New Test Improves Breast Cancer Detection

Some doctors worry that molecular assay provides too many false positives.

February 18, 2009, 2:51 PM

Dec. 16, 2007 — -- A new molecular assay test improves the accuracy of finding cancer in the lymph nodes during a sentinel lymph node biopsy, according to results presented by researchers Saturday at the San Antonio Breast Cancer Symposium.

Results of the study showed that the GeneSearch BLN Assay test, developed by Veridex LLC and approved by the FDA in mid-July, is about 10 percent more sensitive than traditional histology and microscopic exams in finding evidence of tumor cells during a sentinel lymph node biopsy.

One of the challenges of the sentinel lymph node biopsy is that a pathologic examination of the lymph nodes must be done during a halt in the surgery to assess whether there is a tumor in the sentinel nodes. Traditionally, surgeons conduct a sentinel lymph node biopsy by removing less than 5 percent of the lymph node during an intra-operative halt in the surgery. The small node section is then frozen and examined under a microscope for the presence of cancer cells. If cancer cells are found in the nodes, the surgeon will typically remove these lymph nodes during the biopsy procedure.

However, all too often the results of this assessment are inaccurate, requiring the patient to undergo the physical and emotional stress of returning to the operating room for yet another surgical procedure to remove the cancerous lymph nodes.

The GeneSearch molecular assay test, which the FDA approved as a replacement for the standard frozen section method of examining the sentinel lymph nodes during a biopsy, is an ultra-rapid method of doing a genetic screening test to look for evidence of tumor cells in the lymph nodes during the intra-operative halt in the surgery. Researchers reported that this new technique is more sensitive than frozen section, without sacrificing specificity.

Researchers did both standard frozen section and molecular assay tests on 319 breast cancer patients. The pathologists who did the frozen section did not know the results of molecular assay test, and vice versa. After both diagnostic tests were completed, researchers compared the results from each test to the final pathologic report on each patient.

According to Dr. Peter Blumencranz, lead investigator of the study, surgical oncologist and medical director of Moffitt Morton Plant Cancer Care at Morton Plant Hospital in Clearwater, Fla., the GeneSearch assay test correctly diagnosed patients for cancer 91 percent of the time.

Compared with the 65 percent accuracy of the frozen section in detecting tiny breast cancers, the GeneSearch test displayed a remarkable improvement from the traditional pathologic examinations currently in use for sentinel lymph node biopsies.

"Since we began using this test at our [medical] center on Aug. 1, we have tested 85 patients with the molecular assay and only one of them [received a false negative] and had to come back for a second surgery," Blumencranz said. "But in fact, more than that percent is missed in standard histology. So what is the greater truth? Looking at 50 percent of the node with the assay or what amounts to only about 5 percent of the node by microscopic exam."

But despite the proven increased sensitivity of the GeneSearch test in finding small and hard-to-diagnose cancers, some doctors remain more concerned about the risk of false positives from the molecular test than the risk of false negatives.

The GeneSearch assay test works by slicing the node into sections much like a loaf of bread. Each slice is then homogenized, or blended together, and put into the molecular assay machine. The machine then checks the cells for two molecular markers of breast cancer, giving doctors a qualitative positive or negative answer.

However, because the test looks for molecular markers of breast cancer rather than identifying actual cancer cells, some doctors fear it will result in too many false positives.

"This might result in a few patients getting an axillary dissection when the next day the pathologist found that the sentinel node is negative, even though it was called positive by the molecular test," said Daniel Hayes, clinical director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center. "It's a little like if you walk through the woods and see scratches on a tree, you presume there are bears in the woods, though you didn't actually see any bears."

Researchers reported a 4 percent to 5 percent rate of false positives with the GeneSearch test. Dr. Lee Wilke, assistant professor of surgery at Duke University, said it will take more research and a decreased rate of false positives before she is convinced that the GeneSearch test should be used as a replacement for the frozen section.

"Certainly false positive rates are our biggest fear. You don't want to tell a patient they have cancer when they don't. That's why more larger studies need to be done to double check and make sure that what we're seeing is not a large number of false positives," Wilke said. "I would like to see the number [of false positives] go lower [with the GeneSearch test], into the 1 to 2 percent range."

The study reported that the frozen section method of diagnosing cancer in the sentinel nodes has sensitivity rate somewhere between 60 and 80 percent, meaning that this test misses cancers in 40 to 20 percent of women. The reason for the large disparity in the rate of accuracy with the frozen section is that this method often fails at detecting hard to diagnose cancers, such as lobular carcinoma. About 15 to 20 percent of all breast cancers are lobular cancers.

Because the GeneSearch test has a heightened sensitivity in finding evidence of lobular cancer, Hayes said he believes the important question facing breast surgeons is whether it is better to have a few patients undergo an unnecessary operation to remove lymph nodes due to a false positive by the molecular assay test, or to have many patients undergo a second surgery due to a false negative from a frozen section.

"I think this is going to cause a lot of hand-wringing for us doctors to determine which outcome is better for the patient," Hayes said. "I think we should probably use this in addition to the final pathology report, rather than have the molecular test replace the frozen section."

However, Blumencranz maintains that breast surgeons should adopt the GeneSearch test into their practice as a method of providing each woman with the most accurate assessment of their disease as possible.

"The burden on us, as surgeons and pathologists, is to assure the patient as much as possible that we are accurately diagnosing disease where it is present. And if there's a tool that can do that better, then I think we should be using it," Blumencranz said.