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Future perspectives: implications of the use of CDK4&6 inhibitors on breast cancer management

Lesley-Ann Martin

Speaker: Lesley-Ann Martin.

Duration: 16:45.

Voting results

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Dr Lesley-Ann Martin discusses the need for biomarkers to identify patients who may benefit from CDK4&6 inhibition, examines possible combinations and the patients likely to respond to them, and considers other cohorts of patients who may benefit from CDK4&6 inhibition. Response to a CDK4&6 inhibitor requires an intact Rb pathway and, probably, upregulation of cyclin D and low levels of p16. In vitro, cells sensitive to CDK inhibition tend to express oestrogen receptor, increased levels of Rb and cyclin D1, and low levels of p16. However, the same was not found in patients in the PALOMA 1 study, in which the determinant of response appeared to be ER positivity alone. A strong rationale for combining CDK4&6 inhibitors with an endocrine agent was tested in the PALOMA 3 trial in endocrine-resistant breast cancer. The median PFS increased from 3.8 months with single-agent fulvestrant to 9.2 months with the combination. Adding a PI3 kinase inhibitor to block any cross-talk between the oestrogen receptor and the survival pathway, to push the cells into an apoptotic state, also makes sense, and there is a rationale for combining anti-HER2 therapies with CDK4&6 inhibition. This approach is being tested in HER2+ tumours. Preclinical studies have shown that the response to chemotherapy is influenced by the timing and duration of exposure to CDK4&6 inhibitors, and this approach may improve targeting of therapy. Finally, CDK4&6 inhibition may also benefit the luminal A population and patients with HER2+ tumours and a functional Rb pathway.