Κυριακή, 20 Μαρτίου 2016

GENETICS OF LOBULAR BREAST CANCER

In a study reported in the Journal of Clinical Oncology, Desmedt et al identified genomic alterations in invasive lobular breast cancer, including several that may serve as targets for current treatment and for treatment research.
Invasive lobular breast cancer cells are characterized by expression of the estrogen receptor (encoded by ESR1), lack of HER2 amplification, and loss of the cell-adhesion molecule E-cadherin (encoded by CDH1). The study evaluated the presence of substitutions, insertions, and deletions of 360 cancer genes in 413 invasive lobular breast cancer samples and copy number aberrations in 170 samples.
Characteristic Alterations
In addition to the expected high frequency of CDH1 mutation (65% of tumors), 50% of tumors had alterations in the PI3K pathway genes PIK3CAPTEN, or AKT1HER2 mutation was present in 5.1% of tumors, and HER3 mutation was present in 3.6%. FOXA1 mutation was present in 9% of tumors, and ESR1copy number gain was noted in 25%.
Compared with findings in 338 estrogen receptor–positive, HER2-negative invasive ductal breast cancer samples from The Cancer Genome Atlas, AKT1, ARID1A, CDH1, HER2, HER3, FOXA1, PIK3CA, PTEN, and TBX3were more frequently altered in the estrogen receptor–positive, HER2-negative invasive lobular breast cancer samples, and MAP3K1, MAP2K4, and TP53 were less frequent. In addition to CDH1 loss, copy number aberrations that were more common in invasive lobular breast cancer included ESR1 and ETV1 gains.
By invasive lobular breast cancer histologic type, the mixed nonclassic subtype was enriched for HER2 mutation, and the solid subtype was enriched for ARID1A mutation, with both being associated with TP53mutation. The solid subtype was characterized by 11p and 6q25.1 (ESR1) gains and 1p36.22 (ARID1A) deletions; the mixed nonclassic subtype, by 1p36.22 (ARID1A) deletions; and the alveolar subtype, by 11q13.3 (CCND1) and 11q14 (PAK1) gains.
Association With Outcomes
Survival analysis showed that chromosome 1q gains were associated with better outcome, and 17q12 and 11p gains were associated with worse outcome, and that HER2 and AKT1 mutations were associated with an increased risk of early relapse.
The investigators concluded: “This study demonstrates that we can now begin to individualize the treatment of invasive lobular breast cancer, 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.”
The study was supported by Susan G. Komen, Fondation MEDIC, Les Amis de Bordet, Fonds National de Recherche Scientifique, Breast Cancer Research Foundation, Wellcome Trust Clinical Research Training Fellowship Programs, Italian Association for Leukemia and Lymphoma, and Italian Association for Cancer Research.
Christine Desmedt, PhD, of the Institut Jules Bordet, Brussels, Belgium, is the corresponding author of the Journal of Clinical Oncology article. 

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