Tyrosine kinase inhibitors (TKIs) have greatly improved the survival of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-TKI sensitive mutations such as L858R and exon 19 deletions. The third-generation EGFR-TKI osimertinib, an irreversible TKI, is approved as a therapy for advanced NSCLC with EGFR sensitive mutations. Recently, osimertinib showed antitumor activity against NSCLC in patients harboring an uncommon mutation such as an exon 20 insertion. Herein, we present a patient diagnosed with stage IV NSCLC with an EGFR L858R/V843I mutation complex who benefited remarkably from osimertinib therapy. The patient was a 41-year-old Chinese female who complained of backache in October 2018. Computed tomography (CT) and magnetic resonance imaging (MRI) scans showed a mass in the right lung and brain metastasis. A whole-body bone scan revealed bone metastases. Targeted next-generation sequencing (NGS) of hydrothorax was performed and the coexistence of somatic L858RI and V843I mutations in EGFR exon 21 was discovered on November 13, 2018. Osimertinib therapy (80 mg daily) was administered for 12 months which resulted in an initial partial response (PR). At that point, the right lower lung lesion enlarged, indicating disease progression.Thus, the patient began combination therapy with osimertinib (80 mg daily) and bevacizumab (500 mg daily), leading to disease stabilisation until June 2020. Of note, during treatment, the patient achieved sustained control of metastatic brain and bone lesions. To the best of our knowledge, we report here the first known case of an NSCLC patient with a somatic EGFR L858R/V843I mutation complex who responded well to osimertinib. Our findings provide theoretical guidance and expand the list of potential beneficiaries of EGFR-TKI therapy.
Anaplastic lymphoma kinase (ALK) rearrangement is a common driver mutation in patients with non-small-cell lung carcinoma. 1 Apart from EML4-ALK, which is the most common and best-studied fusion type, 2 many uncommon ALK fusion partners have been discovered recently by next-generation sequencing; however, their clinical significance remains mostly unknown. Here, we present the first case of an LRRC4C-ALK fusion in a patient with lung adenocarcinoma, who responded differently to multiple ALK inhibitors.A 34-year-old male patient, who was a smoker, complained of cough and chest pain in July 2019. Chest computed tomography (CT) scan revealed a 7.2 cm × 5.0 cm mass in the right lung upperfusion in a patient with lung adenocarcinoma and dynamic monitoring of the treatment response. (A) Sequencing reads of ALK and LRRC4C were viewed via integrative genomics viewer. (B) Schematic of the intergenic region of the fusion. (C) Haematoxylin and eosin staining revealed poorly differentiated adenocarcinoma. (D) Immunohistochemical staining by D5F3
Background: Adenosquamous carcinoma of the pancreas (PASC) is a mixed tumor type which contains squamous cell carcinoma and also ductal adenocarcinoma components. PASC is a rare type representing about 1-4% of the total incidence. Due to the rarity of this malignancy, limited genomic data have been performed. In this study, we analyzed the genomic alterations and clinical signatures of PASC. Materials and Methods: Formalin fixed, paraffin embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) assay at OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic alterations including single base substitution, indel, copy number variations, gene fusions and rearrangement were assessed. Tumor mutational burden (TMB) was also analyzed by NGS algorithm. Alterations in homologous recombination repair (HRR) with PASC were analyzed. Results: In total, 31 PASC patients were recruited included 15 females (48.4%) and 16 males (51.6%) with a media age of 59 years old (range 35-78). A total of 32% (10/31) of patients possessed a confirmed cancer-related family history. The most commonly altered genes were KRAS (97%), TP53 (77%), CDKN2A (35%), SMAD4 (23%), FAT3 (13%), CIC (10%) and SPTA1 (10%). The KEGG pathway analysis revealed that those top mutated genes significantly associated with MAPK signaling pathway. 42% (13/31) of the patients had one or more actionable genomic alterations, including BRCA2, STK11, CDKN2A/B, FGFR and PTEN. Germline mutations were identified in 4 patients (13%), including BRCA2 (2/4), SPINK1 (1/4), FANCA (1/4). The most common mutational type was substitution/Indel (56%), followed by truncation (20%) and gene amplification (17%). Three (10%) patients had at least one mutation in HRR genes, including BRCA2 (2/3) and CHEK2 (1/3).The median TMB of patients with PASC was 3.2 muts/Mb (range, 0.5-9.3 muts/Mb). Patients with STK11 alterations had lower value of TMB than STK11 wild type (median TMB 0.85 vs. 3.37 muts/Mb, respectively, P <0.05). In addition, patients with HRR mutations had a significantly higher TMB value than HRR wild type (7.73 vs. 2.73 muts/Mb, respectively, P <0.01). Conclusion: Our study revealed the genomic profiling of the largest sample size of Chinese PASC patients so far. 42% (13/31) of the patients had one or more actionable genomic alterations. HRR pathway alterations are relatively frequent (10%) in PASC and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted. Citation Format: Zheng Wang, Xue Yang, Wei Li, Zheng Wu, Qingyong Ma, Xiaofang Qi, Juan Zhao. Genomic profiling of Chinese adenosquamous carcinoma of the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2659.
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