Successful treatment of a patient with Li–Fraumeni syndrome and metastatic lung adenocarcinoma harboring synchronous EGFR L858R and ERBB2 extracellular domain S310F mutations with the pan-HER inhibitor afatinib

Jia, Yuxia; Ali, Siraj M.; Saad, S.; Chan, Courtney A; Miller, Vincent A.; Halmos, Balázs

doi:10.4161/cbt.29173

Cited by 11 publications

(6 citation statements)

References 28 publications

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“…Affected breast cancer at 44, gluteal schwannoma at 46 and atypical leiomyoma. Sister and Aunt with breast cancer at 40s; Cousin with brain tumour at a young age; Mother with leukaemia.Jia, et al 2014 [53] TP53 exon 19 deletion3422ProbandF51WhiteNSADCL858RProband: bilateral breast cancers and malignant fibrous histiocytoma affected. Mother, maternal aunts, two first cousins and maternal grandmother died of early-onset cancers (< 60 years)Michalarea, et al 2014 [54] TP53 p.H179Y3523ProbandM55NRNSADC19delT790 M mutation (post-TKI) detected; No somatic alterations on HER2 , PI3KCA , BRAF , KRAS or ALK genes.…”

Section: Resultsmentioning

confidence: 99%

“…The median age of the index patients was 34 years old at the diagnosis of lung cancer (range 22–57), and females (7/9) and never-smokers (7/9) predominated. One case had concurrent somatic EGFR activating mutation and HER2 point mutation [53]. Usually, these two driver mutations occur mutually exclusively [83]; but in this case may result from defective DNA repair due to TP53 mutation.…”

Section: Discussionmentioning

confidence: 99%

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Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta-analysis and literature review

et al. 2019

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Background: Accumulating evidence indicates inherited risk in the aetiology of lung cancer, although smoking exposure is the major attributing factor. Family history is a simple substitute for inherited susceptibility. Previous studies have shown some possible yet conflicting links between family history of cancer and EGFR mutation in lung cancer. As EGFR-mutated lung cancer favours female, never-smoker, adenocarcinoma and Asians, it may be argued that there may be some underlying genetic modifiers responsible for the pathogenesis of EGFR mutation. Methods: We searched four databases for all original articles on family history of malignancy and EGFR mutation status in lung cancer published up to July 2018. We performed a meta-analysis by using a random-effects model and odds ratio estimates. Heterogeneity and sensitivity were also investigated. Then we conducted a second literature research to curate case reports of familial lung cancers who studied both germline cancer predisposing genes and their somatic EGFR mutation status; and explored the possible links between cancer predisposing genes and EGFR mutation. Results: Eleven studies have been included in the meta-analysis. There is a significantly higher likelihood of EGFR mutation in lung cancer patients with family history of cancer than their counterparts without family history, preferentially in Asians (OR = 1.35[1.06-1.71], P = 0.01), those diagnosed with adenocarcinomas ((OR = 1.47[1.14-1.89], P = 0.003) and those with lung cancer-affected relatives (first and second-degree: OR = 1.53[1.18-1.99], P = 0.001; first-degree: OR = 1.76[1.36-2.28, P < 0.0001]). Familial lung cancers more likely have concurrent EGFR mutations along with mutations in their germline cancer predisposition genes including EGFR T790 M, BRCA2 and TP53. Certain mechanisms may contribute to the combination preferences between inherited mutations and somatic ones. Conclusions: Potential genetic modifiers may contribute to somatic EGFR mutation in lung cancer, although current data is limited. Further studies on this topic are needed, which may help to unveil lung carcinogenesis pathways. However, caution is warranted in data interpretation due to limited cases available for the current study.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta-analysis and literature review

et al. 2019

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“…The two patients were respectively treated with trastuzumab in combination with endocrine therapy or pertuzumab and endocrine therapy, and both achieved a prolonged response 23,24. A metastatic lung adenocarcinoma patient harboring EGFR L858R and ERBB2 S310F mutations was treated with afatinib and achieved a rapid, complete, and durable response both clinically and radiographically 25. Moreover, a lung adenocarcinoma case harboring the HER2 S310Y mutation who was treated with afatinib has been reported 19.…”

Section: Discussionmentioning

confidence: 97%

Clinical benefit from afatinib in an advanced squamous cell lung carcinoma patient harboring <em>HER2</em> S310Y mutation: a case report

