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The success story of an academic trial that has the potential to change the future of breast cancer treatment

Intro text: 

Patients’ needs and quality of life are at the heart of our clinical research. We now understand that breast cancer is not one single disease, but many different subtypes. Therefore, all patients are different and require a unique treatment approach. Our aim is to find the right treatment for every patient.

This is exactly what the MINDACT trial is about: enabling women who would not benefit from chemotherapy to avoid this heavy treatment.

Discover the story of MINDACT as told by its principal actors. Discover how research impacts lives.

Assessing the risk of cancer relapse

After surgically removing a patient’s tumour, it is crucial to evaluate the risk of cancer returning or spreading to other parts of the body. If the risk is high, the patient may be advised to receive chemotherapy. As each person’s risk depends on many factors, it is not easy to define ‘’high’’ risk accurately.

The tumour is first analysed by pathologists. Traditionally, the factors considered to evaluate this risk include the patient’s age, the tumour’s size, the number of lymph nodes containing cancer, the presence of hormone-receptors, HER2*-receptors and other features that affect how quickly a tumour will grow and how well a treatment is likely to work.

Based on this assessment, if the risk of recurrence is high, doctors will generally propose chemotherapy. Unfortunately, this traditional clinical way of assessing risk is not homogeneous and not always consistent.

Nowadays, because we don’t know how to pick up the patients who really need this type of treatment, and we know that once breast cancer has spread it becomes an uncurable disease, we tend to give chemotherapy anytime we are in doubt, because as an oncologist, you don’t want to take a risk as this is the only opportunity you have to cure the patient” says Dr Fatima Cardoso, Chair of the EORTC (European Organisation for Research and Treatment of Cancer) Breast Cancer Group (member of BIG), Study Chair of the MINDACT trial.

*HER2 = Human EGF Receptor 2  (EGF = Epidermal Growth Factor)

It's crucial to evaluate the risk of cancer returning or spreading to other parts of the body.

-Dr Fatima Cardoso-

The effects of chemotherapy

Chemotherapy is an anti-cancer treatment that has real benefits and that can save lives. However, it also has a number of unwanted side effects. This happens because chemotherapy is not a specific treatment and not only kills tumour cells but also some good or ‘normal’ cells in the body.

Tumours can grow very quickly because they contain rapidly dividing cells. Chemotherapy works by attacking these rapidly dividing cells. Tumour cells are not the only dividing cells in the human body. Cell division goes on everywhere, and many areas can be affected. As your hair grows, for example, cells divide rapidly in the follicles. That is why hair can fall out when chemotherapy attacks these cells.

Simone was diagnosed in 2002. She received chemotherapy for six months. During treatment, she experienced many unwanted side effects.

When I was told I would receive chemotherapy, my first thought was ‘oh no, I’m going to lose my hair… I need a wig’. Before starting therapy, I wanted my daughter to come with me to the shop and buy a wig. Having one, I felt ready to start the treatment. But when you start therapy, you feel other things can go wrong. That’s when you understand that losing your hair is not important at all. The first session is really heavy because the effects are unexpected. You don’t know if the pain you feel is from the chemotherapy or not. And you are not confident, because even if the physician explained the effects in detail, you didn’t experience such pain and discomfort before. And then it comes at you. You feel very uncomfortable. I had a lot of pain in my joints and everywhere in my body.

Chemotherapy can be hard to handle. “They say it’s like having a bad hangover” says Ilaria, “But I would say it’s like having the worst hangover ever on top of having the worst flu you’ve ever had. And on top of that, you feel pretty depressed.” 

Ilaria was 33 when she was diagnosed with breast cancer. Because of her age and the type of cancer she had, she received a particularly aggressive form of chemotherapy. “It’s an attack on every single cell of your body. You really do feel attacked. And it’s a mental struggle as well because you know that next Friday at 3 o’clock you’re going to feel absolutely terrible for a week or ten days. On top of that you put on weight, you lose hair and you have hot flushes and …  (silence). You know, it’s grim.

