What is the current situation with research into TNBC?

What is happening in the search for new targeted treatments for TNBC? What progress is being made and what is the realistic outlook for patients? What is available now or in the near future?

The world’s leading laboratory and clinical breast cancer researchers met, most virtually but some physically, at the annual conference in San Antonio Texas (called SABCS) in December 2021. This is the single most important conference where the latest treatment trials research and new scientific discoveries are shared, and areas for further research are discussed.

The good news is that there was far more TNBC content than ever before, and more reasons for optimism looking to the future. This compares with 10 years ago when there was almost no TNBC content but has steadily become more prominent over the last 5 years.

It was also very noticeable that UK based researchers were involved, even leading many of these developments.

However, there still is no ‘silver bullet’ drug, nor does it seem likely that there will be a single solution for all patients with TNBC like there is for example with hormone treatment for oestrogen receptor positive breast cancer. We now know that there are many different forms of TNBC and its biology is very diverse, so progress is likely to be incremental rather than one big breakthrough. So much more needs to be done and as soon as possible.

There are, however, some new treatments, specifically for people with TNBC, which can add to and augment existing well established chemotherapy treatments. This shows it is possible to find new treatments for people with TNBC and gives some optimism that there will be more to come.

1. PARP INHIBITORS

PARP inhibitor drugs have been shown to be effective in breast cancer patients with a mutation or fault in genes BRCA 1 and BRCA 2; such cancers are referred to as BRCA positive. About 1 in 10 women with breast cancer are thought to have BRCA positive disease and since TNBC is more likely to be inherited than other forms of breast cancer, this is especially important for such patients.

PARP is one of the tools or pathways with which the body repairs damaged DNA in both normal cells and cancers. Cancers with mutations in BRCA1 lack another of the DNA repair pathways, so they are more dependent on PARP. If these cancers are treated with PARP inhibitors they are no longer able to repair damaged DNA and die.

Two drugs called olaparib and talazoparib can prolong life and improve quality of life in people with BRCA positive secondary or metastatic breast cancer (i.e. that has spread outside the breast and lymph glands close by) who have previously received chemotherapy. They are given by mouth and are already approved for use in the UK. As yet, they are not funded through the NHS but negotiations are ongoing.

In the meantime, under specific conditions, the drug companies may provide these drugs for individual patients. They may also be available privately.

In trials, olaparib and talazoparib also reduced recurrence in people with early stage BRCA mutated breast cancers and it is expected they will soon be approved for use in the UK. Other PARP inhibitors are also being developed.

People with TNBC should ask their oncologist if they are eligible for the genetic test to determine whether their cancer carries a BRCA gene mutation, and if so, whether they may be suitable for a PARP inhibitor. As with other cancer drugs, PARP inhibitors do have side effects.

2. IMMUNOTHERAPY

Immunotherapy drugs have been around for some time and shown to be very effective in many cancers, particularly skin and lung, but until recently, not in breast cancers. These drugs work by getting around the ways cancer cells have of ‘hiding’ from the immune system.

PD-L1 is a chemical or protein found on the surface of cells that blocks the immune system from attacking healthy cells. Cancer cells can hijack this process and immunotherapy drugs work by activating the immune system to destroy the cancer cells. Not all cancer cells, however, make PD-L1 and the benefits tend to apply if significant levels of PD-L1 are present in a person’s cancer. Before people with breast cancer can be treated with these drugs their cancers are tested for PD-L1.

In May 2020, NICE approved the intravenous immunotherapy drug atezolizumab for use in people with TNBC whose cancers have PD-L1, and who have secondary or metastatic disease but have not yet received chemotherapy for that disease. Clinical trials have shown that, when given with the chemotherapy drug nab-paclitaxel, atezolizumab can shrink cancer and delay progression

More recently, a second immunotherapy drug called pembrolizumab, also given intravenously, showed benefits in trials when given with a number of different chemotherapy drugs to people both with early stage TNBC and those with secondary or metastatic TNBC. Pembrolizumab (Keytruda) is now available for some patients in the UK with metastatic TNBC to extend their life, and also more recently for those with early stage TNBC to reduce the chances spreading outside the breast to other parts of the body.

Again, immunotherapy drugs do have side effects and can make the body’s immune system turn against otherwise healthy parts of the body.

3. ANTIBODY DRUG CONJUGATES

Antibody drug conjugates (ADCs) are a smart, better way of getting more intravenous chemotherapy to the cancer and less to the rest of the patient; this should make the treatments work better, and reduce side effects. ADCs rely on first identifying a ‘target’ on cancer cells and then developing something called a monoclonal antibody that homes in on that target; finally a chemotherapy drug is loaded into the monoclonal antibody to complete the ADC.

Although ADCs can have similar side effects to chemotherapy, they are usually less severe than with ordinary chemotherapy. An ADC is already widely used for people with another form of breast cancer called HER2 positive breast cancer.

Recently, another target called Trop 2 has been found that in 90% of all TNBCs. An ADC called sacitzumab govitecan is given intravenously and in trials could shrink and control TNBC that is no longer responding to at least 2 types of earlier chemotherapy.

Sacitzumab govitecan has been approved for use in the UK but NICE has not yet agreed funding through the NHS. NICE is due to make another evaluation in March 2022 and reaching an agreement on pricing will be critical. The charity Breast Cancer NOW is leading a campaign to urge agreement so that ‘all eligible women can benefit’.

In December 2021, the first patient in Britain received sacitzumab govitecan at Mount Vernon Hospital in London after agreement with the producers, Gilead, under their ‘early access scheme’.

Sacitzumab govetine is now being tested in people with TNBC at other stages of their condition.