MammaPrint

Key takeaways

MammaPrint belongs to science; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect MammaPrint to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of MammaPrint from memory before moving on to harder problems.

Reference excerpt

MammaPrint is a prognostic and predictive diagnostic test for early stage breast cancer patients that assess the risk that a tumor will metastasize to other parts of the body. It gives a binary result, high-risk or low-risk classification, and helps physicians determine whether or not a patient will benefit from chemotherapy. Women with a low risk result can safely forego chemotherapy without decreasing likelihood of disease free survival. MammaPrint is part of the personalized medicine portfolio marketed by Agendia. MammaPrint is based on the Amsterdam 70-gene breast cancer gene signature and uses formalin-fixed-paraffin-embedded (FFPE) or fresh tissue for microarray analysis. It is a laboratory developed test (LDT) which falls into the class of In Vitro Diagnostic Multivariate Index Assays (IVDMIA). MammaPrint was the first (2007) IVDMIA to be cleared by the Food and Drug Administration (FDA) in a De Novo Classification Process (Evaluation of Automatic Class III Designation) and is the only molecular diagnostic test with a randomized prospective clinical trial validating clinical utility. The test uses RNA isolated from tumor samples and run on custom glass microarray slides in order to determine the expression of a 70-gene signature. The expression profile is then used in a proprietary algorithm to categorically classify the patient as being at either high or low risk of breast cancer recurrence. MammaPrint has been prospectively, clinically validated for use in early stage (I and II) breast cancer patients regardless of estrogen receptor (ER) or Human Epidermal Growth Factor Receptor 2 (HER2) status, with a tumor size ≤ 5.0 cm, and 0-3 positive lymph nodes (LN0-1), with no special specifications for N1mi pathology. This differentiates MammaPrint from other multi-gene assays in use today that have only shown predictive value in ER positive, HER2 negative, lymph node (LN) negative patients. MammaPrint is also indicated for patients with ER negative tumors (15% of tumors). There are no exclusion criteria based on histopathologic tumor type (i.e. ductal, lobular, mixed, etc.) or age. MammaPrint is predictive for pre- and post-menopausal women.

Development The Human Genome Project identified approximately 25,000 genes in the human genome and created the possibility for personalized medicine. The Netherlands Cancer Institute (NKI) in Amsterdam utilized this information and applied it specifically to breast cancer, creating the Amsterdam 70-gene signature (70-GS). MammaPrint is the commercialized assay that measures the 70-GS. The NKI hypothesized that breast cancer is a genetic, heterogeneous disease, where gene expression would be different in aggressive breast tumors that develop recurrences following surgery than from those that are less aggressive and do not recur or spread throughout the body. To identify a novel and independent predictor of breast cancer recurrence, DNA microarray technology was used to interrogate all 25,000 genes in untreated tumor samples from women where follow-up categorized them as being disease free or having distant metastases within five years. Supervised classification identified significantly different expression patterns in 70 genes that were strongly predictive of a short interval to distant metastases.

Implications for utility The paradigm used to development the 70-GS makes it unique in molecular breast cancer diagnostics because it allowed the tumor biology itself to show the genes most predictive of known patient outcomes. Rather than pre-selecting a few genes based on literature and known information at a given time, supervised learning from the entire expressed genome gives it farsighted utility as the knowledge of cancer biology evolves. Furthermore, development using untreated tumors allows physicians to know their patient's risk of recurrence, without any treatment bias or assumptions, before making a patient's treatment plan.

Clinical Utility Molecular diagnostics are used in combination with traditional clinicopathologic factors to decide on a treatment plan. MammaPrint provides a binary result, either high risk or low risk. Patients with a low risk result are unlikely to develop distant metastases and are therefore unlikely to benefit from chemotherapy. Since many breast cancers are considered genomically low-risk independent from clinicopathology, a significant number of patients can be saved from overtreatment with chemotherapy.

Guideline Inclusion MammaPrint is included as standard of care with the highest medical level of evidence in the following guidelines

Dutch Institute CBO Guidelines for treatment of primary breast cancer St. Gallen's International Oncology Guidelines for the treatment of early stage breast cancer German Gynecological Oncology Group (AGO) guidelines for breast cancer management European Group on Tumour Markers (EGTM)

Ordering indications In February 2007, the U.S. Food and Drug Administration (FDA) cleared the MammaPrint test for use in the U.S. for lymph node negative breast cancer patients of all ages, ER negative or ER positive, with tumors of less than 5 cm. MammaPrint can be considered as a part of standard of care disease management for early stage breast cancer and has significant insurance coverage in the US, including coverage through Medicare and Medicaid. The American Medical Association has granted a Category 1, MAAA Current Procedural Terminology (CPT) code for MammaPrint. Indications for ordering MammaPrint include:

USA- Breast Cancer Stage 1 or Stage 2 Invasive carcinoma (infiltrating carcinoma) Tumor size <5.0 cm Lymph node negative Estrogen receptor positive (ER+) or Estrogen receptor negative (ER-) Women of all ages Samples from the United States and North America are processed and run in CLIA certified lab in Irvine, CA.

International- Breast Cancer Stage 1 or Stage 2 Invasive carcinoma (infiltrating carcinoma) Tumor size <5.0 cm Lymph node status: negative or positive (up to 3 nodes) ER+ or ER- Samples from outside North America are processed and run in Amsterdam, Netherlands.

Pakistan- Mammaprint is now exclusively available in Pakistan through Precision Diagnostic Laboratory

Tissue sampling technique Tumor samples may be submitted as core needle biopsies or surgical specimen. MammaPrint is FDA cleared to accept fresh, frozen, and formalin fixed paraffin embedded (FFPE) specimen types. There are two specimen types that can be submitted:

… excerpt ends here. Continue reading the full article.

Worked examples

Example 1 — a first encounter with MammaPrint

Start with the simplest possible case. Write down what MammaPrint claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In science, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to MammaPrint before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about MammaPrint ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of MammaPrint

In research: MammaPrint appears in science research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses MammaPrint in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: MammaPrint is common in secondary-school and first-year university syllabi. It links to neighbouring topics Microarrays, so understanding it makes those chapters shorter.
In everyday life: Look for MammaPrint outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study MammaPrint in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what MammaPrint means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain MammaPrint out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is MammaPrint in simple terms?

MammaPrint is a prognostic and predictive diagnostic test for early stage breast cancer patients that assess the risk that a tumor will metastasize to other parts of the body. It gives a binary result, high-risk or low-risk classification, and helps physicians determine whether or not a patient wil…

Why does MammaPrint matter?

Because it connects several science ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study MammaPrint?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on MammaPrint.