutations in resected epidermal growth factor receptor (EGFR)‐mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment. Materials and Methods Mutation profiling of 416 cancer‐relevant genes was conducted for 139 resected stage I–IIIa lung ADCs with EGFR mutations using targeted next‐generation sequencing. Co‐mutation profiles were systematically analyzed. Results Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first‐generation TKIs. Ninety‐one percent of patients harbored at least one co‐mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II–III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty‐four percent of patients with EGFR TKI‐sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1. Conclusion Operable lung ADCs with EGFR TKI‐sensitizing mutations are associated with a high proportion of co‐mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy. Implications for Practice The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next‐generation sequencing of 416 cancer‐relevant genes in 139 resected lung cancers revealed the co‐mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI‐resistant mutations in 34.71% of patients with a drug‐sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.

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Section: Discussionmentioning

confidence: 96%

Mutation Profile of ResectedEGFR-Mutated Lung Adenocarcinoma by Next-Generation Sequencing

Zhao

Lin

et al. 2019

The Oncologist

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“…Unfortunately, acquired resistance still occurs after a median of 10 months with various resistance mechanisms . Moreover, emerging data indicated the co‐occurrence of TP53 mutations is associated with shortened progression‐free survival . Identifying other acquired mutations during treatment could allow better prognostication and therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12][13] Moreover, emerging data indicated the co-occurrence of TP53 mutations is associated with shortened progression-free survival. [14][15][16] Identifying other acquired mutations during treatment could allow better prognostication and therapeutic strategies.…”

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confidence: 99%

Co‐mutational assessment of circulating tumour DNA (ctDNA) during osimertinib treatment for T790M mutant lung cancer

Xing

Han

Wang

et al. 2019

J Cellular Molecular Medi

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Osimertinib is designed to target the secondary resistant EGFR T790M mutant and has shown outstanding clinical efficacy. However, the prognostic prediction of osimertinib patients is a big problem in clinical practice. The resistance mechanism of osimertinib is also not fully understood. NGS and a 1021 gene capture panel were used to analyse the somatic mutation profile of thirty‐six lung adenocarcinoma patients' serial ctDNA samples. Progression‐free survival of subgroup patients is analysed. Patients harbour TP53 mutations and patients with higher TMB value in pre‐treatment samples showed a shorter PFS. Moreover, compared to CT evaluation, ctDNA changes generally correlated with treatment responses in most patients. Novel resistance mechanisms are discovered including EGFR mutations and alternative activation pathway. Our results implied a broad potential of ctDNA as an adjuvant tool in practical clinical management of NSCLC patients. ctDNA could help with clinical practice during osimertinib treatment, regarding monitoring tumour response, detecting development of heterogeneity, identifying potential resistance mechanisms, predicting treatment efficacy and patient outcome.

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“…Other mechanisms of TKI resistance in NSCLC patients in which p. T790M mutations are not detected have also been described; this includes activation of downstream signaling pathways (mainly through MET or HER2 amplifications), epithelial‐mesenchymal transition, transdifferenciation to small cell lung cancer, as well as other unknown mechanisms . TP53 somatic alterations in NSCLC patients have been shown to be associated with poor outcomes . Canale et al found a similar proportion of TP53 mutant cases and showed that TP53 mutations in exon 8 were also associated with poor outcomes …”

Section: Resultsmentioning

confidence: 96%

Profiling of circulating tumor DNA in plasma of non‐small cell lung cancer patients, monitoring of epidermal growth factor receptor p.T790M mutated allelic fraction using beads, emulsion, amplification, and magnetics companion assay and evaluation in future application in mimicking circulating tumor cells

et al. 2019

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Cell‐free plasma DNA (cfDNA) and mimicking circulating tumor cells (mCTCs) have demonstrated tremendous potential for molecular diagnosis of cancer and have been rapidly implemented in specific settings. However, widespread clinical adoption still faces some obstacles. The purpose was to compare the performance of a BEAMing (beads, emulsion, amplification, and magnetics) assay (OncoBEAM™‐epidermal growth factor receptor [EGFR] [Sysmex Inostics]) and a next‐generation sequencing assay (NGS; 56G Oncology panel kit, Swift Bioscience) to detect the p.T790M EGFR mutation in cfDNA of non‐small cell lung cancer (NSCLC) patients. CfDNA samples (n = 183) were collected within our hospital from patients having a known EGFR sensitizing mutation, and presenting disease progression while under first‐line therapy. EGFR mutations were detected using NGS in 42.1% of samples during progression in cfDNA. Testing using the OncoBEAM™‐EGFR assay enabled detection of the p.T790M EGFR mutation in 40/183 NSCLC patients (21.8%) versus 20/183 (10.9%), using the NGS assay. Samples that were only positive with the OncoBEAM™‐EGFR assay had lower mutant allelic fractions (Mean = 0.1304%; SD ± 0.1463%). In addition, we investigated the detection of p.T790M in mCTCs using H1975 cells. These cells spiked into whole blood were enriched using the ClearCellFX1 microfluidic device. Using the OncoBEAM™‐EGFR assay, p.T790M was detected in as few as 1.33 tumoral cells/mL. Overall, these findings highlight the value of using the OncoBEAM™‐EGFR to optimize detection of the p.T790M mutation, as well as the complementary clinical value that each of the mutation detection assay offers: NGS enabled the detection of mutations in other oncogenes that may be relevant to secondary resistance mechanisms, whereas the OncoBEAM™‐EGFR assay achieved higher sensitivity for detection of clinically actionable mutations.

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Prognostic and predictive effects of TP53 co-mutation in patients with EGFR -mutated non-small cell lung cancer (NSCLC)

Cited by 173 publications

References 36 publications

Mutation Profile of ResectedEGFR-Mutated Lung Adenocarcinoma by Next-Generation Sequencing

Mutation Profile of ResectedEGFR-Mutated Lung Adenocarcinoma by Next-Generation Sequencing

Co‐mutational assessment of circulating tumour DNA (ctDNA) during osimertinib treatment for T790M mutant lung cancer

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