ASCO: Emerging Biomarkers in Triple-Negative Breast Cancer

About 15% of women receiving a diagnosis of breast cancer also get the unwelcome news that their disease is non-responsive to therapies that target HER2, estrogen or progesterone receptors. Triple-negative breast cancer (TNBC) continues to carry a poor prognosis. However, novel prognostic and potentially predictive biomarkers may soon improve that bleak outlook, according to a series of studies presented on Saturday at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

"We're making progress in finding new markers of response," Steven J. Isakoff, MD, PhD, of Massachusetts General Hospital in Boston, told CancerNetwork. "There's a lot of reason to be optimistic."

Researchers are looking beyond HER2 and endocrine receptors to identify other helpful additions to the panel of protein markers evaluated by immunohistochemistry. They are also assessing whether some of the more standard expression categorizations are really all that black-and-white.

BCL-2 human isoforms; image source: Dan Cojocari, Wikimedia Commons

Tarek M. A. Abdel-Fatah, MD, of the Unviersity of Mansoura, in Egypt, shared results of a study he led evaluating the prognostic and predictive power of Bcl-2 (abstract 1024). Based on immunohistochemical profiles of 912 breast cancers treated with CMF chemotherapy (cyclophosphamide, methotrexate and fluorouracil 5FU), his team found that expression of the protein reclassified these TNBC patients into two groups: lower risk with expression and higher risk without.

"It's very clear that Bcl-2 is a prognostic factor," Stephen K. L. Chia, MD, of the University of British Columbia, in Vancouver, who was not involved in the study, told the crowd at a poster discussion session. "But how we integrate that into clinical use is the next step."

In a neighboring poster, researchers presented findings on the prognostic significance of two members of the p53 family, p63 and p73, which are expressed in about 40% of TNBC patients (abstract 1025).

They studied 86 patients with triple-negative disease and found expression of these proteins predicted sensitivity to cisplatin or carboplatin. The overall response rate to the platinum chemotherapies was 30%, with complete and partial response in 5% and 26% of patients, respectively.

"If these biomarkers pan out, we can analyze someone's tumor tissue before treatment and see how likely they are to respond," said Dr. Isakoff, lead author of the abstract.

Still, the researchers agreed that identifying targeted treatments for TNBC remains a complicated task. For one thing, TNBC is not simply one disease.

Some patients initially classified as having triple-negative disease, for example, may have tumors that still show a little endocrine receptor expression. So could they actually benefit from endocrine therapy? With results from a retrospective review of 1,257 patients, one team of researchers halted that hope (abstract 1023).

"Within the subgroup of breast cancer tumors with 1% to 10% estrogen- and progesterone- receptor expression, there was no significantly different effect of endocrine therapy compared to tumors with no expression," Kanwal Pratap Singh Raghav, MD, of the M.D. Anderson Cancer Center in Houston, and lead author of the abstract, told CancerNetwork.

Then there is the ongoing issue of TNBC misdiagnosis. A group from Spain and Latin America presented findings from 1,441 patient specimens sent to central laboratories after local labs had determined the tumors were triple-negative (abstract 1022). While there was significant variability between centers, some determined that up to 9% of the samples were not triple-negative after all.

In his discussion of the abstract, Dr. Chia noted that other studies have found discordant rates as high as 18%. "We recognize that quantification of protein expression by immunohistochemistry is challenging," said Dr. Chia. "To overcome this, every clinical lab should be participating in quality assurance programs."

Meanwhile, efforts to identify tests and treatments to stretch survival for true cases of TNBC continue. "We'll get there," added Dr. Isakoff. "It just takes time."