Targeted therapy extends breast cancer survival

About 150 women are diagnosed with breast cancer in the UK every day. It is one of the leading causes of death amongst females aged 50-64. We all know someone who has been affected by the disease.

Now a clinical trial tracking a combination of drug therapies for nearly ten years has reported its final analysis.

The study, which originally began in 2013, had already shown the longest average survival reported to date in any advanced breast cancer Phase III clinical trial.

However, whether overall survival would also be extended by the targeted therapy was not known.

The MONALEESA-2 clinical trial

Endocrine therapy targeting the hormones that fuel breast cancer growth is standard care for postmenopausal women with advanced breast cancer.

However, many patients develop resistance to treatment, which requires the use of sequential therapies that have alternative ways of working.

The MONALEESA-2 trial was set up to discover whether new ways of targeting hormone receptor positive, HER2 negative, advanced breast cancers worked better than traditional treatments.

The trial enrolled 668 women with advanced breast cancer in 223 centres across 29 different countries. The patients were randomly assigned a new targeted drug Ribociclib plus Letrozole (an aromatase inhibitor drug originally licensed in 1996), or a placebo plus Letrozole.

The trial was randomised, placebo-controlled and double-blind (where neither patients nor doctors know who is receiving the treatment or a placebo). Such trials are the gold standard of clinical assessment and validation.

What did the new treatment show?

The final analysis of the trial showed that survival was significantly longer among those receiving Ribociclib plus letrozole than among the placebo control group.

After follow-up just over 6 years into the trial, 181 deaths had occurred among the Ribociclib group and 219 among the placebo group. Ribociclib plus letrozole thus showed a significant overall survival benefit.

With the trial now finished, median overall survival has been shown to be 63.9 months compared with 51.4 months for the placebo (plus traditional chemotherapy) group.

In plain English, the drug therapy has been proven to extend survival in those with advanced breast cancer by over a year, compared to standard treatment.

How the targeted therapy treats breast cancer

Targeted therapies aim at specific characteristics of cancer cells, such as a protein that allows the cancer cells to grow in a rapid or abnormal way. Targeted therapies are generally less likely than chemotherapy to harm normal, healthy cells.

Ribociclib is a targeted therapy drug called a cancer growth inhibitor. It targets the growth of HER2 (human epidermal growth factor receptor 2) in the body, a gene that can feature in the development of breast cancer.

The HER2 gene makes proteins which form receptors on breast cells. The receptors help to control how breast cells grow, divide and multiply.

In about 10%-20% of breast cancers the HER2 gene becomes faulty and makes too many copies of itself. This is called HER2 gene amplification. The extra genes tell breast cells to make too many receptors. This causes the cells to grow in an uncontrolled way.

Testing for hormone receptors is therefore a key step in treating breast cancer, because the results will help decide whether the cancer is likely to respond to hormonal therapy medicines, like Herceptin.

If a breast cancer is hormone receptor positive, it means tumour growth is fuelled by the hormones oestrogen, progesterone, or possibly both. Most breast cancers are hormone receptor positive.

It the cancer is HER2 negative, it means it does not have human epidermal growth factor receptor (HER2) proteins. That means it will not respond to treatments that target HER2 protein, like Herceptin, but it may respond to therapies that specifically target it, like Ribociclib.

More than two out of every three breast cancers are both hormone receptor positive and HER2-negative. This is why Herceptin is only suitable for a smaller proportion of breast cancers, whilst many more patients may benefit from Ribociclib.

Risks associated with treatment

Although the treatment has now been proven to extend survival, like many drugs it does have side-effects and some risks.

Nearly three-quarters of patients taking the drug developed Neutropenia, which occurs when you have too few neutrophils, a type of white blood cells.

While all white blood cells help your body to fight infections, neutrophils are important for fighting certain infections, especially those caused by bacteria.

Neutropenia can make you more vulnerable to infections. When neutropenia is severe, even the normal bacteria from your mouth and digestive tract can cause serious illness.

The drug caused more people to feel nauseous than those in the control group and the rate of infections, fatigue and diarrhoea that occurred were all higher too.

One death during the trial was considered to be related to the drug, which means all patients taking the drug are monitored with regular ECG’s too.

However, even with the risks associated with the treatment, the proven extension in survival means many patients are likely to be able to benefit from the treatment in the future.

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