MammaPrint Genetic Test

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.[1] 

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.[2] 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.[3] 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.[4] 

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.[5][6] 

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[7]). 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.[8][9]

Assessment

The MammaPrint genetic test can reduce the use of adjuvant chemotherapy following surgery among patients with early-stage breast cancer who are considered at high risk for disease recurrence, a study presented American Academy for Cancer Research (AACR) Annual Meeting 2016 has shown. (10)

For the prospective, international, controlled, phase 3 MINDACT trial, researchers sought to evaluate the clinical utility of the 70-gene signature MammaPrint genetic test combined with common clinical-pathological criteria for selecting patients with breast cancer and 0 to 3 positive nodes for adjuvant chemotherapy.

Researchers enrolled 6693 women who had undergone surgery for early-stage breast cancer. All participants were classified as having low or high risk for cancer recurrence by both the MammaPrint genetic test and Adjuvant! Online, a tool that calculates risk of tumor recurrence based on common clinical and pathological criteria.

Patients were then divided into 4 groups:  2745 were considered having low risk of recurrence by both risk-assessment methods (G-low/C-low), 1806 were classified as having high risk by both methods (G-high/C-high), 592 were categorized as having high risk by MammaPrint and low risk by Adjuvant! Online (G-high/C-low), and 1550 were categorized as having low risk by MammaPrint and high risk by Adjuvant! Online (G-low/C-high).

Patients classified as G-low/C-low were assigned to no adjuvant chemotherapy. Participants categorized as G-high/C-high were assigned to adjuvant chemotherapy. Patients categorized as G-high/C-low or G-low/C-high were randomly assigned to receive either adjuvant chemotherapy or no adjuvant chemotherapy.

Results showed that among the 3356 C-high patients, treatment according to MammaPrint reduced the receipt of chemotherapy by 46%, with a 5-year metastasis-free survival of 94% among G-low/C-high patients whether they received adjuvant chemotherapy or not. The study demonstrated that 14% of patients could avoid chemotherapy by using the 70-gene signature assay to assess risk as compared with the conventional approach.

“At present, most oncologists make recommendations for adjuvant chemotherapy after considering common clinical and biological criteria such as patient’s age, and the stage and grade, as well as the hormonal receptor and HER2 status of his or her tumor,” said lead author Martine Piccart, MD, PhD, head of the Medicine Department at the Jules Bordet Institute in Brussels, Belgium, and co-founder and chair of the Breast International Group (BIG).

“The MINDACT trial results provide level 1A evidence that using MammaPrint could change clinical practice by substantially de-escalating the use of adjuvant chemotherapy and sparing many patients an aggressive treatment they will not benefit from.”

See Exhibit A for part of the Evidence

Exhibit A

Abstract
Purpose
Most node-negative breast cancer patients are older and postmenopausal and are increasingly being offered adjuvant chemotherapy despite their low overall risk of distant relapse. A molecular diagnostic test with high negative predictive value (NPV) for distant metastasis in this subgroup would spare many older breast cancer patients adjuvant treatment.
Experimental Design
We determined the NPV and positive predictive value of the MammaPrint assay in breast cancer patients who were consecutively diagnosed and treated at the Massachusetts General Hospital between 1985 and 1997. Primary tumors from 100 patients with node-negative, invasive breast cancer (median age, 62.5 years; median follow-up, 11.3 years) were subjected to MammaPrint analysis and classified as being at either low or high risk for distant metastasis.
Results
The MammaPrint 70-gene signature displayed excellent NPV as in previous studies, correctly identifying 100% of women at low risk for distant metastases at 5 years. However, this assay had a lower positive predictive value (12% at 5 years) than previously observed. (Source)
Clin Cancer Res. 2008 May 15; 14(10): 2988–2993.
Analysis of the MammaPrint Breast Cancer Assay in a Predominantly Postmenopausal Cohort

References


  1. ^ “Agendia | Agendia”. www.agendia.com. Retrieved 2017-03-27.
  2. ^ Cardoso, Fatima; van’t Veer, Laura J.; Bogaerts, Jan; Slaets, Leen; Viale, Giuseppe; Delaloge, Suzette; Pierga, Jean-Yves; Brain, Etienne; Causeret, Sylvain (2016-08-25). “70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer”. New England Journal of Medicine. 375 (8): 717–729. doi:10.1056/NEJMoa1602253. ISSN 0028-4793. PMID 27557300.
  3. ^ van ‘t Veer LJ, Dai H, van de Vijver MJ, et al. (2002). “Gene expression profiling predicts clinical outcome of breast cancer”. Nature. 415 (6871): 530–6. doi:10.1038/415530a. PMID 11823860.
  4. ^ Simon, Richard M.; Paik, Soonmyung; Hayes, Daniel F. (2009-11-04). “Use of archived specimens in evaluation of prognostic and predictive biomarkers”. Journal of the National Cancer Institute. 101 (21): 1446–1452. doi:10.1093/jnci/djp335. ISSN 1460-2105. PMC 2782246. PMID 19815849.
  5. ^ Cardoso, Fatima; van’t Veer, Laura J.; Bogaerts, Jan; Slaets, Leen; Viale, Giuseppe; Delaloge, Suzette; Pierga, Jean-Yves; Brain, Etienne; Causeret, Sylvain (2016-08-25). “70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer”. New England Journal of Medicine. 375 (8): 717–729. doi:10.1056/NEJMoa1602253. ISSN 0028-4793. PMID 27557300.
  6. ^ Drukker, C. A.; Bueno-de-Mesquita, J. M.; Retèl, V. P.; van Harten, W. H.; van Tinteren, H.; Wesseling, J.; Roumen, R. M. H.; Knauer, M.; van ‘t Veer, L. J. (2013-08-15). “A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study”. International Journal of Cancer. 133 (4): 929–936. doi:10.1002/ijc.28082. ISSN 1097-0215. PMC 3734625. PMID 23371464.
  7. ^ “Hormone Therapy for Breast Cancer”. www.cancer.org. Retrieved 2017-03-27.
  8. ^ Mook, S.; Schmidt, M. K.; Weigelt, B.; Kreike, B.; Eekhout, I.; van de Vijver, M. J.; Glas, A. M.; Floore, A.; Rutgers, E. J. T. (2010-04-01). “The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age”. Annals of Oncology. 21 (4): 717–722. doi:10.1093/annonc/mdp388. ISSN 1569-8041. PMID 19825882.
  9. ^ Wittner, Ben S.; Sgroi, Dennis C.; Ryan, Paula D.; Bruinsma, Tako J.; Glas, Annuska M.; Male, Anitha; Dahiya, Sonika; Habin, Karleen; Bernards, Rene (2008-05-15). “Analysis of the MammaPrint breast cancer assay in a predominantly postmenopausal cohort”. Clinical Cancer Research. 14 (10): 2988–2993. doi:10.1158/1078-0432.CCR-07-4723. ISSN 1078-0432. PMC 3089800. PMID 18483364.
  10. Piccart M, Rutgers E, van ‘t Veer LJ, et al. Primary analysis of the EORTC 10041/ BIG 3-04 MINDACT study: A prospective, randomized study evaluating the clinical utility of the 70-gene signature (MammaPrint) combined with common clinical-pathological criteria for selection of patients for adjuvant chemotherapy in breast cancer with 0 to 3 positive nodes. Oral presentation at: AACR Annual Meeting 2016; April 16-20, 2016; New Orleans, LA
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