February 19, 2009 — A genomic test may add significant prognostic and predictive information to standard parameters for breast cancer patients. Designed by a multi-institutional team of researchers, the new test is broadly applicable to all women diagnosed with breast cancer, according to report a published online February 9 in the Journal of Clinical Oncology.
"It's an evolution in the testing process," said Matthew Ellis, MD, PhD, a member of the Siteman Cancer Center at Washington University and Barnes-Jewish Hospital, in St. Louis, Missouri, who is one of the study's authors. "The critical issue is targeting the therapy."
Among patients with a poor prognosis, he explained, the goal is to find a way to target the disease effectively. Among those with cancers who have a better prognosis, the goal is to define the minimum amount of therapy.
Dr. Ellis and colleagues investigated the development of a new genomic assay test to improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit. Their model is a 50-gene subtype predictor, developed using microarray and quantitative reverse-transcriptase–PCR data from 189 prototype samples, that incorporates the gene-expression-based "intrinsic" Luminal A, Luminal B, HER2-enriched, and Basal-like subtypes.
Differs From Other Tests
The new assay is different from the genomic tests that are currently available, and may offer a broader array of benefits. "In gene numbers, we fall between the 70-gene MammaPrint microarray assay and the 21-gene OncotypeDx assay," Dr. Ellis told Medscape Oncology, referring to assays that are already commercially available.
The OncotypeDx assay can be used to risk stratify early-stage estrogen-receptor (ER)-positive node-negative disease, whereas the new genomic test can be used in node-positive disease and, thus, is applicable to a much wider range of women diagnosed with breast cancer.
"The MammaPrint is also only applicable for node-negative disease and requires a fresh frozen sample," he said. "Our format allows for retrospective studies, using samples from patients treated a while ago."
Soonmyung Paik, MD, who was not involved in the study or the development of the test, commented to Medscape Oncology that, in essence, this study shows that Luminal A subtype defined by gene expression has good prognosis. "This has been known for a while now, and the investigators developed it into a test format that can be applied to routinely processed biopsy tissue specimens," said Dr. Paik, director, Division of Pathology, National Surgical Adjuvant Breast and Bowel Project, in Pittsburgh, Pennsylvania.
"So it is not a novel finding, but it is a step forward to implement what we already know to a clinical test," he added. "The test is similar to the OncotypeDx test — the only difference is that it was developed purely by academic labs."
Predictive of Treatment Response
The intrinsic Luminal A, Luminal B, HER2-enriched, Basal-like, and Normal-like subtypes have been extensively studied by microarray and hierarchical clustering analysis, the researchers note. In this study, they evaluated the utility of these subtypes alone and as part of a risk-for-relapse predictor in 2 cohorts.
In the first cohort, patients received no adjuvant systemic therapy, whereas in the second, women received paclitaxel, 5-fluorouracil, doxorubicin, and cyclophosphamide neoadjuvant chemotherapy. The researchers compared risk-for-relapse models with standard models using pathologic stage, grade, and ER and HER2 status.
A 50-gene subtype predictor was developed using data from 189 prototype samples. Test sets from the 761 patients in the first cohort were evaluated for prognosis, whereas those from the 133 patients in the second cohort were evaluated for prediction of pathologic complete response to a taxane and anthracycline regimen.
The subtype diagnoses demonstrated markedly different distributions, depending on ER or HER2 status, but all subtypes were represented in ER-positive, ER-negative, HER2-positive, and HER2-negative categories. This finding shows that ER and HER2 status alone are not accurate surrogates for true intrinsic subtype status, the researchers observed. Instead, the intrinsic subtypes showed a significant impact on prognosis for relapse-free survival among patients who did not receive systemic therapy and when stratified by ER status.
When evaluating response to chemotherapy, they found that the genetic test was highly sensitive and very predictive for therapeutic response (94% sensitivity and 97% negative predictive value for identifying nonresponders to chemotherapy). Their assay was more predictive than the clinical molecular markers that are typically used, including ER status, progesterone-receptor status, and HER2 gene-expression status.
"The gene test allows for identifying Luminal B tumors, which have a poor prognosis," said Dr. Ellis. "This type is worrisome, because it is not very responsive to current treatments, exemplifying the need for new agents and new approaches for this group."
This test is a potential starting point for a variety of new clinical-trial designs, which will focus on patients with a poorer prognosis. "Unlike the Oncotype trials, which are focused on finding out which groups do not need adjuvant chemotherapy, this test has much more to do with patients with poor-prognosis breast cancer who need entirely new systemic therapy approaches," explained Dr. Ellis.
According to Dr. Ellis, the test should become available later this year. But Dr. Paik pointed out that for this test to be offered to patients, it has to be commercialized. "The cost of the assay should be much lower than, for example, the OncotypeDx assay, but it all depends on their market evaluation, so I cannot speculate at this point."
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου