Somatic mutation, copy number and transcriptomic profiles of primary and matched metastatic estrogen receptor-positive breast cancers.
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.



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.



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).



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.
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Free University of Bruxelles, Brussels, Belgium.
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Fumagalli
Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA.
T R
TR
Wilson
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Free University of Bruxelles, Brussels, Belgium.
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R
Salgado
Department of Biostatistics, Genentech Inc., South San Francisco, CA, USA.
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X
Lu
Department of Biostatistics, Genentech Inc., South San Francisco, CA, USA.
J
J
Yu
Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA.
C
C
O'Brien
Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA.
K
K
Walter
Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA.
L Y
LY
Huw
Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, Milan, Italy.
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C
Criscitiello
Department of Pathology, Institut Jules Bordet, Brussels, Belgium.
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I
Laios
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Free University of Bruxelles, Brussels, Belgium.
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V
Jose
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Free University of Bruxelles, Brussels, Belgium.
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DN
Brown
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Free University of Bruxelles, Brussels, Belgium.
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F
Rothé
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Free University of Bruxelles, Brussels, Belgium.
M
M
Maetens
Breast International Group, Brussels, Belgium.
D
D
Zardavas
Division of Clinical Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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P
Savas
Department of Pathology, Institut Jules Bordet, Brussels, Belgium.
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D
Larsimont
Division of Medical Oncology, Institut Jules Bordet, Brussels, Belgium.
M J
MJ
Piccart-Gebhart
Division of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, France INSERM U1018, CESP, University of Paris, Villejuif, France.
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S
Michiels
Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA.
M R
MR
Lackner
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Free University of Bruxelles, Brussels, Belgium Division of Medical Oncology, Institut Jules Bordet, Brussels, Belgium.
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C
Sotiriou
Division of Clinical Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia sherene.loi@petermac.org.
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Loi
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D009154:Mutation; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen
ER; ESR1; IDO1; PIK3CA; breast cancer; metastatic