D Fumagalli1, T R Wilson2, R Salgado1, X Lu3, J Yu3, C O'Brien2, K Walter2, L Y Huw2, C Criscitiello4, I Laios5, V Jose1, D N Brown1, F Rothé1, M Maetens1, D Zardavas6, P Savas7, D Larsimont5, M J Piccart-Gebhart8, S Michiels9, M R Lackner2, C Sotiriou10, S Loi11. 1. Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Free University of Bruxelles, Brussels, Belgium. 2. Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA. 3. Department of Biostatistics, Genentech Inc., South San Francisco, CA, USA. 4. Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, Milan, Italy. 5. Department of Pathology, Institut Jules Bordet, Brussels, Belgium. 6. Breast International Group, Brussels, Belgium. 7. Division of Clinical Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. 8. Division of Medical Oncology, Institut Jules Bordet, Brussels, Belgium. 9. Division of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, France INSERM U1018, CESP, University of Paris, Villejuif, France. 10. Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Free University of Bruxelles, Brussels, Belgium Division of Medical Oncology, Institut Jules Bordet, Brussels, Belgium. 11. Division of Clinical Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia sherene.loi@petermac.org.
Abstract
BACKGROUND: Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy. MATERIALS AND METHODS: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material. According to the availability of tumor material, samples were characterized using a 120 mutational hotspot qPCR, a 29 gene copy number aberrations (CNA) and a 400 gene expression panels. ESR1 mutations were assayed by droplet digital PCR. Molecular alterations were correlated with overall survival (OS) using the Cox proportional hazards regression models. RESULTS: The median follow-up was 6.4 years (range 0.5-26.6 years). Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. Mutations and CN amplifications were largely concordant between P and matched M (>84%). ESR1 mutations were found in 10.8% of the M but none of the P. Thirteen genes, among which ESR1, FOXA1, and HIF1A, showed significant differential expression between P and M. In P, the differential expression of 18 genes, among which IDO1, was significantly associated with OS (FDR < 0.1). CONCLUSIONS: Despite the large concordance between P and matched M for the evaluated molecular alterations, potential actionable targets such as ESR1 mutations were found only in M. This supports the importance of characterizing the M disease. Other targets we identified, such as HIF1A and IDO1, warrant further investigation in this patient population.
BACKGROUND:Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy. MATERIALS AND METHODS: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material. According to the availability of tumor material, samples were characterized using a 120 mutational hotspot qPCR, a 29 gene copy number aberrations (CNA) and a 400 gene expression panels. ESR1 mutations were assayed by droplet digital PCR. Molecular alterations were correlated with overall survival (OS) using the Cox proportional hazards regression models. RESULTS: The median follow-up was 6.4 years (range 0.5-26.6 years). Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. Mutations and CN amplifications were largely concordant between P and matched M (>84%). ESR1 mutations were found in 10.8% of the M but none of the P. Thirteen genes, among which ESR1, FOXA1, and HIF1A, showed significant differential expression between P and M. In P, the differential expression of 18 genes, among which IDO1, was significantly associated with OS (FDR < 0.1). CONCLUSIONS: Despite the large concordance between P and matched M for the evaluated molecular alterations, potential actionable targets such as ESR1 mutations were found only in M. This supports the importance of characterizing the M disease. Other targets we identified, such as HIF1A and IDO1, warrant further investigation in this patient population.
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