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RESEARCH PRODUCT
Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion
Ramon PerezKen ChenAbel Gonzalez-perezFunda Meric-bernstamShuying LiuGordon B. MillsEva CarrascoAna M. Gonzalez-anguloAgda Karina EterovicAngel Guerrero-zotanoJoan AlbanellDavid CasadevallJose Ignacio ChaconFederico RojoRosalia CaballeroAleix PratEduardo Martínez De DueñasAna LluchI. BlancasSilvia AntolínPaula López-serraXiaofeng Zhengsubject
0301 basic medicineAdultCancer ResearchSkin NeoplasmsBioinformaticsBone NeoplasmsBreast Neoplasmsmedicine.disease_causeMetastatic tumours03 medical and health sciences0302 clinical medicineBreast cancerBreast cancermedicineBiomarkers TumorHumansProspective StudiesPAM50AgedAged 80 and overMutationIntrinsic subtypebusiness.industryHuman epidermal growth factorBrain NeoplasmsClonal architectureHigh-Throughput Nucleotide SequencingClonal remodellingMiddle Agedmedicine.diseasePrognosisGene Expression Regulation Neoplastic030104 developmental biologyOncology030220 oncology & carcinogenesisLymphatic MetastasisCancer cellMutationCancer researchFemaleNeoplasm Recurrence LocalClinical subtypeHeterogeneitybusinessHormoneFollow-Up Studiesdescription
Background: Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples. Methods: A total of 57 paired primary and metastatic tumours from GEICAM/2009-03 (ConvertHER, NCT01377363) study participants with centrally assessed CS (n = 57) and IS (n = 46) were analysed. Targeted capture and next-generation sequencing of 202 genes on formalin-fixed paraffin-embedded samples was performed. The cancer cell fraction (CCF) of mutations in primary and metastatic pairs was estimated as a surrogate of tumour clonal architecture. Changes in mutation CCF between matched primary and metastatic tumours were analysed in the presence or absence of subtype conversion. Findings: CS conversion occurred in 24.6% and IS conversion occurred in 36.9% of metastases. Primary tumours and metastases had a median of 11 (range, 3-29) and 9 (range, 1-38) mutations, respectively (P = 0.05). Overall, mutations in metastases showed a higher estimated CCF than in primary tumours (median CCF, 0.51 and 0.47, respectively; P = 0.042), consistent with increased clonal homogeneity. The increase in mutation CCF was significant in CS-converted (P = 0.04) but not in IS-converted (P = 0.48) metastases. Clonal remodelling was highest in metastases from hormone receptorepositive and human epidermal growth factor 2 (HER2)-positive tumours (P = 0.006). Conclusions(1): Mutations in BC metastases showed significantly higher estimated CCF than primary tumours. CCF changes were more prominent in metastases with CS conversion. Our findings suggest that changes in BC subtypes are linked to clonal remodelling during BC evolution. (C) 2019 Elsevier Ltd. All rights reserved.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-01-01 |