Response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation: A case report

BACKGROUND Although common in lung cancer,somatic epidermal growth factor receptor(EGFR)mutations are rarely found in colorectal cancer,occurring in approximately 3%of cases.Treatment with anti-EGFR antibodies is commonplace,but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal cancer.Here we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA analysis.CASE SUMMARY A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair,scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic metastases.Next generation sequencing revealed a RAS/RAF wild-type,microsatellite stable,PD-L1 negative malignancy.Mutations in TP3 and APC were also identified,as well as EGFR amplification.Cell-free DNA analysis revealed an EGFR T790M mutation.She was unable to tolerate first-line treatment with panitumumab,5-fluorouracil and leucovorin,progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab,and was unable to tolerate third-line treatment with regorafenib.She was started on fourth-line treatment with off-label osimertinib,with clinical response–decrease in size of hepatic metastases and a pericardial effusion.She remained on treatment with osimertinib for seven months.CONCLUSION This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.

Sequential occurrence of T790M mutation and small cell lung cancer transformation in EGFR-positive lung adenocarcinoma:A case report

BACKGROUND The emergence of secondary drug resistance when treating epidermal growth factor receptor(EGFR)mutated non-small cell lung cancer(NSCLC)using EGFRtyrosine kinase inhibitors(EGFR-TKIs),seriously affects the therapeutic efficacy and survival of patients.Here,we report a case of advanced NSCLC focusing on the application of multiple biopsy modalities to reveal the development of multiple resistance mechanisms during targeted therapies.CASE SUMMARY A 54-year-old male patient presented with EGFR 19Del-mutated advanced lung adenocarcinoma,and exhibited the development of a T790M mutation during initial TKI treatment.Following 3 mo of Osimertinib treatment,a mixed response was observed.Tissue biopsy of the progressive lesion showed transformation to small cell lung cancer(SCLC)harboring RB1 and TP53 mutations,with loss of the original T790M mutation.A standard chemotherapy regimen with Anlotinib for SCLC was administered.Repeat biopsy revealed adenocarcinoma combined with SCLC after tumor progression.The patient’s overall survival was 24 mo.CONCLUSION Multiple biopsy modalities can reveal the development of multiple resistance mechanisms which help with treatment decision-making.Comprehensive treatment regimens according to the drug resistance mechanism significantly improved the prognosis of such patients.

Significant benefits of osimertinib in treating acquired resistance to first-generation EGFR-TKIs in lung squamous cell cancer: A case report

BACKGROUND Lung squamous cell cancer(LSCC)rarely harbors epidermal growth factor receptor(EGFR)mutations,even much rarer for acquired T790M mutation.Although clinical trials of AURA series illustrated that non-small cell lung cancer(NSCLC)with EGFR T790M mutation can benefit from osimertinib,only five LSCC patients were enrolled in total;moreover,the efficacy for LSCC was not shown in the results.Therefore,the response of LSCC to osimertinib is still unclear to date.CASE SUMMARY We report an LSCC case with T790M-related acquired resistance after treatments with first-generation EGFR-tyrosine kinase inhibitors(EGFR-TKIs)and benefited from osimertinib significantly.A 63-year-old Chinese man was diagnosed with stage IV(cT2N2M1b)LSCC harboring an EGFR exon 19-deletion mutation.Following disease progression after gefitinib and multi-line chemotherapy,rebiopsy was conducted.Molecular testing of EGFR by amplification refractory mutation system-polymerase chain reaction detected the exon 19-deletion without T790M mutation.Therefore,the patient was given erlotinib,but progression developed only 3 mo later.Then the frozen re-biopsy tissue was tested by next-generation sequencing(NGS),which detected an EGFR T790M mutation.However,he was very weak with symptoms of dysphagia and cachexia.Fortunately,osimertinib was started,leading to alleviation from the symptoms.Four months later,normal deglutition was restored and partial response was achieved.Finally,the patient achieved an overall survival time period of 29 mo.CONCLUSION Our findings highlight that EGFR T790M mutation may also be an important acquired drug resistance mechanism for LSCC and offer direct evidence of the efficacy of osimertinib in LSCC with T790M mutation.NGS and better preservation conditions may contribute to higher sensitivity of EGFR T790M detection.

Epidermal growth factor receptor (EGFR) T790M mutation identified in plasma indicates failure sites and predicts clinical prognosis in non-small cell lung cancer progression during first-generation tyrosine kinase inhibitor therapy: a prospective observational study

Introduction:Plasma circulating tumor DNA(ctDNA)is an ideal approach to detecting the epidermal growth factor receptor(EGFR)T790M mutation,which is a major mechanism of resistance to first-generation EGFR-tyrosine kinase inhibitor(TKI)therapy.The present study aimed to explore the association of ctDNA-identified T790M mutation with disease failure sites and clinical prognosis in non-small cell lung cancer(NSCLC)patients.Methods:Patients who progressed on first-generation TKIs were categorized into failure site groups of chest limited(CF),brain limited(BF)and other(OF).Amplification refractory mutation system(ARMS)and droplet digital PCR(ddPCR)were used to identify the T790M mutation in ctDNA.Prognosis was analyzed with Kaplan-Meier methods.Results:Overall concordance between the two methods was 78.3%.According to both ARMS and ddPCR,patients in the OF group had a significantly higher rate of T790M mutation than did patients in the BF and CF groups(P<0.001),and a significantly higher T790M mutation rate was also observed in OF-group patients than in those in the CF and BF groups(P<0.001).AZD9291 was found to be an excellent treatment option and yielded the longest survival for T790M+patients in all groups who had progressed on EGFR-TKIs;for other treatments,the prognosis of T790M−patient subgroups varied.Conclusions:The present study demonstrates that T790M mutation in ctDNA is associated with failure sites for NSCLC patients after EGFR-TKI therapy and indicates that both failure site and T790M mutational status greatly influ-ence treatment selection and prognosis.