TY - JOUR
T1 - Genomic Characterization of Primary Invasive Lobular Breast Cancer
AU - Desmedt, Christine
AU - Zoppoli, Gabriele
AU - Gundem, Gunes
AU - Pruneri, Giancarlo
AU - Larsimont, Denis
AU - Fornili, Marco
AU - Fumagalli, Debora
AU - Brown, David
AU - Rothé, Françoise
AU - Vincent, Delphine
AU - Kheddoumi, Naima
AU - Rouas, Ghizlane
AU - Majjaj, Samira
AU - Brohée, Sylvain
AU - Van Loo, Peter
AU - Maisonneuve, Patrick
AU - Salgado, Roberto
AU - Van Brussel, Thomas
AU - Lambrechts, Diether
AU - Bose, Ron
AU - Metzger, Otto
AU - Galant, Christine
AU - Bertucci, François
AU - Piccart-Gebhart, Martine
AU - Viale, Giuseppe
AU - Biganzoli, Elia
AU - Campbell, Peter J.
AU - Sotiriou, Christos
N1 - Publisher Copyright:
© 2016 by American Society of Clinical Oncology.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84974539687&partnerID=8YFLogxK
U2 - 10.1200/JCO.2015.64.0334
DO - 10.1200/JCO.2015.64.0334
M3 - Article
C2 - 26926684
AN - SCOPUS:84974539687
SN - 0732-183X
VL - 34
SP - 1872
EP - 1880
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 16
ER -