Genomic assays are used to analyse a sample of breast cancer tissue in order to predict the risk of the various cancers, including breast as well as colon/colorectal cancer. While there are a number of genomic assays available, there has never been a real comparison between two of the major commercially available genomic assays, Oncotype DX?.(Genomic Health, Redwood City, CA, USA) and MammaPrint?, BluePrint? and TargetPrint?(Agendia; Irvine, CA, USA/Amsterdam, The Netherlands).
Genomic and genetic tests are not the same. Although related, genetics and genomics focuses on different information. Generally speaking, scientists studying genetics are trying to understand how certain inherited traits are passed on from one generation to the next through the genes. They are also looking at specific traits and how new traits may appear as a result of genetic mutations. Physicians are looking how a predisposition to certain types of diseases can be inherited. BRCA1 and BRCA2 genes are one example. Under normal conditions, these two genes help to control cell growth, however, a person who inherits a mutated version of these genes may have a higher risk of developing breast and ovarian cancer.
The 70-gene MammaPrint test provides the foundational risk classification of High Risk or Low Risk about breast cancer recurrence without the ambiguity of Intermediate results…
Following the completion of the Human Genome Project, which identified all 25,000 genes of the human genome, leading scientists and researchers hypothesized that since cancer is a genetic disease, gene expression should be different in aggressive breast tumors that develop recurrences following surgery from those that do not spread throughout the body. This concept, and a rapid growth in the understanding of the possibilities and options of molecular diagnostics was crucial in the commercial development of genomic assays.
Beyond decision making
Today, genomic assays, such as MammaPrint, are are not used to look at individual genes. Rather, using genomic assays, physicians are looking at groups of genes to analyse how active they are. Understanding the activity of these groups of genes in an individual patient can help them predict the likelihood that a cancer to grows or recurs. Patients and their oncologists must decided between a number of treatment options and genomic assays help them to make these decisions.Hence, the results of a genomic assay are important in guiding treatment decisions. Decisions between various surgical options and the dose, volume, and technique of radiotherapy or the specific drug used to treat the patients have a significant impact on treatment-related morbidity and survival from breast cancer. These decisions are different for each individual patient.
Better understanding of the risk has greatly facilitated – and improved – therapeutic decision making. But what’s more important, analyzing this genetic data also givens physicians tools to predict if an individual patient will benefits or respond to treatment. Genomic assays have really ‘personalized’ diagnostics and, as a result medicine.
First and second generation assays
According to findings presented at the recently concluded 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), which was held May 30 – June 3, 2014 in Chicago, Ill, there are substantial differences between the results provided by next-generation breast cancer tests and more limited results from the first-generation assays.
Researchers from the University of Pittsburgh School of Medicine reported the first independent study to directly compare clinical data from the next-generation MammaPrint and BluePrint tests to data from the first-generation 21-gene test. David J. Dabbs, M.D., Adam Brufsky, M.D. and colleagues at the University of Pittsburgh and related institutions presented the findings, which encompassed five-year outcome data from 437 patients.
Trial results
In this trial, Oncotype DX’s recurrence score on 437 patients with pathologically characterized ER+ tumors who had a minimum of 5 years follow-up from diagnosis was compared with MammaPrint, BluePrint and TargetPrint.
When tested by the 21-gene assay, nearly 37% of patient samples were classified as “intermediate” clinical risk for the likelihood that the breast cancer would recur in the future. This compared to a definitive high-risk or low-risk result for all patient samples tested using the MammaPrint assay. The results further showed that of 301 MammaPrint low risk cases, 191 were low risk by Oncotype DX (63% agreement) and of 136 MammaPrint high risk, 63 were high risk by Oncotype DX (46%). The results showed of Oncotype DX intermediate risk cases (161). A total of 104 were MammaPrint low risk (65%) and 57 (35%) were MammaPrint high risk.
