Dutch Diagnostic Company to Play Pivotal Role in ISPY-2 Trial for Breast Cancer

Agendia, a Netherlands genomics cancer diagnostics company and a world leader in molecular cancer diagnostics focused on the personalized treatment of breach cancer patients, will play a major role in the I-SPY 2 TRIAL for breast cancer. The trial is set to launch at the first of nearly twenty research sites.


I-SPY 2 is an exciting and groundbreaking new clinical trial model that will help scientists quickly and efficiently test the most promising drugs in development for women with higher risk, rapidly growing breast cancers-women for whom an improvement over standard treatment could dramatically change the odds of survival. I-SPY is an initiative of The Biomarkers Consortium, a unique public-private partnership that includes the U.S. Food and Drug Administration (FDA), the National Institutes of Health (NIH), and major pharmaceutical companies, led by the Foundation for the National Institutes of Health (FNIH).

"Cancer tumor profiling in the neoadjuvant setting is critical to the success of the I-SPY 2 trial. Agendia is uniquely positioned to be a part of the Biomarker Consortium in this landmark study, and proud to be working side by side with a large number of visionary therapeutic companies and research centers," said Bernhard Sixt, Chief Executive Officer of Agendia. "Agendia's MammaPrint has proven value for breast cancer recurrence in the neoadjuvant and adjuvant settings, Agendia's TargetPrint provides objective, quantitative information about the expression of ER, PR and Her-2neu, while our DiscoverPrint measures the expression of the whole genome. In concert they will form an integral part of the clinically relevant discoveries the Consortium aims to make."

MammaPrint, the first and only highly accurate breast cancer recurrence test cleared by the U.S. Food and Drug Administration under the in vitro diagnostic multivariate index assay (IVDMIA) guidelines, identifies patients with early metastasis risk - patients who are likely to develop metastases within five years following surgery. Several authoritative studies have shown that chemotherapy particularly reduces early metastasis risk. In planning treatment, the MammaPrint test results provide doctors with a clear rationale to assess the benefit of chemotherapy in addition to other clinical information and pathology tests.

Scientists from the National Cancer Institute (NCI), FDA, and nearly 20 major cancer research centers across the United States have united to develop and conduct this unprecedented large-scale scientific collaboration to test novel breast cancer drugs in the neoadjuvant clinical trial setting. Results will be made broadly available to the cancer research and development community in order to foster this integrated approach to improve clinical trial success and the efficacy of cancer therapeutics.

Test Identifies Low-risk Subgroup in HER2-positive Breast Cancer

HER2, human epidermal growth factor receptor 2, is a protein found on the surface of breast cancer cells. When functioning normally, HER2 is a key component in regulating cell growth. However, when altered, extra HER2 protein receptors may be produced.

This overexpression of HER2 is considered a negative prognostic factor and associated with increased cell growth and reproduction, often resulting in a more aggressive form of breast cancer with increased disease recurrence and worse prognosis. Studies show that HER2/neu is overexpressed in approximately 15-20% of invasive breast cancers. Because HER2+ tumors tend to grow and spread more quickly than tumors that are not HER2+, accurate and timely diagnostic procedures are crucial.

High Risk
There are a number of different kinds of breast cancer and each is treated differently. Patients with Her2+ breast cancer are generally classified as high risk. As a result, current treatment guidelines recommend adjuvant trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990, co-marketed by F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland) and chemotherapy as the best treatment option for all HER2-positive breast cancer patients at high risk of relapse, increasing their chance of living longer. At the same time, results from the HERA-trial (HERceptin Adjuvant), a randomized, two-arm, open label study of the efficacy, safety and tolerability of trastuzumab compared to observation in women who have completed standard adjuvant treatment of HER2 positive primary breast cancer, showed that 74% of patients remained distant recurrence-free at 3 years without trastuzumab.

A highly sensitive prognostic tool
Dr. Michael Knauer, MD, from the Netherlands Cancer Institute presented the results from a study investigating the benefits of a highly sensitive diagnostic assay during the 2008 San Antonio Breast Cancer Symposium (SABCS). In the study, researchers used MammaPrint®, (Agendia BV, Amsterdam Science Park, Kruislaan 406, NL-1098 SM Amsterdam, The Netherlands), a prognostic genomic test developed with micro-array technology that has the potential to greatly improve risk assessment and treatment decision making for early breast cancer, to identify a subgroup of patients with low risk and favorable outcome. This test looks at the expression of 70 genes linked to breast cancer with an accuracy level of 96.7% as determined by a study published in the New England Journal of Medicine. This prognostic signature of genetic 'fingerprint' is validated as an independent prognostic indicator for patients with up to three positive lymph nodes.

