Larger tumors are associated with inferior progression‐free survival of first‐line EGFR‐tyrosine kinase inhibitors and a lower abundance of <i>EGFR</i> mutation in patients with advanced non‐small cell lung cancer

Pan, Yingying; Gao, Guanghui; Chen, Xiaoxia; Tian, Qinrui; Wu, Fengying; Liu, Qian; Wang, Yan; Jiang, Tao; Liu, Yiwei; Li, Xuefei; Yang, Shuo; Xu, Chuan; Su, Chunxia; Zhou, Fei; Ren, Shengxiang

doi:10.1111/1759-7714.12986

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…Although large tumors might theoretically be more heterogeneous than smaller ones because of poor blood supply and hypoxia, we did not find a significant difference in tumor size for participants with high or low mutation abundance. Also, no association between the extent of target lesion shrinking to EGFR-TKI and PFS was found, which further supports previous results (35)(36)(37).…”

Section: I Q U I D B I O P S Y B a S E D O N C T D N A I S C O N S I D E R E D Complementary To Detection Of Egfr Mutations In Tissuessupporting

confidence: 89%

Plasma EGFR mutation abundance affects clinical response to first-line EGFR-TKIs in patients with advanced non-small cell lung cancer

et al. 2021

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Background: Activated epidermal growth factor receptor (EGFR) mutation is the main pathogenic cause of non-small cell lung cancer (NSCLC) in Asia. However, the impact of plasma EGFR mutation abundance, especially of the ultra-low abundance of EGFR mutation detected by highly sensitive techniques on clinical outcomes of first-line EGFR tyrosine kinase inhibitors (TKIs) for advanced NSCLC patients remains unclear.Methods: We qualitatively detected baseline EGFR status of NSCLC tissues using amplification-refractory mutation system and quantified the plasma abundance of EGFR mutations through next-generation sequencing (NGS). Every 8-12 weeks, we performed dynamic detection of plasma mutation abundance and imaging evaluation. We analyzed the association between plasma abundance of EGFR sensitizing mutations, tumor size, tumor shrinkage percentage, concomitant TP53 mutations, and clinical response to TKIs.Results: This prospective study enrolled 135 patients with advanced NSCLC. The objective response rate (ORR) and disease control rate (DCR) for EGFR mutation-positive patients were 50.0% and 87.0%, respectively. When the cutoff value of plasma EGFR mutation abundance was 0.1%, the ORRs of TKItreated patients were significantly different (60.0% for the >0.1% group vs. 21.4% for the ≤0.1% group, P=0.028). Median progression-free survival (PFS) was significantly longer for participants with a mutation abundance above 0.1% compared to those with a 0.01-0.1% abundance (log rank, P=0.0115). There was no significant association between plasma abundance of EGFR sensitizing mutations and tumor size, tumor shrinkage percentage, or concomitant TP53 mutations. Cox multivariate analysis demonstrated that plasma mutation abundance was an independent predictive factor for PFS [hazard ratio (HR) 2.41, 95% confidence interval (CI): 1.12-5.20; P=0.025]. We identified 11 participants with the acquired T790M resistance mutation according to serial dynamic plasma samples.Conclusions: Liquid biopsy screening based on highly sensitive NGS is reliable for detecting drug

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Section: I Q U I D B I O P S Y B a S E D O N C T D N A I S C O N S I D E R E D Complementary To Detection Of Egfr Mutations In Tissuessupporting

confidence: 89%

Plasma EGFR mutation abundance affects clinical response to first-line EGFR-TKIs in patients with advanced non-small cell lung cancer

et al. 2021

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“…NSCLC patients with low-abundance EGFR mutation may experience reduced ORR and shorter PFS time compared to groups with high-abundance EGFR mutation. [ 15 , 16 ] Data from these studies indicate that treatment with EGFR-TKI for the patient in our case would probably be relatively ineffective, and the patient did indeed experience primary resistance to EGFR-TKI therapy.…”

Section: Discussionmentioning

confidence: 79%

Efficacy and safety of pembrolizumab monotherapy in EGFR-mutant squamous cell lung cancer with PD-L1 over-expression: A case report

