(Disponível em Português)
Chemotherapy is an important, life-saving treatment for breast cancer. But it’s not risk free. While some of its side effects are short-term and reversible, others are not and could even result in severe repercussions to the patient’s health. It is therefore of paramount importance that doctors would be able to assess whether the benefits of administering chemotherapy outweigh the risks on a case by case basis.
Until now, making this assessment has been a particularly difficult problem when dealing with early breast cancer. Fatima Cardoso, director of the Breast Unit at the Champalimaud Clinical Centre, has been leading the effort towards finding a solution to this problem and is now at the final stages of certifying the answer – a test called MammaPrint (link1, link2).
Cardoso is a principal figure in the field of breast cancer. She holds positions in multiple european cancer organisations, including the EORTC (European Organisation for Research and Treatment of Cancer), which is the organisation that coordinates the pan-european study to validate the clinical utility of MammaPrint.
When the study met its five-years midpoint last year, it already showed MammaPrint’s clear value: “We found that within a group of early breast cancer patients that would traditionally receive chemotherapy, about 46% would be able to forego it according to MammaPrint’s assessment. It’s a very large percentage that will allow us to substantially decrease the number of patients that undergo aggressive chemotherapy treatment without deriving significant benefit from it”, says Cardoso.
The 70-gene signature
What is the cause of the discrepancy in assessment between the traditional method and MammaPrint? “The traditional method of assessing a patient’s risk of relapse, and therefore the necessity to administer chemotherapy, involves a complicated consideration of multiple factors”, Cardoso explains. “These include tumor size, whether the tumour is present in the lymph nodes of the armpit and the presence or absence of specific biological markers. All these and more are taken together and added to what is called ‘patient characteristics’, which are the age of the patient, her menopausal status and the presence of any pre-existing conditions.”
MammaPrint, on the other hand, focuses on the tumor’s genomic composition. It specifically targets of a set of 70 genes that were found to be predictive of tumour relapse and metastasis.
“The original study that identified this ‘70-gene signature’ was conducted at the Molecular Lab of the Netherlands Cancer Institute”, Cardoso recounts. “In this study, the genomic composition of tumours from breast cancer patients were analysed. Out of 44.000 genes that were studied in each tumour, the team isolated a group of 70 genes that were very important – the way they were expressed (over- or under-expressed) was indicative of the long-term prognosis of the disease. More specifically, they predicted whether the tumour would relapse after a period of ten years in patients that did not receive chemotherapy.”
According to Cardoso, this discovery was very encouraging, but it was only the first step. Next, it was necessary to confirm the test’s value for chemotherapy-decision-making in a large prospective randomized trial with an independent set of patients. “It wasn’t easy to find frozen tumour samples from untreated patients with at least ten-year follow-up, but we finally succeeded. The results confirmed the original finding: the 70-gene signature could identify which patients have a high or a low risk of relapse“.
Putting MammaPrint to the test
This additional validation launched a large-scale, ten-year clinical trial called MINDACT, involving 6.693 patients from nine european countries. Led by Cardoso, who was working in Brussels at the time and serving as Scientific Director of the TRANS-BIG network, which orchestrates the trial, it set out to compare the ability of MammaPrint to predict a patient’s chances of relapse with that of the traditional method.
In the trial, the risk of relapse of each patient was assessed using both the traditional method and MammaPrint. The patients were then classified into one of three groups: both methods said high risk of relapse, both methods said low risk of relapse, or they differed. The patients in the third group were randomly assigned to be treated according to the assessment of either the traditional method or MammaPrint. Then, depending on whether the assessed risk was high or low, they were offered, or not offered, chemotherapy.
The results reported after five years of follow-up were impressive: they showed that “if a patient is classified as high risk by the traditional method, but low risk by the genomic method, receiving chemotherapy doesn’t result in a significant benefit to the patient. Furthermore,” Cardoso says, “it showed that within the clinical classification of high risk, about 46% could be classified as low risk by MammaPrint and not receive chemotherapy. It’s a huge percentage that will allow us to substantially decrease the number of patients that receive chemotherapy.”
Bringing MammaPrint to the clinic
MammaPrint is already commercially available, but despite the strong results obtained up to now, most public health systems and private insurers have not yet made it reimbursable to patients. This is linked to the cost of test, which ranges from about 2.500 to 3.000 Euros. However, cost-effectiveness studies have shown that its adequate use, namely in the correct group of patients, can actually save financial resources.
According to Cardoso, there is a substantial group of patients where the test can be very helpful, but they do not have access to it since at the moment, with few exceptions (in Portugal: IASFA and CGD), it is not reimbursed and not everyone can afford the cost. “This trial provides level one evidence (the strongest) regarding the value of the test. MammaPrint helps patients and is cost-effective. There is no reason not to use it”, she concludes.
Liad Hollender works as a Science Writer at the Science Communication Office at Champalimaud Research
Edited by: Ana Gerschenfeld & Catarina Ramos(Science Communication office). Image credit: © 2016 Fotografia de Joaquim Leal.