When you start therapy, you feel other things can go wrong. That’s when you understand that losing your hair is not important at all. The first session is really heavy because the effects are unexpected. You don’t know if the pain you feel is from the chemotherapy or not.

-Simone was diagnosed in 2002-

There are also some side effects from chemotherapy that can occur after treatment. One of them is intense fatigue, which can last for several months. Another side effect that was underestimated in the past is memory loss, which is a problem that women occasionally report to their doctors. Fortunately, this usually improves with time.

There are two long-term side effects of chemotherapy that are much more serious, but fortunately are extremely rare. One of them is toxicity to the heart, which weakens the heart muscle. It mainly occurs with certain specific chemotherapies and can be treated by a cardiologist. Nevertheless, the effect on quality of life can be substantial. The second very rare but potentially serious side effect is chemotherapy-induced leukaemia. Leukaemia is a deficient condition of the blood, in which white blood cells are produced uncontrollably. This disease can be lethal and it must be treated with chemotherapy as well. Luckily it is seen in less than 1% of patients with breast cancer treated with chemotherapy, but when it does occur, it can be devastating.

Prof Martine Piccart, Co-founder and Chair of the Breast International Group (BIG) and Study Chair of the MINDACT trial states: “Clearly, when we look at all the side effects of chemotherapy in the short and long term it becomes obvious that we don’t want to give this treatment to a woman who doesn’t need it.

“Clearly, when we look at all the side effects of chemotherapy in the short and long term it becomes obvious that we don’t want to give this treatment to a woman who doesn’t need it.”

-Prof Martine Piccart-

Journey to finding a new prognostic too

Dr Laura Van ‘t Veer, world renowned molecular biologist, Professor at the University of California, San Francisco and Chief Research Officer at Agendia, is one of the inventors of the MammaPrint® test (the 70-gene prognosis signature), developed while she worked at the Netherlands Cancer Institute. “Early 2000 at the Netherlands Cancer Institute, we had the opportunity to work with a small start-up company that had developed a technology where one could analyse the activity of all genes of a cell in just one experiment."

"This microarray technology has revolutionised molecular biology research and we took it upon ourselves to see if we could use it for premenopausal breast cancer to find the genes whose activity would be related to either ‘no breast cancer recurrence’ or ‘recurrence within five years’. We wanted to use this knowledge to understand who needed chemotherapy, and for whom the risk of recurrence was so low that they could safely forego chemotherapy and not suffer from the side effects.

The results of a first study that identified a 70-gene signature to help with decision-making about chemotherapy were very promising. The prognostic information seemed good and reliable.

It almost looked too good to be true. We could possibly hold a key that would help clinicians make better decisions and avoid unnecessary treatment. Today, at the front line of breast cancer treatment, clinicians have very few biomarkers to help with treatment decisions.’’ said Prof Emiel Rutgers, Surgical Oncologist at the Netherlands Cancer Institute and Study Chair of the MINDACT trial. Before being able to use this tool to enhance the quality of treatment decision-making, it needed to undergo large-scale scientific and statistical validation.

We could possibly hold a key that would help clinicians make better decisions, sparing many women from a chemotherapy they would not benefit from.

-Prof Emiel Rutgers-

How did it work?

After the protocol (design of the study) had been approved, the logistical complexity of the trial had been tested and validated, and the initial funding had been secured, the MINDACT trial could start recruiting patients.

From 2007 to 2011, doctors at 112 centres in nine countries enrolled in the trial 6,693 patients (out of 11,288 women screened) who had undergone surgery for early-stage breast cancer. All participants were categorised as low or high risk for tumour recurrence in two ways: first, through the genomic analysis of tumour tissue using MammaPrint (= innovative method, genomic test) by Agendia in Amsterdam; and second, using Adjuvant! Online, a tool that calculates the risk of breast cancer recurrence based on common clinical and biological criteria (= traditional method, clinical test).

The participants were then divided into different groups: When both the genomic and the clinical tests showed high risk, the patients received chemotherapy. When both tests showed low risk, no chemotherapy was proposed