Rapid response to fifth-line brigatinib plus entrectinib in an ALK-rearranged lung adenocarcinoma with an acquired ETV6-NTRK3 fusion: a case report.

The management of non-small cell lung cancer (NSCLC), specifically targeting the anaplastic lymphoma kinase (ALK) with tyrosine kinase inhibitors (TKIs), is challenged by the emergence of therapeutic resistance. Resistance mechanisms to ALK TKIs can be broadly classified into ALK-dependent and ALK-independent pathways. Here, we present a case with lung adenocarcinoma (LUAD) harboring an ALK rearrangement. The patient had developed resistance to sequential ALK TKI therapies, with an acquired ETV6-NTRK3 (E4:N14) fusion as a potential mechanism of ALK-independent resistance to lorlatinib. Subsequently, the patient was treated with the combination of brigatinib plus entrectinib and demonstrated a positive response, achieving an 8-month progression-free survival. Our case provides a potential treatment option for LUAD patients with ALK rearrangements and highlights the utility of next-generation sequencing (NGS) in uncovering genetic alterations that can guide the selection of effective treatment strategies.

A Primary Lung and Breast Cancer Patient with Germline EGFR R776H Mutation: A Case Report and Literature Review.

For advanced non-small cell lung cancer (NSCLC) patients with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or the exon 21 L858R mutation), tyrosine kinase inhibitors (TKIs) are the standard therapies. However, EGFR germline mutations are extremely rare in lung cancer, and the effective therapy is unclear. This study reports a patient with primary breast and lung cancer carried rare germline EGFR R776H and somatic L861Q mutation, who benefit from EGFR TKIs. Her family cancer history review demonstrated that her three out of four sisters with lung cancer were positive for EGFR R776H. Interestingly, only her healthy sister had type O blood, different from other sisters with type B blood. Our study provides a meaningful insight into the potential treatment option for patients with germline EGFR R776H and somatic L861Q mutation and highlights the importance of next-generation sequencing (NGS) in discovering rare genetic alterations to guide the prevention of genetic disease.

NGS-Based ctDNA Profiling After the Resistance of Second-Line Osimertinib for Patient with EGFR-Mutated Pulmonary Adenocarcinoma.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is effective in EGFR T790M positive non-small-cell lung cancer (NSCLC). Despite the efficacy of osimertinib, patients inevitably develop resistance and the mechanisms of osimertinib resistance are heterogeneous. Here, we report that a lung adenocarcinoma patient with EGFR L858R mutation who was treated with second-line osimertinib therapy acquired multiple resistance to osimertinib by the non-invasive circulating tumor DNA (ctDNA) genotyping. This case provides the possible mechanisms of osimertinib resistance that occur during the disease progression and supports the longitudinal monitoring of ctDNA for the detection of novel acquired resistance and tumor heterogeneity.

[Clinical Value of Cerebrospinal Fluid ctDNA in Patients 
with Non-small Cell Lung Cancer Meningeal Metastasis].

BACKGROUND: The mortality rate of lung cancer meningeal metastasis is extremely high. Circulating tumor DNA (ctDNA) has been confirmed to be contain the genomic alterations present in tumors and has been used to monitor tumor progression and response to treatments. Due to the presence of blood-brain barrier and other factors, peripheral blood ctDNA cannot reflect the information of brain lesions for patients with meningeal metastases. However, cerebrospinal fluid ctDNA as a test sample can better reflect the genetic status of intracranial tumors and guide clinical targeted treatment of intracranial lesions. This study explored the feasibility of cerebrospinal fluid ctNDA for evaluating non-small cell lung cancer (NSCLC) meningeal metastasis and the potential clinical value of cerebrospinal fluid ctDNA detection in NSCLC meningeal metastasis. METHODS: A total of 21 patients with NSCLC meningeal metastasis were included. Tumor genomic variation was performed on the cerebrospinal fluid and peripheral blood samples of patients by second-generation gene sequencing technology. The situation was examined, and pathological evaluation of cerebrospinal fluid cytology and head magnetic resonance imaging (MRI) enhanced examination were performed. RESULTS: ctDNA was detected in the cerebrospinal fluid of 21 patients. The sensitivity of cerebrospinal fluid ctDNA detection was superior to cytology in the diagnosis of meningeal metastasis (P<0.001). The detection rate and gene mutation abundance of cerebrospinal fluid were higher than plasma (P<0.001). Cerebro-spinal fluid had a unique genetic profile. In 6 patients with dynamic detection, changes of ctDNA allele fraction occurred at the same time or earlier than clinical disease changes, which could timely monitor drug resistance mechanism and relapse trend. CONCLUSIONS: The detection rate of ctDNA in cerebrospinal fluid is higher than that in cytology and imaging. The detection of ctDNA in cerebrospinal fluid can reveal the specific mutation map of meningeal metastasis lesions. The dynamic monitoring of ctDNA in cerebrospinal fluid has hint significance for clinical response of lung cancer patients.

Molecular diagnosis and clinical outcome of a lung cancer patient with TP53-E285K mutated Li-Fraumeni syndrome harboring a somatic EGFR-KDD mutation.

OBJECTIVES: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition, mostly caused by germline TP53 mutations. Lung adenocarcinoma (ADC) has been identified as the most frequent LFS-related cancer outside the common LFS core spectrum. EGFR-kinase domain duplication (KDD) is rare in lung cancer and the effective therapy for LFS patients with EGFR-KDD mutated ADC is unclear. This study reports the first case of a TP53-mutated LFS patient with confirmed family history, developing advanced lung ADC harboring EGFR-KDD. MATERIALS AND METHODS: The patient's lung tumor, lymph nodes, liquid biopsies and germline control sample at various disease stages were subjected to next-generation sequencing (NGS). The TP53 germline mutation was confirmed using the peripheral blood of the patient's relatives by Sanger sequencing. RESULTS: A rare EGFR-KDD somatic mutation that was missed in the routine EGFR hotspots test, and a TP53-E285K temperature-sensitive germline mutation were identified by NGS. The patient was diagnosed with breast cancer in 2006 and her family cancer history review revealed that seven out of 13 relatives were diagnosed or died from LFS-spectrum cancers before the age of 45 years. Three of the six relatives were positive for the TP53-E285K germline mutation. This patient received multi-line chemotherapy followed by anlotinib, a multi-target tyrosine kinase inhibitor, upon the identification of EGFR-KDD, and achieved an overall survival of 18 months. CONCLUSIONS: Our study highlights the importance of NGS in discovering rare genetic alterations to guide treatment decision-making, and provides meaningful insight into the potential treatment options for LFS patients with EGFR-KDD mutations.