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MammaPrint testing pinpoints risk of breast cancer recurrence from the primary tumour`s genetic make-up

Posted on: 30 Sep 08
MammaPrint testing pinpoints risk of breast cancer recurrence from the primary tumour`s genetic make-up


Deciding whether or not women with breast cancer require adjuvant chemotherapy after removal of the primary tumour has traditionally been based on a series of prognostic clinical features such as tumour size, lymph node involvement, and other factors. If risk of recurrence is deemed low, adjuvant therapy and its associated toxicity can be avoided. Molecular technology is now available to help clinicians decide on the risks of a particular tumour recurring, based on its genetic fingerprint.
Women with very small breast cancer tumours <20mm, are usually considered by clinical guidelines to have a good prognosis. However, results of a small study reported at the recent European Society for Medical Oncology (ESMO) annual congress in Stockholm, Sweden, suggest that for a substantial proportion their risk of recurrence and later distant metastases is much higher than previously thought.

The study conducted by researchers at the Netherlands Cancer Institute, Amsterdam, and the Bioinformatics division of Agendia Laboratories, used the latter’s microarray gene-expression analysis tool, MammaPrint, to assess whether tumour tissue showed gene profiles indicating a high or low risk of metastasis. The MammaPrint test compares how many of a reference set of 70 key genes linked to breast cancer, and which have been shown to influence risk of recurrence, are present in a tumour’s gene signature.

Lead study author Dr Annuska Glas of Agendia, said that, of 319 small tumours analysed with MammaPrint, 39 were below 11mm and of these 19 (49%) showed a good prognostic gene signature with a predicted 10-year overall survival of >90%. The remaining 20 (51%) had a poor prognostic gene signature and their 10-year distant metastasis-free survival (DMFS) was calculated as being only 60%. In the 280 patients with tumours between 11 and 20mm, the probability of remaining free of distant metastases at 10 years was 85% in the group with a good prognostic signature (44%) and 60% in the group with a poor prognostic signature (56% of patients), In a further sample of tumours from 145 patients of indeterminate clinical risk (lymph node-negative, estrogen receptor-positive and grade 2), 90 (62%) had a good prognostic signature with a predicted 10 year survival of 92% while 55 (38%) had a poor prognostic signature with a 10-year projected survival of 60%.

Even when tumours in the study were very small, below 11mm, patients at high risk were able to be identified by their tumour gene signature in comparison to the reference gene set in MammaPrint, said Dr Glas. Results of the test have important implications for how women are then treated over the next 10 years and choice of any adjuvant therapy selected for them. The test can also predict tumour sensitivity to specific chemotherapy agents. Patients identified by the test as being at high risk can be pre-tested to see what treatments offer their particular cancer the best chance of tumour response, progression free survival and a good outcome. The MammaPrint DNA microarray will complement other tests such as TargetPrint used to decide which patients are likely to respond best to certain targeted therapies

MammaPrint results provide extra guidance for oncologists over clinical guidelines on whether or not adjuvant therapy is required, said Dr Glas. The test has been independently validated in several cohort studies and is claimed to be a more reliable predictor than tests involving standard prognostic markers. Identifying patients at low risk is as important as identifying those at high risk for purposes of deciding on adjuvant chemotherapy. Oncologist Michae Wolf of Vivantes Klinikum am Urban, Berlin, Germany, commented: “In comparison with the St Gallen criteria, MammaPrint identifies significantly more patients (approx 40% vs 15%) with a lower recurrence risk.”

New era of personalised medicine

Molecular testing with sophisticated assay technology is an essential component in new moves to offer patients treatment tailored specifically to their individual cancer rather than treatments that have been demonstrated to benefit average patients in large groups, commented pathologist Professor Giuseppe Viale of University of Milan and a director of the European Institute of Oncology during an Agendia-sponsored briefing. “There are approximately 400,000 new cases of breast cancer diagnosed in Europe each year but currently they are treated with one of only 10 chemotherapy combinations. This means 40,000 of them get exactly the same treatment. Patients are not being treated according to their individual risk profile and predictive parameters but according to what worked best in large groups of patients,” he pointed out. Basing decisions on results of tests like MammaPrint was introducing a whole new philosophy, he said. “It’s a new paradigm where we are listening to what individual tumour cells tell us they need to transform, grow, progress and survive and then choosing treatments targeting those processes.”

Agendia CEO Professor Rene Bernards, claims the test is superior to conventional means of assessing risk of future metastatic disease such as histological assessment of tumour aggressiveness, and has been well validated. The fresh tumour samples used in Mamma Print testing are considered more effective at yielding RNA-based information than parrafin-fixed samples in conventional laboratory testing yielding degraded RNA.

MammaPrint’s FDA submission was supported by a study in women up to age 60. Tumour samples and clinical data from 302 patients under 61 at five European centers in the TRANSBIG study confirmed the test was useful in predicting time to distant metastasis in the two earliest stages of the disease (Stage I and Stage II) where tumour size is equal to or less than 50 mm and when the cancer is lymph node negative. A prospective study MINDACT (Micro-array In Node-negative Disease may Avoid ChemoTherapy) is now comparing the relative accuracy of MammaPrint against traditional prognostic assessment methods in predicting the outcomes of 6000 patients focusing on patients where there is discordant assessment between the two methods.

By using MammaPrint testing as a basis for clinical decision-making, it is hoped women at low risk can be spared the hazards of unnecessary adjuvant chemotherapy which can cause myelosuppression, mucositis, cardiac problems, peripheral neuropathy, central neurotoxicity or leukaemia. This is particularly important where treatments are likely to have no impact on tumour recurrence. “Approximately 70% of all breast cancer patients with stage 1 or II disease could stay free of metastases without any adjuvant therapy,” said French oncologist Dr Joseph Gligorov of Tenon Hospital, Paris. “It is important to identify this group accurately.” Cutting out unnecessary treatment, improves quality of life and could save costs of up to €50,000 per patient, he estimates.

• MammaPrint was the first in vitro diagnostic multivariate index assay (IVDMIA) device to be approved by the US FDA and was cleared for use in August 2007. Before then it had been approved by European regulators in 2005. It is now available in a large number of centres worldwide, said Prof Bernards. “MammaPrint technology is just the tip of the iceberg. We are at the beginning of a new era of truly personalised medicine where precise tumour diagnosis will mean we will be able to identify the right drug therapy for the right patient. There will no longer be a one size fits all approach.”

As well as MammaPrint, Agendia has developed TargetPrint, a test to determine gene expression levels of ER, PR and HER2 in tumour biopsies; and CupPrint, a test which identifies the origin of a metastasis when the location of a primary tumour is unknown. In addition, it is involved with DiscoverPrint, a collaborative service with Pharma companies to develop personalised cancer drugs.

Reference: Glas AM, Roepman P, de Snoo F and van’t Veer, L. MammaPrint predicts survival in small T1 breast cancer tumours. Abstract 189PD Annals of Oncology 2008 ; vol 19: suppl’t 8 pviii79.

Olwen Glynn Owen - Pharmiweb Field reporter

Last updated on: 27/08/2010 11:40:18

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