Genetic Analysis Identifies New Targets in Triple-Negative Breast Cancer

Justin M. Balko, PharmD, PhD

Patients with triple-negative breast cancer who have residual disease after receiving neoadjuvant chemotherapy have a series of genetic alterations that are clinically targetable and may warrant further study with various targeted therapies already available or in development, according to research presented at the 35th San Antonio Breast Cancer Symposium.

The research showed that triple-negative breast cancer has tremendous molecular heterogeneity, with some patients in the study having as many as 6 or 7 different alterations based on deep sequencing that looked for 182 different oncogenes and tumor suppressors known to be altered in human cancers.

Approximately 30% of patients with triple-negative breast cancer achieve a pathological complete response after receiving neoadjuvant chemotherapy, which leads to a favorable diagnosis. However, the remaining 70% of patients who do not respond to neoadjuvant chemotherapy have residual disease that leads to worse outcomes.

“In treatment, those patients don’t really have therapeutic options,” said Justin M. Balko, PharmD, PhD, a research faculty member who works in the lab of Carlos Arteaga, MD, at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, and lead author of the study. “In particular, they have no targeted therapeutic options. We already know that their tumors were not completely responsive to chemotherapy, so using more chemotherapy down the road may or may not be effective. Our goal was to use state-of-the-art molecular techniques to profile those residual tumor cells and see if we could find some clinically actionable alterations that are present in that residual disease in triple-negative breast cancer.”

Of the 81 tumors that were evaluated for oncogenes using next-generation sequencing, 72 (89%) had mutations in TP53, 22 tumors were MCL1-amplified (27%), and 17 tumors were MYC-amplified (21%). At least 15 additional mutations among the 182 that were tested for using the sequencing method were identified in the study.

“This diversity states that we really need to not just look at single biomarkers alone but be able to organize these alterations into pathways,” Balko said.

Using this information, the researchers identified clinically targetable pathways for which various targeted therapies are either already available or in development. Pathways identified in the study included alterations of the PI3K/mTOR pathway in 27 tumors (33%), alterations in cell cycle genes in 25 tumors (31%), DNA repair pathway alterations in 16 tumors (20%), the Ras/MAPK pathway alterations in 10 tumors (12%), and sporadic growth factor receptor amplifications occurred in EGFR, IGFR1, FGFR1, KIT, and others.

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Justin Balko on the Diversity of Genetic Alterations in TNBC

Additionally, amplifications in the JAK2 locus were identified in 11% (8 of 72) of the patients in whom copy number aberrations were identified among the 81 original tumor samples. Balko said that the survival of patients with this particular amplification is very poor. Since pan-JAK and JAK2 inhibitors are currently in clinical trials, Balko said that this is another potential therapeutic target that can be explored.

“I think the timing would be right to not only identify the biomarker but also identify the drug and identify the patients and hit that in an adjuvant study,” Balko said. “I would be very encouraged to do that based on our data.”

Balko JM, Wang K, Sanders ME, et al. Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in the treatment-refractory residual disease. Presented at: 2012 CTRC-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas. Abstract S3-6.

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