Ana Lluch1, Ana M González-Angulo2, David Casadevall3, Agda K Eterovic2, Eduardo Martínez de Dueñas4, Xiaofeng Zheng2, Ángel Guerrero-Zotano5, Shuying Liu2, Ramón Pérez6, Ken Chen2, Jose Ignacio Chacón7, Gordon B Mills8, Silvia Antolín9, Isabel Blancas10, Paula López-Serra11, Eva Carrasco11, Rosalía Caballero11, Aleix Prat12, Federico Rojo13, Abel Gonzalez-Perez14, Funda Meric-Bernstam15, Joan Albanell16. 1. Hospital Clínico Universitario de Valencia, Valencia, Spain; GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Spain; Universidad de Valencia, Valencia, Spain; Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain. 2. MD Anderson Cancer Center, Houston, TX 77030, USA. 3. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Spain; IMIM Hospital del Mar Medical Research Institute; Barcelona, Spain; Medical Oncology Department Hospital del Mar, Barcelona, Barcelona, Spain. 4. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Hospital Provincial de Castellón, Castellón, Spain. 5. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Instituto Valenciano de Oncología, Valencia, Spain. 6. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Hospital Universitario Quirón de Madrid, Madrid, Spain. 7. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Hospital Virgen de la Salud, Toledo, Spain. 8. MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology and Institute of Personalized Cancer Therapy, The University of Texas, USA. 9. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Complejo Hospitalario Universitario A Coruña, A Coruña, Spain. 10. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Hospital Clínico San Cecilio, Granada, Spain. 11. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain. 12. Medical Oncology Department, Hospital Clínic of Barcelona, Barcelona, Spain. 13. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Spain; Fundación Jiménez Díaz, Madrid, Spain. 14. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Institut de Recerca Biomedica Barcelona, Spain. Electronic address: abel.gonzalez@irbbarcelona.org. 15. MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: fmeric@mdanderson.org. 16. GEICAM (Grupo GEICAM de Investigación en Cáncer de Mama), Madrid, Spain; Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Spain; IMIM Hospital del Mar Medical Research Institute; Barcelona, Spain; Medical Oncology Department Hospital del Mar, Barcelona, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain. Electronic address: 96087@parcdesalutmar.cat.
Abstract
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 receptor-positive and human epidermal growth factor 2 (HER2)-positive tumours (P = 0.006). CONCLUSIONS: 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.
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 receptor-positive and human epidermal growth factor 2 (HER2)-positive tumours (P = 0.006). CONCLUSIONS: 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.
Authors: Allen Li; Jamie M Keck; Swapnil Parmar; Janice Patterson; Marilyne Labrie; Allison L Creason; Brett E Johnson; Molly Downey; George Thomas; Carol Beadling; Laura M Heiser; Annette Kolodzie; Alexander R Guimaraes; Christopher L Corless; Joe W Gray; Gordon B Mills; Raymond C Bergan; Zahi I Mitri Journal: NPJ Precis Oncol Date: 2021-03-26
Authors: Athina Giannoudis; Alexander Sartori; Lee Eastoe; Rasheed Zakaria; Christopher Charlton; Nicholas Hickson; Angela Platt-Higgins; Philip S Rudland; Darryl Irwin; Michael D Jenkinson; Carlo Palmieri Journal: Breast Cancer Res Treat Date: 2021-09-09 Impact factor: 4.872