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Estrogen independent gene expression defines clinically relevant subgroups of estrogen receptor positive breast cancer.

ABSTRACT: BACKGROUND: Human breast cancer represents a significantly heterogeneous disease. Global gene expression profiling measurements have been used to classify tumors into multiple molecular subtypes. The capacity to define subtypes of breast tumors provides a framework to enable improved understanding of the mechanisms of breast oncogenesis, as well as to provide opportunities for improved therapeutic intervention in patients. METHODS: We used publicly available gene expression profiling data to identify 'estrogen independent' genes in estrogen receptor alpha (ER+) breast tumors, and subsequently identified 6 subgroups of ER+breast tumors. RESULTS: Each of the 6 identified subgroups exhibited distinct clinical behaviors and biology. Patients whose tumors comprised subgroups 2,5&6 experienced excellent long-term survival, whereas those patients whose tumors belonged to subgroups 1&4 experienced much poorer survival. Breast tumor cell lines representative of the different subgroups responded to therapeutic compounds in accordance with their subgroup classification. CONCLUSIONS: These data support the existence of 6 distinct subgroups of ER+breast cancer and suggest that knowledge of the ER+subgroup status of patient samples have the potential to guide therapy choice.

SUBMITTER: Hallett RM

PROVIDER: S-EPMC4289221 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Estrogen independent gene expression defines clinically relevant subgroups of estrogen receptor positive breast cancer.

Hallett Robin M RM Hassell John A JA

BMC cancer 20141124

<h4>Background</h4>Human breast cancer represents a significantly heterogeneous disease. Global gene expression profiling measurements have been used to classify tumors into multiple molecular subtypes. The capacity to define subtypes of breast tumors provides a framework to enable improved understanding of the mechanisms of breast oncogenesis, as well as to provide opportunities for improved therapeutic intervention in patients.<h4>Methods</h4>We used publicly available gene expression profilin ...[more]

PMID: 25420785

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Project description:Simple Summary Hormone receptor-positive (HR+)/HER2-negative is the most frequent subgroup of metastatic breast cancer (MBC). Important therapeutic advances in the treatment of this tumor type have been observed in the last 20 years, with the approval of numerous endocrine therapies (ET) with or without target therapies (TT). To improve our current knowledge and support clinical decision-making, we conducted a systematic literature and meta-analysis focused on the most relevant/promising first-/second-line ET ± TT of the last 20 years. We observed that CDK4/6-inhibitors(i) + ET were the most effective regimens. At the same time, mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant patients. Single agent ET might still be a valuable upfront treatment in endocrine sensitive and non-visceral disease. Abstract A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26–41% and 12–27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60–0.65 vs. HR range for single agent ET: 0.59–1.37; OS HR range for combinations: 0.74–0.87 vs. HR range for single agent ET: 0.68–0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral (p = 0.63) and endocrine sensitive disease (p = 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making.

Dataset Information

Estrogen independent gene expression defines clinically relevant subgroups of estrogen receptor positive breast cancer.

Publications

Estrogen independent gene expression defines clinically relevant subgroups of estrogen receptor positive breast cancer.

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