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Genomic Characterization of Primary Invasive Lobular Breast Cancer
Christine Desmedt1, Gabriele Zoppoli2, Gunes Gundem2
1Christine Desmedt, Gabriele Zoppoli, Denis Larsimont, Debora Fumagalli, David Brown, Françoise Rothé, Delphine Vincent, Naima Kheddoumi, Ghizlane Rouas, Samira Majjaj, Sylvain Brohée, Roberto Salgado, Martine Piccart-Gebhart, and Christos Sotiriou, Institut Jules Bordet; Christine Galant, Cliniques Universitaires Saint Luc, Brussels; Peter Van Loo, University of Leuven; Thomas Van Brussel and Diether Lambrechts, VIB Vesalius Research Center, Leuven, Belgium; Gabriele Zoppoli, University of Genoa and Istituto di Ricerca a Carattere Clinico-Scientifico San Martino-National Cancer Institute, Genoa; Giancarlo Pruneri, Patrick Maisonneuve, and Giuseppe Viale, European Institute of Oncology; Marco Fornili and Elia Biganzoli, University of Milan, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale Tumori, Milan, Italy; Gunes Gundem and Peter J. Campbell, Wellcome Trust Sanger Institute, Cambridgeshire; Peter Van Loo, The Francis Crick Institute, London, United Kingdom; Ron Bose, Washington University School of Medicine, St Louis, MO; Otto Metzger, Dana-Farber Cancer Institute, Boston, MA; and François Bertucci, Institut Paoli-Calmettes, Marseille, France. christine.desmedt@bordet.be.
Purpose:
Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications.
Methods:
From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features.
Results:
Besides the high mutation frequency of CDH1 in 65% of tumors, alterations in one of the three key genes of the phosphatidylinositol 3-kinase pathway, PIK3CA, PTEN, and AKT1, were present in more than one-half of the cases. HER2 and HER3 were mutated in 5.1% and 3.6% of the tumors, with most of these mutations having a proven role in activating the human epidermal growth factor receptor/ERBB pathway. Mutations in FOXA1 and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than in IDBC. The histologic diversity of ILBC was associated with specific alterations, such as enrichment for HER2 mutations in the mixed, nonclassic, and ESR1 gains in the solid subtype. Survival analyses revealed that chromosome 1q and 11p gains showed independent prognostic value in ILBC and that HER2 and AKT1 mutations were associated with increased risk of early relapse.
Conclusion:
This study demonstrates that we can now begin to individualize the treatment of ILBC, with HER2, HER3, and AKT1 mutations representing high-prevalence therapeutic targets and FOXA1 mutations and ESR1 gains deserving urgent dedicated clinical investigation, especially in the context of endocrine treatment.
