Test Being Developed to Determine Risk of Recurrence in Triple-negative Breast Cancer

A new test — based on genetic markers of immune response and with potential to be assayed in tumor biopsies — holds promise for identifying patients with triple-negative breast cancer (TNBC) who are at lower risk of disease recurrence, and therefore would benefit from less aggressive treatments.

Experiments are underway or being planned to confirm the test can be used to predict each patient’s outlook. Researchers also hope it could be used for other types of breast cancers or other cancers that have similar immune responses.

The study, “A Multigene Assay Determines Risk of Recurrence in Patients with Triple-Negative Breast Cancer,” was published in the journal Cancer Research.

Chemotherapy tends to be the only option for TNBC patients, following breast cancer surgery. But while approximately 60% of these patients will live more than five years without the disease returning, the remaining 40% will have a rapid recurrence of cancer with a peak at three years after diagnosis.

No tests are available to assess the risk of recurrence in these patients, so all receive aggressive chemotherapy that can include up to four different agents and six months of treatment.

“That’s significant because chemotherapy can lead to long-term heart and nerve problems,” Katherine Varley, PhD, from Huntsman Cancer Institute and the University of Utah, and the study’s principal investigator, said in a news release.

“If we can understand which patients need aggressive treatment and which patients will likely do well with less aggressive treatment, we could make a big difference in their lives,” she said.

Varley and her collaborators developed a test that scores patients according to how much their immune systems have been activated in response to TNBC. These scores can potentially predict each patient’s risk of cancer recurrence.

“We could very accurately predict which patients were going to have long-term disease-free survival and which patients were likely to have recurring disease. This is very exciting because it could be the first clinical test to enable personalized prognosis for triple-negative breast cancer patients,” said Varley.

She and her team previously discovered that TNBC patients whose tumors turned on an immune response — involving the MHC (major histocompatibility complex) class II pathway — experienced a much longer life free of cancer, than those who did not activate such a response.

Studies in mice showed that MHC class II activation on tumor cells triggered the recruitment of T-cells (a type of immune cell that’s able to kill cancer cells) to the tumor site, inhibiting the tumor’s growth.

MHC class II molecules are found in specific cells of the immune system, and in a few other non-immune cells. They are important in activating T-cells to recognize and attack harmful agents such as bacteria and tumor cells.

The researchers wanted to find a way to translate their discovery into a test to predict which patients are more likely to have a good prognosis, and thus may be treated safely with less aggressive therapy.

First, the team identified 36 genetic markers of recurrence risk, using TNBC tumor samples that were collected more than five years ago from patients. Only samples from patients with stage I–III breast cancer were included in the study.

The test was designed to measure how active or “turned on” these genetic markers were. It assayed genes producing MHC class II components and proteins from tumor-infiltrating immune cells, and was dubbed “MHCII Immune Activation assay.”

Basically, higher scores corresponded to heightened gene activity, which reflected a stronger immune response against the tumor — this was highly correlated with reduced risk of recurrence.

Initial experiments confirmed the test’s accuracy and reliability in formalin-fixed, paraffin-embedded tumor samples, which is how biopsies are routinely preserved for analysis.

In a validation trial using 56 samples, patients with higher scores were more likely to have a longer life free of cancer, independent of disease stage (from I to III).

A threshold score was set, above which patients were at very low risk of relapse, equivalent to 100% specificity. In other words, none of the patients with high activation scores relapsed over the observed period, which suggests that these patients would benefit from less intensive chemotherapy and perhaps immunotherapy.

The researchers are now testing TNBC patient samples from clinical trials of chemotherapy and immunotherapy. The next step is to confirm that their test is reliable to predict patient prognosis and to help choose the safest, most effective treatments.

“We’re working as fast as possible to validate the test so it can benefit patients,” said Varley. “One of my goals is to translate the discoveries we make in basic science and in our genomics research into clinical tests because I know patients are waiting.”