Knauer showed that the highly accurate MammaPrint was able to differentiate between patients at high risk for recurrence and a low risk subgroup of HER2+ patients. The assay helped uncover a substantial group of traditionally miscategorized low risk HER2+ patients.

Study results
In the study population of 169 HER2+ patients, Mammaprint, the first ‘in vitro diagnostic multivariate index assay’ (IVDMIA) cleared by the U.S. Food and Drug Administration (FDA) designed to identify patients with early metastasis, classified 16 percent of patients as having a good prognosis signature with a 10-year distant disease-free survival (DDFS) of 89 percent, even in the absence of (neo)adjuvant trastuzumab and chemotherapy, compared to 84 percent of patients classified as having a poor prognosis signature with a DDFS of 64 percent. Additionally, in a subgroup of highly endocrine responsive HER2/neu positive patients, MammaPrint low risk patients had no relapse.

All 169 patients with HER2-positive breast cancer were selected from a pooled dataset of 1280 patients with known HER2-status. Patients had a unilateral T1-3, N0-1 tumor and were treated with either breast-conserving therapy or mastectomy. Samples were analyzed and classified by the 70-gene signature as good or poor prognosis by Agendia Laboratories.

The strength of the assay is underscored by the 70 gene panel unique to the test and a resulting gene profile that covers all molecular pathways associated with breast cancer.

Personalized medicine
MammaPrint accurately identified a subgroup of patients with a good clinical outcome in HER2+ early breast cancer. These patients will be further studied in the ongoing MINDACT-trial (EORTC 10041/ BIG 3-04), a multicentre, prospective, phase III trial coordinated by the EORTC (European Organisation for Research and Treatment of Cancer) and run under the BIG and TRANSBIG network, which will accrue 6000 node-negative patients designed to determine the prospects of withholding chemotherapy and/or trastuzumab in HER2+, MammaPrint low risk patients.

This study compares MammaPrint to traditional clinical-pathological methods to assess the risk of breast cancer recurring in women with lymph node negative disease. Since breast cancer tumors with similar clinicopathological characteristics can have strikingly different outcomes, the traditional selection for adjuvant chemotherapy is far from accurate.

Based on the initial results with MammaPrint, it is hypothesized that using the genomic test in addition to traditional methods will result in more accurate risk assessment. It is expected that 10% to 20% of patients with node negative breast cancer will, in the future, safely be able to avoid chemotherapy and its potential side effects.

The current trend in research cancer is to develop ways of individualizing breast cancer treatment. This goal toward ‘personalized medicine’ requires better identification of type of systemic treatment and better identification of patients who are highly likely to develop distant metastases, and therefore, may benefit the most from adjuvant chemotherapy.

MammaPrint may be one of the tools helping to realize these goals.

For more information, read:

• Knauer M, Cardoso F, Mook S. et al. Identification of a low risk subgroup in Her2-positive breast cancer by the 70-gene prognosis signature. SABCS, Saturday, December 13, 2008 - 7:00 AM Poster Session IV: Late Acceptances (7:00AM-9:00AM). Abstract 4171.

Watch:

• Options for HER2+ Breast Cancer (video).

Also review PubMed abstracts:

• Haibe-Kains B, Desmedt C, Piette F, et al. Comparison of prognostic gene expression signatures for breast cancer. BMC Genomics. 2008 Aug 21;9:394. Free Full Text Article (PDF);
• Mook S, Schmidt MK, Viale G, et al. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2008 Jul 27. [Epub ahead of print];
• Cardoso F, Van't Veer L, Rutgers E, et al. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008 Feb 10;26(5):729-35.
• Marchionni L, Wilson RF, Marinopoulos SS et al. Impact of gene expression profiling tests on breast cancer outcomes. Evid Rep Technol Assess (Full Rep). 2007 Dec;(160):1-105;
• Mook S, Van't Veer LJ, Rutgers EJ et al. Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics. 2007 May-Jun;4(3):147-55;
• Van de Vijver MJ, He YD, van't Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002 Dec 19;347(25):1999-2009.

More information:

• EORTC – The Mindact brochure.
• EORTC – The Mindsact website.
• Clinical trial: Trastuzumab in Treating Women With Primary Breast Cancer (EORTC, NCIC, BIG); Phase III.