Rare mutation-dominant compound EGFR-positive NSCLC is associated with enriched kinase domain-resided variants of uncertain significance and poor clinical outcomes

Zhao, Weixin; Song, Ailing; Xu, Yang; Wu, Qian; Liu, Cuicui; Yin, Jiani C.; Ou, Qiuxiang; Wu, Xue; Shao, Yang; Zhao, Xia

doi:10.1186/s12916-023-02768-z

Cited by 6 publications

(7 citation statements)

References 58 publications

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“…Multiple studies have consistently shown that patients with compound EGFR mutations tend to exhibit reduced sensitivity to TKI therapies compared with those with single EGFR mutations [ 6 , 7 , 23 , 24 ]. Furthermore, emerging evidence suggests that the specific types of compound EGFR mutations may be linked to different treatment response patterns [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several studies indicate that individuals with compound EGFR mutations may show reduced responsiveness to TKI therapies compared with those with single mutations [ 6 – 9 ]. Additionally, different treatment efficacies have been associated with different types of EGFR compound mutations [ 10 , 11 ]. While first-generation EGFR -TKIs could be a useful treatment option, recent studies suggest considering afatinib and osimertinib for patients with compound EGFR mutations, depending on their specific cases [ 12 , 13 ] .…”

Section: Introductionmentioning

confidence: 99%

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An epidermal growth factor receptor compound mutation of L858R with S768I in advanced non-small-cell lung cancer: a case report

Boukansa,

Mouhrach,

El Agy

et al. 2024

J Med Case Reports

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Background In the current treatment landscape for non-small cell lung cancers, epidermal growth factor receptor-tyrosine kinase inhibitors have emerged as a well-established treatment option for patients with advanced or metastatic disease. This is particularly true for those with commonly occurring epidermal growth factor receptor mutations. However, the therapeutic efficacy of these agents for so-called rare epidermal growth factor receptor mutations, and in particular those characterized by a high degree of complexity, such as double mutations, remains a subject of clinical uncertainty. Case presentation In this context, we present the case of a 64-year-old man of Moroccan descent, a lifelong non-smoker, diagnosed with metastatic non-small cell lung cancer characterized by a complex epidermal growth factor receptor mutation encompassing L858R and S768I. The patient subsequently underwent afatinib-based treatment, showing notable clinical results. These included a remarkable overall survival of 51 months, with a median progression-free survival of more than 39 months. Conclusions This case report is a compelling testimony to the evolving therapeutic landscape of non-small cell lung cancers, providing valuable insight into the potential therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in the realm of rare and complex epidermal growth factor receptor mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An epidermal growth factor receptor compound mutation of L858R with S768I in advanced non-small-cell lung cancer: a case report

Boukansa,

Mouhrach,

El Agy

et al. 2024

J Med Case Reports

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“…Matched white blood cells from each patient were sequenced in parallel to remove sequencing artifacts, germline variants, and clonal hematopoiesis. Copy number variant (CNV) analysis was conducted by adjusting copy number values according to sample ploidy using FACETS [23,24]. Structural variants (SVs) were detected by FACTERA using default parameters [25].…”

Section: Methodsmentioning

confidence: 99%

“…Copy number variant (CNV) analysis was conducted by adjusting copy number values according to sample ploidy using FACETS [23,24]. Structural variants (SVs) were detected by FACTERA using default parameters [25].…”

Section: Data Processing and Mutation Callingmentioning

confidence: 99%

“…The 30 mutational signatures (v2) listed on the COSMIC website (https://cancer.sanger.ac.uk/signatures/signatures_ v2/) were classified into 10 groups, including age (COSMIC_1), APOBEC (COSMIC_2 and COSMIC_13), BRCA (COSMIC_3), smoking (COSMIC_4), DNA mismatch repair (MMR) deficiency (COSMIC_6, COSMIC_15, COSMIC_20, and COSMIC_26), ultraviolet (COSMIC_7), POLE (COSMIC_10), temozolomide (COSMIC_11), immunoglobulin (COSMIC_9), and others (the rest of the signatures). The contribution of each mutational signature in each patient was calculated as the proportion of the selected signature over all signatures as previously described [24,31]. In addition, we also extracted mutational signature features that had the most cosine similarity to the previously defined COSMIC signatures using the 'NFM' package in R [32].…”

