NEW YORK – Research showing that Agendia's MammaPrint and BluePrint tests can predict which breast cancer patients are likely to have the cancer in their lymph nodes downstaged following neoadjuvant chemotherapy has the company optimistic about a potentially new use for its gene expression tests.
In MINT, or the Multi-Institutional Neoadjuvant Therapy MammaPrint Project I, researchers enrolled 387 patients with invasive breast cancer between 2011 and 2016. A sub-analysis recently published in the Annals of Surgical Oncology focused on 146 patients with stage II to stage III invasive disease who had node-positive tumors in pretreatment biopsies. Agendia used the same core biopsies to run the genomic classifiers and determine patients' hormone receptor (HR) and HER2 status. Then, after these patients received neoadjuvant chemotherapy, they underwent axillary lymph node dissection.
Patients whose tumors were genomically high risk, according to the 70-gene expression MammaPrint assay or according to MammaPrint and the 80-gene expression BluePrint assay, were more likely to experience nodal downstaging with neoadjuvant chemotherapy compared to the overall group of patients with lymph node-positive breast cancer. Nodal downstaging means that patients initially had signs of cancer in their lymph nodes, but this went away with neoadjuvant chemotherapy.
The MammaPrint assay, which classifies breast cancer patients' risk of distant metastases, is cleared by the US Food and Drug Administration as a tool to help determine whether patients may avoid chemo. BluePrint, which is also FDA-cleared and often used in conjunction with MammaPrint, categorizes patients' breast cancers as luminal A-type, luminal B-type, HER2-type, or basal-type based on the tumors' gene signaling pathways.
"Which genes are turned on and off will actually determine how that cancer cell is going to behave, and, to a certain extent, it'll determine what kind of medications it will be sensitive to," William Audeh, Agendia's chief medical officer, said on a recent call with members of the media. "When we want to look at those genes, we simply take a small sample of a breast cancer and analyze it from those genes … and that helps us guide some of our decisions for therapy."
Agendia has already amassed data on these genomic signatures' value in guiding pre- and post-surgery chemotherapy decisions, but the firm is touting the new sub-analysis as a way to determine which patients could undergo less invasive surgeries than those involving axillary lymph node dissection. In this procedure, surgeons remove surrounding lymph nodes to test them for cancer. The procedure is highly accurate at determining how extensively a cancer has spread into nearby lymph nodes, but it is also invasive, leading to complications, side effects, and longer recovery.
Among the 146 patients in the sub-analysis, 45.2 percent of patients whose cancers had been lymph-node positive initially ended up having a complete nodal response by the time of their surgery. Of these patients, 60.6 percent also had a complete response of their primary breast tumor and 39.4 percent had residual disease in their primary tumor.
To determine how MammaPrint and BluePrint could be used to predict nodal downstaging, researchers at Agendia compared the number of patients with nodal downstaging versus those who still had cancer in their lymph nodes and analyzed their subclassifications according to the genomic tests. Here, they found that a larger proportion of patients with tumors deemed to be high risk by MammaPrint experienced nodal downstaging than did those with MammaPrint low-risk tumors. Indeed, 57.1 percent of patients with MammaPrint high-risk tumors had a partial or complete nodal downstaging. The same was true of just 20 percent of those with MammaPrint low-risk tumors.
While MammaPrint was informative on its own, combining BluePrint provided further value. Among patients with HR-positive HER2-negative luminal A-type tumors, 15.8 percent experienced nodal downstaging. The same was true of 26.7 percent of genomically high-risk, luminal B-type tumors, 73.6 percent of HER2-positive tumors, and 53.7 percent of basal-type tumors.
"Data from the trial suggests that treating patients with clinically hormone receptor-positive, HER2-negative, but MammaPrint low-risk and BluePrint luminal subtype, genomically luminal A tumors with chemotherapy for the purpose of nodal downstaging is likely to yield suboptimal results," Agendia said in a statement in conjunction with the publication of the MINT sub-analysis.
On the whole, the results suggested that genomically testing patients' initial core biopsies with MammaPrint plus BluePrint could predict which patients' tumors would have nodal downstaging in response to neoadjuvant chemotherapy, which, in turn, could help oncologists home in on patients who might not need to undergo full axillary lymph node dissection during their surgery. According to Agendia, this could spare patients the potential complications of this invasive procedure, including post-surgery lymphedema.
For patients more likely to experience nodal downstaging following surgery, researchers at Agendia suggested that alternatives to axillary lymph node dissection could be considered, such as newer, less invasive methods of removing only the positive lymph nodes. Targeted axillary dissection, which involves incorporating radiotracers into the less-invasive method of sentinel lymph node biopsy, could be one option, for instance. This could make a difference in patients' post-surgery quality of life and outcomes, since lymphedema, a condition where fluid builds up in tissues after the lymph nodes have been damaged or blocked, can be painful and risky.
The latest data bolsters Agendia's efforts to expand the use of its gene expression tests beyond guiding chemotherapy decisions for early-stage breast cancer patients. The firm recently published data on its 53-gene ImPrint test as a tool to predict response to immunotherapy among triple-negative or HR-positive, HER2-negative breast cancer patients. The firm has also been conducting the PROOFS registry trial to confirm whether MammaPrint is useful in premenopausal women with breast cancer, not just those who have already gone through menopause. Last year, Agendia also began testing whether MammaPrint could help identify patients who could discontinue adjuvant endocrine therapy based on their tumors' risk category.
"[We want to] create new signatures beyond MammaPrint and BluePrint that will help identify which drugs may be best for one person versus another, or even why there might be differences between people treated with the very same drugs based on ethnicity or genetic ancestry," Audeh said.