Leading scientists funded by Breast Cancer Now have identified a potential new treatment approach for some ‘triple negative’ breast cancers (TNBCs) after discovering them to be highly sensitive to new drugs called CDK4/6 inhibitors.
In a new study, published in journal Clinical Cancer Research, researchers at the charity’s centre at The Institute of Cancer Research, London, demonstrated in cell-lines and in mice that palbociclib could be used effectively to treat certain triple negative breast cancers – opening the door to an exciting new use for this first-in-class drug, which now needs to be trialled in patients.
‘Triple negative’ actually represents a diverse group of subtypes of the disease that lack the three molecules typically used to classify breast cancers: the oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBCs tend to exhibit aggressive behaviour and are more likely to spread to another part of the body, becoming incurable – and they are more likely to be diagnosed in black women than Caucasian women.
A subset of these TNBCs are known to have cells which produce androgen receptors and are therefore known as ‘Luminal Androgen Receptor’ (LAR) breast cancers.
It is estimated that around 1,000 women each year in the UK are diagnosed with LAR triple negative breast cancer – which accounts for around 2% of all breast cancers. This form of breast cancer cannot be treated with targeted drugs commonly used to treat other types, such as tamoxifen and aromatase inhibitors (ER and PR-positive) or Herceptin (HER2-positive).
This leaves this group of patients with fewer treatment options, namely chemotherapy drugs in addition to surgery and/or radiotherapy. Using cell lines that represent different triple negative subtypes, and cancer cells implanted into mice, the researchers – led by Professor Nicholas Turner in the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research (ICR) – showed that LAR triple negative breast cancers are very sensitive to palbociclib, while basal-like (another triple negative sub-type) breast cancer cells are largely resistant to the drug.
Crucially, the research also reveals why different cancer cells are sensitive or resistant to palbociclib, which has wider implications for the use of this very promising drug – which, thus far, has been focused on treating ER-positive breast cancer.
By investigating how individual cells progress through the cell cycle (the strictly controlled process a cell goes through when it’s dividing into two cells), the researchers found that in breast cancer cells with low levels of the CDK2 protein, blocking the CDK4/6 protein with palbociclib creates a ‘roadblock’ for the cell at a critical point in the cell cycle, meaning that the cells can’t carry on dividing.
Conversely, cells with high levels of CDK2 aren’t dependent on CDK4/6 for the next stage in the cell cycle and are therefore able to bypass the roadblock caused by CDK4/6 inhibition, making them resistant to palbociclib. Significantly, the researchers found that the levels of CDK2 are controlled by a protein called Cyclin E1, and so it is hoped that Cyclin E1 levels could now act as a ‘biomarker’ of resistance, helping to identify which patients’ tumours may be resistant or sensitive to palbociclib.
Furthermore, the research team was able to show in cell-lines and in mice that another class of drug known as PIK3 inhibitors (such as pictilisib and taselisib) could be combined with palbociclib to help treat triple negative patients with a mutation in a gene called PIK3CA even more effectively – with a trial to test the efficacy of this combination in patients now ongoing.
Professor Nicholas Turner, Professor of Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:
“Triple negative breast cancer has limited treatment options as there are no effective targeted treatments for these patients.
“But this discovery suggests that, for some women with triple negative breast cancer, there is a target in their tumour we can aim for. And fortunately a new class of drug already exists that does this – the CDK4/6 inhibitors.
“CDK4/6 inhibitors, such as palbociclib, are one of the most important breast cancer advances of the past two decades and our new findings suggest they could be even more promising than we thought. We now need to further develop a test to identify which women with triple negative breast cancer would benefit from the treatment and carry out clinical trials in these patients.”
Baroness Delyth Morgan, Chief Executive at Breast Cancer Now, which funded the study, said:
“The possibility of an existing drug being used to treat some triple negative breast cancers – a patient group which desperately lacks targeted treatments – is highly promising.
“This exciting study uncovers a potential new use for palbociclib, which is now being used in the clinic to treat hormone positive breast cancer. The signs in the lab are very positive, but clinical trials are now needed to confirm whether palbociclib could offer some triple negative patients a long-awaited lifeline.
“Crucially, this research also uncovers why some breast tumours are resistant to palbociclib, which could have major implications for the wider use of this drug. We hope further studies can now fully develop a biomarker to identify patients that will benefit from CDK4/6 inhibitors and guide their use in the clinic.”
This research was funded by Breast Cancer Now – thanks to generous support from the Mary-Jean Mitchell Green Foundation, and a clinical fellowship awarded to lead author Dr Uzma Asghar funded by Breast Cancer Now’s partnership with the Avon Foundation. Additional funding from Cancer Research UK and the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.