Identifying in primary breast cancers the molecular features and phenotypic and geneotypic determinants of response/benefit to aromatase inhibitors.

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Our group and others have found that almost all ER+ primary breast cancers in postmenopausal patients show an antiproliferative response to AIs over the first 2 weeks of treatment as judged by the expression of the nuclear antigen, Ki67, but degree of response is very heterogenous.

This provides further support to the validity of Ki67 as an intermediate index of benefit from endocrine therapy but also has major implications for prognosis and prediction: that molecular profiling after short-term presurgical therapy with the endocrine agent of choice may integrate intrinsic prognosis with treatment-determined prognostic change thereby improving prediction of long-term outcome.

Although change in proliferation is considered a key mechanism of effectiveness of endocrine therapies, eventual clinical outcome of AI-treated patients would also be expected to depend on the initial expression and treatment-induced change in factors controlling apoptosis, angiogenesis and invasiveness/metastasis.

We therefore aim to:

• identify metagenes for proliferation, apoptosis, angiogenesis and invasion/metastasis in ER+ breast carcinomas from postmenopausal women

• characterize the effects of AI-treatment upon them and thereby determine our ability to modify those processes with aromatase inhibitors in individual patients

• assess the degree to which pre-treatment phenotypes affect these AI-induced changes

• integrate these metagenes to create optimised recurrence predictors (i) before and (ii) after 2 week exposure to AIs.