The trial further showed of BluePrint low risk luminal tumors, 188/287(66%) were Oncotype DX low, 95/287 (33%) Oncotype DX intermediate, and 4/287 (1%) Oncotype DX high risk. Tumor grade was significantly correlated at P<.0001 with risk assessment by both tests blueprint class was correlated ER, PR and HER2 results.
Overall agreement between clinical ER, PR, HER2 (IHC+FISH) results with TargetPrint results were 92% (401/435), 85% (370/436), 95% (412/435), but percent positive agreement for HER2 was only 50% (20 of 40 unequivocally HER2 positive cases identified correctly by TargetPrint).
Four percent of Oncotype DX low risk, 34% of intermediate and 77% of Oncotype DX high risk Oncotype DX patients received chemotherapy. There were 7 distant recurrences: 4 were MammaPrint high, 3 MammaPrint low. For Oncotype DX, 5 were intermediate, 1 high,1 low.
Based on these findings, the authors concluded that:
- There are real differences in risk assignments between MammaPrint and Oncotype DX that may affect treatment decisions.
- There was close correlation between pathologic variables and MammaPrint and BluePrint, but HER2 TargetPrint -FISH/IHC agreement is low.
- Further follow-up of this cohort is required, along with prospective trials, to determine clinical utility of these tests compared to pathologic analysis.
“Together, MammaPrint and BluePrint reassign a substantial number of intermediate recurrence scores into ‘Low’ or ‘High’ risk, based on tumor intrinsic phenotype and gene expression analysis,” Dabbs noted. Brufsky added that this is “valuable information because it can help us better determine how best to treat each patient. With a high-risk, low-risk finding, you don’t have the uncertainty that occurs in the intermediate range.”
Foundational risk classification
The 70-gene MammaPrint test provides the foundational risk classification of High Risk or Low Risk about breast cancer recurrence without the ambiguity of intermediate results. Additional significant, therapy-relevant information is then conferred by the 80-gene BluePrint assay that identifies the molecular subtype. Blueprint provides insight into the predominant genomic pathway driving the cancer, thereby facilitating prediction of tumor response to pathway-targeted therapies before and after surgery. These tests are the only widely available assays that provide “functional” molecular subtyping to guide breast cancer treatment decisions.
“By looking at the activity of the genes through molecular subtyping, the 80-gene test tells us more about what’s happening in the cancer cells,” Brufsky explained.
African-American women
In another study presented at ASCO, researchers from MedStar Washington Hospital Center reported African-American
women are more likely to be diagnosed with higher-risk breast cancer.
Their study used MammaPrint and BluePrint to determine recurrence risk and molecular subtype in a group of 100 African-American women with breast cancer. Patients in that group often presented with disease that had a high risk of recurrence, regardless of the stage of the disease. More information on the study is available here.
Among the other studies at ASCO, Peter Beitsch, M.D. of Medical City Dallas Hospital and colleagues reported data from the “NBRST” registry, in which 55 U.S. institutions utilizing TheraPrint? (Agendia; Irvine, CA, USA/Amsterdam, The Netherlands) were able to identify 15 gene expression markers that correlated with response to neoadjuvant chemotherapy as part of breast cancer treatment. Researchers concluded that the novel TheraPrint assay may help predict an individual patient’s preoperative response to chemotherapy, thereby making a potentially valuable contribution to clinical decision-making.
Also at this year’s annual ASCO meeting, a research team headed by Pat Whitworth, M.D. (Nashville Breast Center) reported that molecular subtyping using MammaPrint and BluePrint more accurately reclassified 23% of 336 tumors that were initially classified using traditional IHC-FISH pathology methods. The research is also part of the Neoadjuvant Breast Registry Symphony Trial (NBRST) trial.
For more information:
[1] Dabbs DJ, Brufsky A, Jankowitz RC, Puhalla S, Lee A, Oesterreich S, Lembersky BC, Bhargava R. et al Comparison of test results and clinical outcomes of patients assessed with both MammaPrint and Oncotype DX with pathologic variables: An independent study. 2014 ASCO Annual Meeting, General Poster Session, Breast Cancer – HER2/ER. Abstract Number: 550. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr 550)
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