Cancer

This summary provides conclusions and recommendations from the Sixth Cambridge Conference on Endocrine and Targeted Manipulation of Breast Cancer, which was convened to assess the most recent data in the field, articulate current best practices, and identify the next steps to advance both patient care and research.

By using a breast cancer intratumoral aromatase model, the authors demonstrated that the transition from a responsive state to a letrozole-resistant state was associated with molecular mechanisms of adaptation that involved the activation of growth factor receptor pathways, particularly the HER-2/Raf/mitogen-activated protein kinase signaling pathway. Blockade of the crosstalk between the HER-2 signaling pathway and the estrogen receptor with signal-transduction inhibitors or pure antiestrogen fulvestrant restored the response to aromatase inhibitors.

Microarray analysis of RNA from sequential biopsies of breast cancers that were taken before and after 10 to 14 days of neoadjuvant treatment with the aromatase inhibitor letrozole suggested that 1) classic estrogen-dependent and proliferation genes are unlikely to be robust markers of hormone response or resistance, and 2) resistance to endocrine therapy is heterogeneous.

Pharmacogenomics examines the relation between a patient's genetic makeup and response to a given drug and forms the basis for true personalized medicine. Pharmacogenomic studies are beginning to yield important findings relating to tamoxifen and are under way for aromatase inhibitors, the 2 most important classes of drugs in the endocrine therapy of breast cancer.

Several studies have evaluated the safety and efficacy of aromatase inhibitors (AIs) for the treatment of early breast cancer in postmenopausal women. The results from these studies suggest that AIs should be considered when planning a patient's course of endocrine therapy.

Signal transduction inhibitors (STIs) are being combined with endocrine therapies in an effort to enhance endocrine responsiveness and delay the emergence of acquired resistance to hormonal therapy. Although these agents have shown early promise in selected breast cancer models, the clinical results have been disappointing to date. Ongoing combination trials and recommendations for future trials are discussed.

In metastatic breast cancer and in the adjuvant setting, it would be most useful to have trials that evaluated the order of sequential hormone therapy and chemotherapy versus concurrent administration of hormone and chemotherapy. To the author's knowledge, few trials of this type have been conducted to date, but when they have, the combined response rate, response duration, and overall survival were not different.

NCI-sponsored Cooperative Group phase 3 trials are evaluating several endocrine treatment strategies. Ongoing trials are evaluating new agents, optimal timing of treatment as well as determination of which hormone-responsive tumors benefit from inclusion of chemotherapy.