Section: Mutational Signature Analysismentioning

confidence: 99%

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Comprehensive genomic profiling of pulmonary spindle cell carcinoma using tissue and plasma samples: insights from a real‐world cohort analysis

Sun,

Qin,

Wang

et al. 2024

The Journal of Pathology CR

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Pulmonary spindle cell carcinoma (PSCC) is a rare and aggressive non‐small cell lung cancer (NSCLC) subtype with a dismal prognosis. The molecular characteristics of PSCC are largely unknown due to its rarity, which limits the diagnosis and treatment of this historically poorly characterized malignancy. We present comprehensive genomic profiling results of baseline tumor samples from 22 patients histologically diagnosed with PSCC, representing the largest cohort to date. Somatic genetic variant detection was compared between paired plasma samples and primary tumors from 13 patients within our cohort. The associations among genomic features, treatment, and prognosis were also analyzed in representative patient cases. TP53 (54.5%), TERT (36.4%), CDKN2A (27.3%), and MET (22.7%) were most frequently mutated. Notably, 81.8% of patients had actionable targets in their baseline tumors, including MET (22.7%), ERBB2 (13.6%), EGFR (9.1%), KRAS (9.1%), ALK (9.1%), and ROS1 (4.5%). The median tumor mutation burden (TMB) for PSCC tumors was 5.5 mutations per megabase (muts/Mb). TMB‐high tumors (>10 muts/Mb) exhibited a significantly higher mutation frequency in genes such as KRAS, ARID2, FOXL2, and LRP1B, as well as within the DNA mismatch repair pathway. The detection rates for single nucleotide variants and structural variants were comparable between matched tumor and plasma samples, with 48.6% of genetic variants being mutually identified in both sample types. Additionally, a patient with a high mutation load and positive PD‐L1 expression demonstrated a 7‐month survival benefit from chemoimmunotherapy. Furthermore, a patient with an ALK‐rearranged tumor achieved a remarkable 3‐year progression‐free survival following crizotinib treatment. Overall, our findings deepen the understanding of the complex genomic landscape of PSCC, revealing actionable targets amenable to tailored treatment of this poorly characterized malignancy.

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Simulation analysis of EGFR mutation detection: Oncomine Dx target test and AmoyDx panel impact on lung cancer treatment decisions

Hirotsu,

Nakagomi,

Nagakubo

et al. 2024

Sci Rep

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Lung cancer is a leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor (EGFR) driver mutations are crucial for treatment decisions for patients with non-small cell lung cancer (NSCLC). This study aimed to assess the differences in EGFR mutation detection between two companion diagnostic (CDx) tests—the Oncomine Dx Target Test (ODxTT) and the AmoyDx Pan Lung Cancer PCR Panel—and their impact on treatment applicability. To this end, we used an in-house targeted sequencing dataset of 282 samples from 127 EGFR-mutated NSCLC patients to simulate the concordance between the EGFR variants targeted by the ODxTT and AmoyDx panel, the oncogenicity of the variants, and their therapeutic potential. Of the 216 EGFR mutations identified by the in-house panel, 51% were detectable by both CDx tests, 3% were specific to ODxTT, and 46% were not targeted by either test. Most non-targeted mutations did not have oncogenicity and were located outside exons 18–21. Notably, 95% of the mutations detectable by both tests had potential oncogenicity. Furthermore, among the 96 patients harboring actionable EGFR mutations, 97% had mutations detectable by both CDx tests and 1% by ODxTT, while 2% had mutations not covered by either test. These findings suggest that while both CDx tests are effective in detecting almost all actionable EGFR mutations, ODxTT provides slightly broader coverage. These results emphasize the importance of selecting appropriate CDx tests to inform treatment decisions for EGFR-positive NSCLC patients.

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Rare mutation-dominant compound EGFR-positive NSCLC is associated with enriched kinase domain-resided variants of uncertain significance and poor clinical outcomes

Cited by 6 publications

References 58 publications

An epidermal growth factor receptor compound mutation of L858R with S768I in advanced non-small-cell lung cancer: a case report

An epidermal growth factor receptor compound mutation of L858R with S768I in advanced non-small-cell lung cancer: a case report

Comprehensive genomic profiling of pulmonary spindle cell carcinoma using tissue and plasma samples: insights from a real‐world cohort analysis

Simulation analysis of EGFR mutation detection: Oncomine Dx target test and AmoyDx panel impact on lung cancer treatment decisions

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