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RESEARCH PRODUCT

Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer.

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Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ2 tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment. This work was supported by funds from Instituto de Salud Carlos III - PI13/01718 (A.P.), by a Career Catalyst Grant from the Susan Komen Foundation (A.P.), by Banco Bilbao Vizcaya Argentaria (BBVA) Foundation (A.P.) and by the Breast Cancer Research Foundation. This work was also supported by funds from FEDER (RETICC): RD12/0036/0076 (JA), RD12/0036/0051 (JA), RD12/0036/0070 (AL) and RD12/0036/0076 (MM). JMC holds a fellowship from “PhD4MD”, a Collaborative Research Training Programme for Medical Doctors (IDIBAPS, August Pi i Sunyer Institute for Biomedical Research and IRB Barcelona, Institute for Research in Biomedicine) partially funded by Instituto de Salud Carlos III, (ISCIII, project: II14/00019). JMC and RRG research support is provided by the Spanish Ministry of Science and Innovation grant SAF2013-46196 (FEDER Funds) and the Generalitat de Catalunya AGAUR 2014-SGR grant 535.