Li¹,

Wei

Chen

et al. 2022

Medicine

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Background: Epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC) patients are less likely to be programmed death-ligand 1 (PD-L1)-positive compared with wild-type EGFR mutant tumors. Given the rarity of actionable driver genes in squamous cell lung cancer (SQCC), the frequency of SQCC patients simultaneously carrying EGFR driver gene mutation and having PD-L1 over-expression is extremely low. Studies on the effectiveness and safety of EGFR-TKIs or immune-checkpoint inhibitors (ICIs) in this subset of patients are lacking.Patient concerns: The patient suffered from coughing and chest pain for 1 month. A chest CT revealed a mass with a cavity in the right lung, enlarged mediastinal lymph nodes, diffuse pleural thickening in the right pleura, and pleural effusion of the right chest.Diagnosis: A pleural biopsy was performed using a video-assisted thoracoscope. The pathological examination revealed a poorly differentiated squamous cell carcinoma of lung. Further genetic testing identified exon 19 deletion mutation in EGFR with abundance of 0.27%. Meanwhile, immunohistochemical PD-L1 analysis showed a TPS of 90%. Interventions:The patient was initially resistant to EGFR-TKIs but exhibited a rapid and marked response to pembrolizumab.Outcomes: After 5 cycles of pembrolizumab monotherapy, the patient developed Grade 3 immune-related dermatitis, and ICI therapy was suspended.Conclusions: ICI monotherapy could be an effective therapy in SQCC patients with low-abundance of EGFR mutations and PD-L1 over-expression. However, close attention should be paid to immune-related adverse events.Abbreviations: CT = computed tomography, EGFR-TKIs = Epidermal growth factor receptor tyrosine-kinase inhibitors, ICIs = immune-checkpoint inhibitors, NSCLC = non-small cell lung cancer, PD-1 = programmed cell death-1, PD-L1 = programmed death-ligand 1, PET-CT = positron emission tomography-computed tomography, SQCC = squamous cell lung cancer.

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“…Since tumor size has been reported to be inversely correlated to response to EGFR inhibitors and chemotherapy [ 43 - 45 ] in patients and CBA/lac mice, we next investigated the response to cetuximab in more established tumors in both models by delaying treatment initiation to a tumor size of approximately 70 mm 2 . In these more established models, FaDu-S and FaDu-R tumor-bearing mice reached the treatment initiation point on day 18 post inoculation.…”

Section: Resultsmentioning

confidence: 99%

Establishment of head and neck squamous cell carcinoma mouse models for cetuximab resistance and sensitivity

Zaryouh,

Pauw,

Baysal

et al. 2023

Cancer Drug Resist

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Aim: Acquired resistance to the targeted agent cetuximab poses a significant challenge in finding effective anti-cancer treatments for head and neck squamous cell carcinoma (HNSCC). To accurately study novel combination treatments, suitable preclinical mouse models for cetuximab resistance are key yet currently limited. This study aimed to optimize an acquired cetuximab-resistant mouse model, with preservation of the innate immunity, ensuring intact antibody-dependent cellular cytotoxicity (ADCC) functionality. Methods: Cetuximab-sensitive and acquired-resistant HNSCC cell lines, generated in vitro , were subcutaneously engrafted in Rag2 knock-out (KO), BALB/c Nude and CB17 Scid mice with/without Matrigel or Geltrex. Once tumor growth was established, mice were intraperitoneally injected twice a week with cetuximab for a maximum of 3 weeks. In addition, immunohistochemistry was used to evaluate the tumor and its microenvironment. Results: Despite several adjustments in cell number, cell lines and the addition of Matrigel, Rag2 KO and BALB/C Nude mice proved to be unsuitable for xenografting our HNSCC cell lines. Durable tumor growth of resistant SC263-R cells could be induced in CB17 Scid mice. However, these cells had lost their resistance phenotype in vivo . Immunohistochemistry revealed a high infiltration of macrophages in cetuximab-treated SC263-R tumors. FaDu-S and FaDu-R cells successfully engrafted into CB17 Scid mice and maintained their sensitivity/resistance to cetuximab. Conclusion: We have established in vivo HNSCC mouse models with intact ADCC functionality for cetuximab resistance and sensitivity using the FaDu-R and FaDu-S cell lines, respectively. These models serve as valuable tools for investigating cetuximab resistance mechanisms and exploring novel drug combination strategies.

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Larger tumors are associated with inferior progression‐free survival of first‐line EGFR‐tyrosine kinase inhibitors and a lower abundance of EGFR mutation in patients with advanced non‐small cell lung cancer

Cited by 7 publications

References 29 publications

Plasma EGFR mutation abundance affects clinical response to first-line EGFR-TKIs in patients with advanced non-small cell lung cancer

Plasma EGFR mutation abundance affects clinical response to first-line EGFR-TKIs in patients with advanced non-small cell lung cancer

Efficacy and safety of pembrolizumab monotherapy in EGFR-mutant squamous cell lung cancer with PD-L1 over-expression: A case report

Establishment of head and neck squamous cell carcinoma mouse models for cetuximab resistance and sensitivity

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