Examining MammaPrint®: An Interview with Richard Bender, MD

In the United States, more than 200,000 women receive a breast cancer diagnosis annually. Early detection offers patients the best chance for a cure, but may also lead to treatment dilemmas in some patients. Oncology Net Guide (ONG) had the opportunity to interview Richard Bender, MD, FACP, chief medical officer of Agendia, about MammaPrint, a breast cancer recurrence assay that can help oncologists determine the metastatic potential of their early-stage breast cancer patients’ tumors.

ONG: How does MammaPrint work and what is its clinical utility? Dr Bender:

The MammaPrint test is performed on a fresh tumor tissue sample, and measures the gene expression profile of the 70 genes that constitute the test. MammaPrint classifies tumors as either high risk or low risk for recurrence, and when used in conjunction with other risk factors, helps identify patients who will benefit from adjuvant therapy. Compared with standard risk-assessment factors, MammaPrint significantly reduces the number of patients traditionally classified as having a poor prognosis, while at the same time identifying those patients who may be at increased risk for recurrence despite their clinical pathological findings.

Which patients with breast cancer benefit from MammaPrint testing? Or is screening a more appropriate word?

MammaPrint is not a screening device or service; rather, it is a gene expression profile. A breast cancer patient should meet the following criteria to be eligible:

• Stage 1 or stage 2 breast cancer
• Invasive carcinoma (infi ltrating carcinoma)
• Tumor size <5.0 cm
• Lymph node negative
• Estrogen receptor positive (ER+) or estrogen receptor negative(ER-)

What are advantages to using MammaPrint versus other types of molecular screening and how do physicians choose?

MammaPrint is a true next-generation breast cancer recurrence assay. Developed and validated on untreated patient samples, it is equally prognostic for patients who are either ER+ or ER- and avoids therapy requirements assumed by other tests. Based on extensive clinical discussions about early-stage breast cancer treatment thresholds—who may safely forego adjuvant therapy versus who may benefit from more aggressive therapy—MammaPrint was designed to provide a binary “low-risk” or “high-risk” result, thereby ensuring every patient result is clinically relevant and useful. With MammaPrint, physicians and their patients have an FDA-cleared test which aides in therapeutic decision- making every time, compared with other assays which often provide an ambiguous “intermediate” result. MammaPrint’s added value is supported by these differentiators, which competing assays do not provide.

The FDA has given four clearances to MammaPrint. What uses has the FDA cleared?

In February 2007, the FDA cleared MammaPrint as a prognostic tool for patients less than 61 years with stage 1 or stage 2 breast cancer, invasive carcinoma (infiltrating carcinoma), tumor size <5.0 cm, negative lymph nodes, and ER+ or ER- tumors. In June 2007, the FDA cleared the MammaPrint fresh tissue transport methodology with RNARetain®, allowing for room- temperature shipping. In July 2008, MammaPrint was cleared to be run on a new high-density microarray, and in December 2009, FDA clearance was expanded for use in women of all ages.

How does using formalin-fixed, paraffin-embedded tissue (like OncotypeDX) affect results compared with using fresh or frozen tissue samples, like MammaPrint:

The benefit of working with fresh tissue is that mRNA integrity is preserved. Using formalin-fixed, paraffin-embedded tissues, on the other hand, damages mRNA, leaving truncated pieces. Since genomic tests such as these rely on measuring mRNA expression levels, maintaining mRNA integrity is vital. The National Institutes of Health (NIH) Biorepository, moreover, recommends fresh tissue sampling. NIH has recently launched the landmark I-SPY 2 trial in collaboration with the FDA, the National Cancer Institute (NCI), and a host of leading pharmaceutical and biotechnology companies. The use of MammaPrint is one of the key pivots for the study.

Risk assessments are often performed using online questionnaires, such as Adjuvant! Online and the NCI’s Breast Cancer Risk Assessment Tool based on the Gail Model. Are these tests useful and do you have anyconcerns about them?

While such assessments are generally useful, attention should be paid to the fact that one criterion is often more heavily weighted at the expense of another. It is, therefore, crucial to understand how these tools were developed and use them correctly to help inform treatment decisions. For instance, MammaPrint is FDA-cleared to be used in conjunction with other clinical pathological criteria.

