The most common cause of death from breast cancer is not the primary tumor, but metastatic disease, when the cancer travels and takes root in the brain. About 1 in 5 women with metastatic breast cancer will contract a brain lesion, and median survival for those patients is less than a year after diagnosis. Yet physicians currently have few tests to predict which breast tumors will eventually involve the brain and which will not. As it becomes more accepted that no two patients’ cancers are alike, physicians recognize that they need more “biomarkers” that can both reliably predict how the disease will progress and suggest the best method of treatment.
Just as successfully treating cancer often requires the cooperation of different disciplines, finding sufficiently predictive cancer biomarkers needs to be a collaborative effort. An ongoing University of Chicago Medicine search for a factor that can help physicians calculate the risk of brain metastasis in breast cancer patients has united researchers from neurosurgery, oncology, pathology, and Health Studies. The first fruit of that large collaboration, published late last year in the journal Cancer, discovered a promising biomarker with an innocuous name: KISS1.
The interest in brain metastases started in the laboratory of Maciej Lesniak, professor of surgery and neurology and director of neurological oncology. Lesniak, who often treats patients with these types of brain tumors, said that there is a gap in knowledge about what predisposes some women to this serious complication of breast cancer.
“If you have breast cancer, does this automatically mean that you will develop a brain metastasis? We don’t know,” Lesniak said. “Are there any risk factors or biological phenomena behind this form of the disease? That was the question that we set out to answer.”
Fortunately, the means to test that question were available through the Specialized Program of Research Excellence (SPORE) in Breast Cancer at the University of Chicago Comprehensive Cancer Center, led by medical oncologist and Walter L. Palmer Distinguished Service Professor Olufunmilayo Olopade. The Breast Cancer SPORE maintains a bank of tissue and tumor samples that researchers could use to look for potential biomarkers. Working with Peter Pytel, assistant professor of pathology, the research team developed an assay to test levels of target proteins in tissue from metastatic and non-metastatic breast cancer patients.
For the first potential biomarker, the research team led by Ilya Ulasov chose KISS1, levels of which were previously associated with the progression of bladder, ovarian, and other cancer types. Using antibody staining techniques, the researchers measured KISS1 levels in breast tissue from patients with cancer, non-cancerous breast tissue, and brain lesions from metastatic cancer patients. The comparison found lower levels of KISS1 protein in the brain metastases relative to breast tumors, suggesting that a reduction of this protein is associated with increased spread of cancer to the brain. Another analysis correlated KISS1 levels in the patient’s tissue samples with their clinical outcome, finding that those with higher levels of KISS1 expression exhibited slower disease progression and reduced chance of developing brain metastases.
Interestingly, the relationship between brain metastasis and KISS1 expression was not correlated with previously established breast cancer subtypes that use the estrogen receptor, progesterone receptor, and HER2 gene as biomarkers.
“KISS1 is an interesting protein that seems to at least play a role which subset of patients go on to develop brain metastases from breast cancer,” Lesniak said. “The beauty of this paper is that it carries across different subtypes of tumors.”
However promising the data, the authors caution that their study is only the first step toward establishing KISS1 as a valid biomarker for predicting the course of metastatic breast cancer. Until the biological link between KISS1 expression and cancer progression can be determined, the relationship can’t be considered more than a correlation. But if a mechanism is discovered, Lesniak speculated that KISS1 may hold clues to a way to stop or slow brain metastases from occurring.
“The question is how can you modulate KISS1 expression for the benefit of patients,” Lesniak said. “One approach would be to restore KISS1 expression in patients with advanced metastatic breast cancer, and see whether it makes the tumor less aggressive or less prone to metastatic disease. It’s an interesting thought, but it’s probably too premature to know whether that would hold true.”
Regardless, the search for breast cancer biomarkers won’t settle for just one factor, be it KISS1, HER2, or other cellular proteins. The hope is that more and more reliable predictive biomarkers will be discovered, until a patient’s cancer can be tested and diagnosed in detail, pointing the way to effective and personalized treatment.
“I think this shows what kind of studies we have to do to get better at predicting this process,” Pytel said. “At the moment, it’s only one marker, which is not where we want it to be. But it offers hope for a future where we could come up with panel of markers that would be helpful in predicting details about the progression of cancer in a patient.”