Background: Osimertinib (AZD9291; Tagrisso) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) known to be effective for patients harboring the EGFR-T790M variant, which is accounts for more than half of the acquired resistance mechanisms to the first generation EGFR-TKIs. However, limited osimertinib resistance-mechanism was reported. Study on potential osimertinib-resistance mechanisms in advanced NSCLC is necessary. Method: This study enrolled eight T790M-positive (tissue validated) patients, treated with osimertinib after first generation EGFR-TKI (Erlotinib, Gefitinib, Icotinib) resistance and progressed rapidly. Serial plasma samples were collected until disease progressed. Plasma DNA was extracted and sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR T790M mutation was defined if mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR T790M mutation. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population. Result: The median progression-free survival (PFS) of these eight rapidly-progressed patients was 3.82 months [95% CI 2.05-5.01] .Targeted capture sequencing of pretreatment ctDNA showed all of the eight patients (100%) were EGFRpositive (Exon19del [n¼6] and L858R [n¼2]), and seven patients (88%) harbored EGFR T790M mutation, except for the only one patient (P006) who showed an extremely low level of ctDNA. During the Osimertinib treatment, five patients (63%) had osimertinib resistancerelated mutations: EGFR C797S (in cis position), G724S, KRAS G12D, PIK3CA E542K, EGFR amplification, and ERBB2 amplification. Among them, two patients had more than one resistance mechanisms: patient P034 had EGFR G724S, KRAS G12D and EGFR amplification, simultaneously; patient P013 had amplification in both EGFR and ERBB2. Other potential resistance mechanisms were identified including EGFR T751I and K754E mutations in P002 and ERBB2 S603 in P013. Notably, the only one patient (P004) who had not been detected to have any known osimertinib resistance mechanism but progressed in 3 months, was demonstrated to harbor a subclonal EGFR T790M mutation by analysis of ctDNA clonal structure. Serial ctDNA monitoring showed mTBI increased when disease progressed in 88% (7/8) patients, except P006, whose mutation were negative at second (stable disease) and third (progressed disease) therapeutic evaluations due to the extremely low level of ctDNA. Conclusion: This study presented comprehensive the resistance mechanism of osimertinib progressed rapidly in ctDNA including multiple mechanisms co-occurred in same patient. Serial monitoring of plasma ctDNA may be a promising approach to explore resistance mechanism and monitored the treatment response of third generation EGFR-TKI.Background: First/second generation EGFR-tyrosine kinase inhibitors (EGFR-TKI) are eventually met with therapeutic fail...

Background There have been few documented cases of combined primitive neuroectodermal and embryonal rhabdomyosarcomas (ERMS) in the uterus. Due to their rarity, there is no consensus on the optimal treatment for patients with primitive neuroectodermal tumor (PNET) and ERMS of the uterus. Studies on treatment and outcome are limited. Case presentation A 32 year-old female presented with heavy vaginal bleeding. Ultrasound revealed an 18 cm uterus with thickened endometrium. Histopathology revealed embryonal rhabdomyosarcoma. She underwent a total abdominal hysterectomy, bilateral salpingectomy, lymph node dissection, and omentectomy. Pathologic review confirmed a tumor with mainly central-type PNET and focally ERMS within the uterus and cervix. She was treated with adjuvant chemoradiation. Conclusion Treatment of the predominant tumor, PNET, should be the primary goal of therapy. Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide with tumor directed radiation may be efficacious for the treatment of this specific high grade uterine sarcoma.

No abstract

Author affiliation was incorrectly published as Chinese Academy of Agricultural Sciences and should be read as Yangzhou University.