Lead: Professor Mitch Dowsett. Final Spend £137,351. 2018-2021
After surgery for breast cancer, most postmenopausal women are treated with drugs called aromatase inhibitors (A-Inhs), that aim to stop the production of estrogen. A-Inhs reduce the likelihood of the patient dying from breast cancer by about 40%. However, some women become resistant to A-Inhs and the cancer returns. To improve treatment for these patients, we need to fully understand the molecular makeup of the tumours that become resistant to A-Inhs. In this study, the team accessed a uniquely large collection of tumour samples from over 3,000 women all around the UK. All these patients received an AI for two weeks before surgery in the POETIC trial which was the largest trial of its kind in the world. The team compared the molecular makeup of tumours that responded to A-Inhs, to those that developed resistance. By establishing the differences between these tumours, it may then be possible to target the resistance pathways in individual patients. Comparing the molecular makeup of the tumours requires a lengthy and highly skilled process to extract ribonucleic acid (RNA). Each sample is dissected carefully under a powerful microscope using a very fine needle.
Their most significant finding was that A-Inhs suppress the levels of a protein called Ki67 in most patients. Patients whose tumours showed the least Ki67 suppression were the most likely to relapse from their treatment, indicating that Ki67 can be used to identify the patients who are most likely to see their cancer return. By starting the A-Inh two weeks before surgery and looking at how the levels of Ki67 changed in patients’ tumours over time, the researchers were able to distinguish groups of patients with different risks of their cancer coming back. The team analysed each group to find differences in how their cancers behaved at the molecular level. Several immune cell types were found to be unusually active in ER positive cancers that contained progesterone and high levels of estrogen.
Further research is needed to investigate whether this is linked to resistance to A-Inhs. If the link is confirmed, there are already available targeted drugs, such as Interleukin 6, which could be effective to treat these particular tumours. Their findings on immune cell patterns also caution against the indiscriminate use of immunotherapies, which are now being used to treat some ER positive breast cancers but which may actually increase the chances of relapse in this particular group of patients. Results from the trial will be submitted to Nature Cancer.