Background: Patients with disease progression on first-generation tyrosine kinasein hibitors (TKIs) usually have apoorprognosis. The mechanisms of a cquiredresistance toepidermal growth factorreceptor(EGFR)-TKIshavebeenwidelyreported;however, reports of acquired rearrangement-during-transfection (RET) fu- sion are rare. Case Summary: We report a case of lung adenocarcino-ma with a novel sterile alpha motif domain containing 5 (SAMD5)-RET fusion as a mechanism of resistance to the firstgenera- tionEGFRTKI,gefitinib.ShewasdiagnosedwithstageIVA(cT- 3N2M1a) lung adenocarcinoma with metastases to the right lung andrightpleuralcavity. Capture-basedn extgenerations equencing (NGS) onpleuraltumor sample revealedamolecula ralteration in exon19deletion(19del)ofEGFR. Gefitinibtreatment was initi-ated. Two months later, disease progression was confirmed, with enlargementofthelungtumorandincreasedpleuraleffusion,a nd NGS of tumor tissue revealed SAMD5-RET fusion with allelic frequency of 14.9%. Although the patient received the best sup- portive treatment, she died with an overall survival of 9 months. Conclusion: This case extended the understanding of the mechanisms of acquired resistance to first-generation EGFR-TKIs. Re-biopsy and NGS may provide the basis for accurate treatment of advanced NSCLC.
2. BackgroudIn non-small cell lung cancer (NSCLC), acquired epidermal growth factor receptor (EGFR) T790M mutation was found in almost 50%–60% of the EGFRtyrosine kinase inhibitor (TKI) resistant cases [1], followed by human epidermal growth factor receptor2(HER2)amplification(8%–13%)[2],mesenchymaltoepithelial transition factor (MET) amplification (5%–10%) [3,4], small cell lung cancer (SCLC) transformation (5%) [5], endothelial-mesenchymal transition (EMT) (5%) [5], phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit (PIK3CA) mutation (1%–2%) [5] and v-raf murine viral oncogene homolog B1 (BRAF) mutation (1%) [6]. However, some of the resistance mechanismsarestillunknown[7].Here,wepresentthecaseofan EGFR-mutated non-small cell lung cancer (NSCLC) in a patient who developed a novel rearrangement-during-transfection (RET) fusion after progression on a first-generation EGFR-TKI.
3. Case PresentationA 47-year-old never-smoker woman was admitted on April 20, 2017duetorightchestpain,coughanddyspnea.Rightlungbreath sounds decreased, percussion dullness. She was diagnosed with stage IVA(cT3N2M1a) lung adenocarcinoma with metastases to rightlungandrightpleural(Figure1,2).Capture-basednextgenerationsequencing(NGS)onpleuraltumorsamplerevealedamolecularalterationinexon19deletion(19Del)ofEGFR(19exon p. E746_A750del in-frame deletion mutation, c.2235_2249del, p. Glu746_Ala750del,allelicfrequency:63.08%).Subsequently,the patientwasstartedongefitinib250mgonceaday(QD)fromMay 2017.Aftertwomonthsoftreatment,thepatient'scoughanddyspneaworsened.Diseaseprogressionwasconfirmed,withenlargementof thelung tumorand increasedpleural effusion.(Figure 1). Adenocarcinoma was confirmed in the rebiopsy specimen of the pleura, and NGS of tumor tissue revealed a sterile alpha motif domain containing 5 (SAMD5)-RETmutation with an allelic frequencyofthe14.9%,andtheabsenceoftheEGFRmutation(Fig- ure 3).Therefore, the treatment regimen was changed to gefitinib 250mgQD+cabozantinib80mgQD,andthesymptomsofchest pain and dyspnea were alleviated. The patient progressed with a progression-free survival of 6 months in January 2018.Although thepatientreceivedthebestsupportivetreatment,shediedinApril 2018 with an overall survival of 9 months.
4. DiscussionOur patient was diagnosed with lung adenocarcinoma and harboredtheEGFR19delmutationaccordingtotargetedsequencing on initial examination. The effect was poor and the disease progressedrapidlyaftertreatmentwithgefitinib.Biopsyandtargeted sequencing were repeated, and, interestingly, we found a novel SAMD5-RET fusion, and the original EGFR mutation was lost. We suspected whether the new mutation was induced following gefitinib treatment. Zhu et al. identified 86 receptor tyrosine kinase (RTK) fusions as acquired resistance mechanisms to EGFR TKIs in NSCLC from the literature, and RET fusions account for 43%oftheRTKfusions[8].AmongtheacquiredRETfusioncases(SupplementaryTable1)[8-21],coiled-coildomaincontaining 6(CCDC6)-RET(25/42,59.5%)wasthemostcommon,followed by nuclear receptor coactivator 4 (NCOA4)-RET (10/42, 25.0%) and tripartite motif containing 24 (TRIM24)-RET (3/42, 7.1%). SAMD5-RETfusionhasneverbeenreportedbefore.Mostof the acquired fusions emerged after osimertinib treatment (21/42, 50.9%).AlthoughcaseswithacquiredRETmutationmediatedresistancefollowinggefitinibtherapyarerare,furtherstudiesonthe mechanism are warranted. However, even after administering gefitinib treatment combined with cabozantinib, the disease progressed rapidly, indicating that broad-spectrum antitumor drugs have a poor efficacy in patients with EGFR 19del mutation or RET fusion. Previous research foundthat28%ofpatientswithRETrearrangementsexperienced apartialresponseaftertreatmentwithcabozantinib[22].Cabozantinibaloneorincombinationwitherlotinibhassuperiorefficacyto erlotinib alone in EGFR wild-type advanced lung cancer patients [19].However,cabozantinibmighthavehadnoremarkableeffect onourpatient.Previouscasesreportedthatpatientswithacquired RETfusionfollowingtreatmentwitherlotinib,icotinib,orafatinib combinedwithcabozantinibachievedstabledisease(SD)foronly 2– 7months[9,13,15].However,a69-year-oldmalewithCCDC6- RET achieved partial response after receiving osimertinib plus cabozantinib [11]. Two patients achieved partial response (78%) after receiving BLU-667, a selective RET inhibitor [15]. Moreover, our previous research reported a female patient, harboring kinesin-1 heavy chain (KIF5B)-RET fusion with highly positive PD-L1staining,whoachievedapartialresponseformorethanfive
5. ConclusionWereportedaspecialcaseofacquiredRETrearrangementin an EGFR-mutated NSCLC patient whose disease progressed on first-generation EGFRTKI, gefitinib. This case indicates thatrare new mutations may be induced during treatment with EG- FR-TKIs, and that the EGFR mutationitself may be suppressed after treatment. In addition, patients with RET fusion may experiencerapiddiseaseprogressionandmaybepronetopleural,lymph node,anddistantmetastases.Repeatedbiopsiesandgenetestsare necessary for lungcancer patients with rapid disease progression during treatment.
6. FundingThis work was supported by the Central Government Guided Lo- calScienceandTechnologyFreeExplorationProjectsofSichuan Province(2020ZYD005), the National Natural Science Foun- dation of China (81700095, 91859203, 81871890), the NationalKeyDevelopmentPlanforPrecisionMedicineResearchofChina (2017YFC0910004),theNationalMajorSci-TechProjectofChina(2017ZX10103004-012)andtheMajorScienceandTechnolo- gy Innovation Project of Chengdu City (2020-YF08-00080-GX). Department of Science and Technology of Sichuan Prov- ince(2021YFS0130
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