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. However, when the two tests disagreed, patients were randomly assigned to follow the advice provided by one of the two tests.

The trial was not easy to explain, but patients embraced MINDACT

This trial would not have been possible without the support and collaboration of hundreds of healthcare professionals across multiple disciplines and, above all, without the trust and participation of all 6,693 patients.

Europa Donna - The European Breast Cancer Coalition, a patient advocacy organisation, has representation on the MINDACT Steering Committee and was instrumental in preparing informational material to help make the study accessible and understandable.

 

I understand that I won’t directly benefit from this study, but it’s my responsibility to help other women that will be confronted with the disease in future.

-One of the MINDACT patients-

Leaflets and presentations at conferences helped to communicate about MINDACT, in particular its innovative character. The Patient Informed Consent form was carefully written to ensure that the trial could be easily understood despite its complexity, and a DVD was prepared to help physicians and study nurses explain the trial to patients.

The participants grasped the importance of this study to help other patients potentially avoid chemotherapy when not needed in the future. “It was the first time that a patient advocacy organisation was involved so deeply in a clinical trial”, said Karen Benn, deputy CEO and  Head of Public Affairs at Europa Donna.

Extra challenges

Funding the trial: € 47 million

There’s no science without finance” says  Dr Denis Lacombe, Director General of the EORTC, which sponsored and ran MINDACT under the auspices of BIG. The first step was to knock on the door of the European institutions to demonstrate that this trial was a unique opportunity to transform the lives of breast cancer patients, and that it had the potential to save millions of Euros in government health budgets. After BIG received an “EU Framework 6” grant of € 47 million to support MINDACT, scientists became extremely motivated. Prof Martine Piccart remembers being strongly impressed by the level of their engagement: “it was touching to have a group of persons that were ultra-motivated by this fantastic opportunity to de-escalate therapy”.

Beyond the EU grant, in each participating country, local champions were engaged to approach local donors and foundations to support the trial costs in their respective countries. Step-by-step, door-by-door, country-by-country, the costs of running the trial could finally be covered.

Logistics and data management

The MINDACT trial was very demanding in terms of logistics as well. It was described as a true “logistical nightmare”, involving surgeons, oncologists, patho logists, research nurses and many other professionals.

For example, a sample of the tumour of each participant had to be collected by the surgeons and then fresh frozen for further analysis. During the trial, 10s of 1000s of high quality samples (frozen tumour tissue, whole blood and plasma) had to be transported in strictly regulated conditions to a specialised biological storage facility. With the analysis of 44,000 genes of each tumour, a huge amount of data had to be collected and stocked in a genomic database, in addition to all the medical data collected from each patient and stored in the clinical database. Web-based registration forms were developed to allow tracking of samples and to inform doctors about their patients’ screening results, the genomic and clinical test results, whether patients would need to receive chemotherapy, and how patients were randomised.

MINDACT demanded tremendous collaborative efforts. Today, it is a successful example of how, by working together across borders and disciplines, we can develop better treatments – and eliminate those that are not needed – while increasing the likelihood of finding cures.

MINDACT is a successful example of how, by working together across borders and disciplines, we can develop better treatments while increasing the likelihood of finding cures.

-Dr Carolyn Straehle-

Impressive results: 46%

The MINDACT trial, published in the New England Journal of Medicine in 2016, demonstrates that research offers the opportunity to transform both patient’s lives and that of healthcare professionals.

The results of the trial indicate that the use of MammaPrint can potentially reduce overtreatment of breast cancer patients by 46%, even in the presence of high risk clinical features. This means that nearly half of the early-stage breast cancer patients identified as high risk for recurrence based on clinical factors were identified as low risk when using the MammaPrint test. The patients who avoided chemotherapy during the trial thanks to this signature were closely monitored over five years. The data demonstrated that chemotherapy provided no clinically meaningful benefit for these patients.

The MINDACT trial results provide evidence that using MammaPrint could change clinical practice by substantially de-escalating the use of adjuvant chemotherapy and sparing many patients an aggressive treatment they will not benefit from.” says Prof Martine Piccart.

MINDACT demonstrates how our joining efforts has a direct impact on patients’ lives. It takes optimism and the unwavering belief in a grander purpose that enables us to succeed, despite the many daily challenges that broad-scale, international collaboration entails,” said Dr Carolyn Straehle, Managing Director of BIG.

A goldmine for future research

The physicians and scientists who designed MINDACT made sure that the study would serve as a long-term investment in future breast cancer research. Not only did they analyse the 70 genes using MammaPrint, but they also processed over 44,000 genes from the tumours of each of the 6,693 participating patients.

This genomic information, together with the tumour samples and blood donated by the patients, and the clinical data collected during the study, represents a tremendous resource for the future. Researchers from around the world will be able to access these materials for research projects that will be carefully reviewed for their potential scientific value.

According to Dr Denis Lacombe, ‘’MINDACT is not only pioneering in precision medicine, it contributes to something important to the patients and society as a whole: de-escalating therapies. It also created a huge resource for future research, because research using the participants’ tumour samples, blood samples, and clinical outcomes data could allow us to gain a substantially better understanding of the biology of breast cancer.’’

MINDACT is not only pioneering in precision medicine, it contributes to something important to the patients and society as a whole: de-escalating therapies.

-Dr Denis Lacombe-

Changing the future of breast cancer treatment

One of the main challenges in oncology today has become to accurately distinguish between patients who need adjuvant treatment and those who do not. This, together with the identification of the best type of therapy for each individual patient and the development of drugs targeting specific characteristics of tumour cells, are the goals of treatment tailoring or personalised medicine. It is our mission to find ways of ensuring patients receive the treatments most appropriate for them.

The results prove that the MammaPrint gene test could identify woman who will not benefit from chemotherapy, thus sparing them the often gruelling side effects. This is very promising news and demonstrates that working together across disciplines on an international scale contributes to the faster development of better treatments, and increases the likelihood of cures for patients.

We look forward to further results from this and other trials in the future.

The future is bright. Together, we will find a cure for breast cancer.

The MINDACT trial is managed and sponsored by the European Organisation of Research and Treatment of Cancer (EORTC) as part of an extensive and complex partnership in collaboration with BIG, Agendia, and many other academic and commercial partners, as well as patient advocates. The study was supported by grants from the European Commission Framework Programme VI (FP6-LSHC-CT-2004-503426, “TRANSBIG Network of Excellence”), the Breast Cancer Research Foundation, Novartis, F. Hoffman La Roche, Sanofi-Aventis, Eli Lilly, Veridex, the U.S. National Cancer Institute, the European Breast Cancer Council-Breast Cancer Working Group (BCWG grant for the MINDACT biobank), the Jacqueline Seroussi Memorial Foundation (2006 JSMF award), Prix Mois du Cancer du Sein (2004 award), Susan G. Komen for the Cure (SG05-0922-02), Fondation Belge Contre le Cancer (SCIE 2005-27), Dutch Cancer Society (KWF), Association Le Cancer du Sein, Parlons-en!, the Brussels Breast Cancer Walk-Run and the American Women’s Club of Brussels, NIF Trust, Deutsche Krebshilfe, the Grant Simpson Trust and Cancer Research UK. This trial was also supported by the EORTC Charitable Trust. Whole genome analysis was provided in kind by Agendia. Total funding: approx. EUR 47 million.