Is insurance coverage a problem with MammaPrint?

In December 2009, MammaPrint obtained Medicare coverage through Palmetto in California and payors reimbursing MammaPrint cover some 70 million lives in the United States. Currently, MammaPrint falls under a generic CPT code, 84999. A number of private payors reimburse for MammaPrint and Agendia is in discussions to have MammaPrint included in their policies.

What is TargetPrint® and how does it work with MammaPrint?

TargetPrint is a microarray-based gene expression test that offers a quantitative assessment of the level of ER, progesterone receptor (PR), and HER2/neu overexpression in a patient’s breast cancer. It is offered in conjunction with MammaPrint to provide physicians with a more comprehensive information set to help guide treatment decisions. As compared with immunohistochemistry (IHC), TargetPrint delivers an added benefi t to the diagnostic process. While IHC provides a semi-quantitative positive or negative result, the gene expression result provided by TargetPrint allows physicians to integrate the absolute level of ER, PR, and HER2 gene expression for these three biomarkers into treatment planning. The tests are performed on quality-controlled DNA microarrays in Agendia’s state-of-the-art CLIA (Clinical Laboratory Improvement Act) and CAP (College of American Pathologists) registered and compliant genomics laboratories in Huntington Beach, California, and Amsterdam, The Netherlands.

Is MammaPrint used worldwide? Yes, MammaPrint is used worldwide, although our commercial focus is on the US market and principal European markets.

Any additional plans for MammaPrint that you can share? On March 17, Agendia announced that MammaPrint is to play a pivotal role in the I-SPY 2 trial (http://ispy2.org). The trial, which I briefly mentioned earlier, is supported by the NIH, NCI, FDA, and a host of leading pharmaceutical and biotechnology companies. Specifically, information from Agendia’s genome expression profiling will provide “snapshots” of tumor biopsies before and after administration of the neoadjuvant therapies under investigation. Combined with data from the other trial participants, this promises to accelerate trials, reduce patient enrollment numbers, and generate huge savings for commercial, research, and governmental institutions. In short, I-SPY 2 aims to help change the way clinical trials are conducted and biologics and pharmaceuticals are developed. Additionally, Agendia recently launched BluePrint, which is a new microarray-based 80-gene expression profi le which classifies a woman’s breast cancer into the Basal-type, Luminal-type, or ERBB2- type (HER2+) molecular subtypes. Agendia also launched TargetPrint Research Gene Panel, a gene expression panel of 56 genes identified as potential targets for therapeutic response to a variety of treatment for breast cancer. Both of these new signatures hold promise for improved understanding about a patient’s unique tumor biology, and perhaps the key to a greater level of personalized care.

Looking for more information on MammaPrint?Consider these 4 articles:

Gene expression profiling: Decoding breast cancer

AUTHORS: de Snoo F, Bender R, Glas A, Rutgers E. CITATION INFORMATION: Surg Oncol. 2009;18(4):366-378.

ABSTRACT AVAILABLE AT: www.ncbi.nlm.nih.gov/sites/entrez/19879448

Validation of 70-gene prognosis signature in node-negative breast cancer

AUTHORS: Bueno-de-Mesquita JM, Linn SC, Keijzer R, et al. CITATION INFORMATION: Breast Cancer Res Treat. 2009;117(3):483-495.

ABSTRACT AVAILABLE AT: www.ncbi.nlm.nih.gov/sites/entrez/18819002

Metastatic potential of T1 breast cancer can be predicted by the 70-gene MammaPrint signature

AUTHORS: Mook S, Knauer M, Bueno-de-Mesquita JM, et al. CITATION INFORMATION: Ann Surg Oncol. 2010;17(5):1406-1413.

ABSTRACT AVAILABLE AT: www.ncbi.nlm.nih.gov/sites/entrez/20094918

The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer

AUTHORS: Knauer M, Mook S, Rutgers EJ, et al. CITATION INFORMATION: Breast Cancer Res Treat. 2010;120(3):655-661.

ABSTRACT AVAILABLE AT: www.ncbi.nlm.nih.gov/sites/entrez/20204499