Gao¹,

Ai-hong²,

Zhu³

et al. 2018

OTT

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BackgroundHER2 mutations are identified in approximately 2% of non-small-cell lung cancer (NSCLC) cases and are predominantly observed in non-smokers, females, and adenocarcinoma patients. Although afatinib is recommended for treating NSCLC patients with HER2 mutation, the therapy is most efficacious in patients harboring HER2 exon 20 insertions, especially the in-frame insertion YVMA. Research on the treatment of the extracellular domain mutation is relatively rare.Case presentationWe discuss a 76-year-old Chinese man with a heavy-smoking history who was diagnosed with stage IV squamous cell lung carcinoma. First-line treatment with the angiogenesis inhibitor endostar and systemic chemotherapy with docetaxel plus cisplatin were administered, but the patient ceased treatment because of chemotherapy-induced adverse events. Based on the test result from an amplification refractory mutation system PCR, EGFR-inhibitor icotinib was prescribed, but there was still no evidence of a response. Then, next-generation sequencing identified an HER2 S310Y mutation, and afatinib therapy resulted in a gradual, but substantial reduction in tumor size.ConclusionThis is the first published case report of the successful management of HER2 S310Y mutation squamous cell lung carcinoma with afatinib. Considering the fact that this rare HER2 mutation clinically benefited from afatinib treatment, attention should be paid to the incidence of HER2 in NSCLC patients with inconsistent histological characteristics compared with those previous published. With the guidance of a precise diagnosis, we should realize the significance of other HER2 gene mutations and next-generation sequencing as a diagnostic method.

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“…Therefore in 30% of patients, liquid biopsy identified additional therapies that would not have been detected on standard molecular testing. Within this context, Lung 06 may be more amenable to afatinib, evidenced by the success of afatinib in treating metastatic lung adenocarcinoma harboring EGFR (p.L858R) and ERBB2 (p.S310F) co-mutations [ 53 ]. Lung 02 could be treated with BRAF inhibitors as a rescue regimen to EGFR inhibitors, hence broadening the therapeutic options.…”

Section: Discussionmentioning

confidence: 99%

Analytical and clinical validation of a custom 15-gene next-generation sequencing panel for the evaluation of circulating tumor DNA mutations in patients with advanced non-small-cell lung cancer

Chow

Abidin²,

Kow

et al. 2022

PLoS ONE

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Background This is a pilot proof-of-concept study to evaluate the utility of a custom 15-gene circulating tumor DNA (ctDNA) panel as a potential companion molecular next-generation sequencing (NGS) assay for identifying somatic single nucleotide variants and indels in non-small-cell lung cancer (NSCLC) patients. The custom panel covers the hotspot mutations in EGFR, KRAS, NRAS, BRAF, PIK3CA, ERBB2, MET, KIT, PDGFRA, ALK, ROS1, RET, NTRK1, NTRK2 and NTRK3 genes which serve as biomarkers for guiding treatment decisions in NSCLC patients. Method The custom 15-gene ctDNA NGS panel was designed using ArcherDX Assay Designer. A total of 20 ng or 50 ng input ctDNA was used to construct the libraries. The analytical performance was evaluated using reference standards at different allellic frequencies (0.1%, 1%, 5% and parental). The clinical performance was evaluated using plasma samples collected from 10 treatment naïve advanced stage III or IV NSCLC patients who were tested for tissue EGFR mutations. The bioinformatics analysis was performed using the proprietary Archer Analysis Software. Results For the analytical validation, we achieved 100% sensitivity and specificity for the detection of known mutations in the reference standards. The limit of detection was 1% allelic frequency. Clinical validation showed that the clinical sensitivity and specificity of the assay for detecting EGFR mutation were 83.3% and 100% respectively. In addition, the NGS panel also detected other mutations of uncertain significance in 6 out of 10 patients. Conclusion This preliminary analysis showed that the custom 15-gene ctDNA NGS panel demonstrated good analytical and clinical performances for the EGFR mutation. Further studies incorporating the validation of other candidate gene mutations are warranted.

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Successful treatment of a patient with Li–Fraumeni syndrome and metastatic lung adenocarcinoma harboring synchronous EGFR L858R and ERBB2 extracellular domain S310F mutations with the pan-HER inhibitor afatinib

Cited by 11 publications

References 28 publications

Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta-analysis and literature review

Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta-analysis and literature review

Clinical benefit from afatinib in an advanced squamous cell lung carcinoma patient harboring <em>HER2</em> S310Y mutation: a case report

Analytical and clinical validation of a custom 15-gene next-generation sequencing panel for the evaluation of circulating tumor DNA mutations in patients with advanced non-small-cell lung cancer

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