Results from trials demonstrating the superiority of the third-generation aromatase inhibitors (AIs; anastrozole, letrozole and exemestane) vs. tamoxifen have led to changes in clinical practice in the treatment of postmenopausal patients with hormone-sensitive breast cancer. AIs do not inhibit ovarian oestrogen synthesis sufficiently to be a viable monotherapy for premenopausal patients but there is interest in their potential use in combination with luteinising hormone-releasing hormone analogues (LHRHas) such as goserelin (‘Zoladex’). Preliminary results from Phase II combination trials in the advanced breast cancer setting have been promising, but efficacy data in premenopausal patients with early disease are yet to be reported. Here we overview the rationale and preliminary results to date for the combination of AIs with an LHRHa and highlight ongoing trials that will more fully assess the value of such combinations in extending the treatment options for premenopausal breast cancer patients.

Breast magnetic resonance imaging (MRI) has been shown to date to be of value in the high-risk population. Challenges in interpretation are present. Maintaining a high volume of examinations in dedicated centers definitely impacts positively on experience in interpretation. MR-guided intervention is a necessity in all diagnostic centers where breast MRI is performed. Guidelines in interpretation should be used in conjunction with optimum technique and by combining kinetic and morphologic information with clinical history and conventional imaging (mammography and ultrasound) findings, a recommendation for management can be made with more assurance.

Occult dissemination of tumour cells in patients with operable breast cancer is a crucial step in formation of metastasis, yet conventional tumour staging does not reveal it. To identify individual tumour cells that have successfully escaped from the primary tumour and invaded secondary organs, several research groups established sensitive immunocytochemical and molecular assays. Aside of the well documented prognostic impact of lymph node metastasis and micrometastases, respectively, bone marrow plays a prominent role as a determinant for haematogenous micrometastatic organ involvement. In the past decade, several groups have documented the independent prognostic impact of the presence of bone marrow micrometastases, which, in a recent pooled analysis of individual patient data from over 4000 breast cancer patients with Stage I–III disease, could be confirmed for the entire study population, and, in addition, provided data for challenging hypotheses to be tested in future adjuvant therapy trials of clinically relevant subgroups of breast cancer patients. Although the availability of a simple blood test would be highly desirable, no prognostically relevant data so far exists for early breast cancer patients. Options for the applicability of such approaches to detect disseminated (to bone marrow) and circulating tumour cells (in blood) are ample, both in clinical trial settings and for basic as well as translational research. In this overview we provide a brief summary of the prognostic role and the potential clinical utility of bone marrow micrometastases in breast cancer patients.

Citation of original article:

R. Narayanan, D. P. Edwards, N. L. Weigel. Human progesterone receptor displays cell cycle-dependent changes in transcriptional activity. Molecular and Cellular Biology 2005; 25(8): 2885–2898.

Abstract of the original article

The human progesterone receptor (PR) contains multiple Ser-Pro phosphorylation sites that are potential substrates for cyclin-dependent kinases, suggesting that PR activity might be regulated during the cell cycle. Using T47D breast cancer cells stably transfected with an mouse mammary tumor virus (MMTV) chloramphenicol acetyltransferase reporter (Cat0) synchronized in different phases of the cell cycle, we found that PR function and phosphorylation is remarkably cell cycle dependent, with the highest activity in S phase. Although PR expression was reduced in the G2/M phase, the activity per molecule of receptor was markedly reduced in both G1 and G2/M phases compared to the results seen with the S phase of the cell cycle. Although PR is recruited to the MMTV promoter equivalently in the G1 and S phases, recruitment of SRC-1, SRC-3, and, consequently, CBP is reduced in G1 phase despite comparable expression levels of SRC-1 and SRC-3. In G2/M phase, site-specific phosphorylation of PR at Ser162 and at Ser294, a site previously reported to be critical for transcriptional activity and receptor turnover, was abolished. Treatment with the histone deacetylase inhibitor trichostatin A elevated G1 and G2/M activity to that of the S phase, indicating that the failure to recruit sufficient levels of active histone acetyltransferase is the primary defect in PR-mediated transactivation.