Targetable Pathways Revealed for Triple-Negative Breast Cancer

Audrey Andrews

March 2013, Highlights - Breast Cancer

The molecular make-up of triple- negative breast cancer is becoming better understood, and new evidence suggests that the main biologic pathways can be targeted with drugs, according to Justin Balko, PharmD, PhD, Postdoctoral Research Fellow and Researcher, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville. In his study on genetic alterations, 90% of the patients had mutations in 5 well-recognized pathways, and drugs developed to target these markers.

Currently, the treatment of patients with triple-negative breast cancer is more of a hit-and-miss situation, Dr Balko said. No biomarkers have been established—such as HER2 for trastuzumab (Herceptin)—that could enhance the treatment of these patients.

“Neoadjuvant chemotherapy is increasingly used in patients with triple- negative breast cancer. It can induce a pathologic complete response in about 30% of patients, which portends a favorable prognosis, while those patients with residual disease in the breast at surgical resection exhibit worse outcomes,” Dr Balko pointed out.

“There are currently no targeted therapeutic options for triple-negative patients with residual disease after neoadjuvant chemotherapy to be used in the adjuvant setting. We hypothesized that molecular analysis of the residual disease would identify genetic alterations that are ultimately responsible for disease recurrence and could be targeted with clinically available medications,” he noted.

Genetic Analysis of 114 Tumors

Dr Balko and colleagues conducted a genetic analysis of this residual tumor tissue to look for genetic aberrations that might be targeted by specific therapies. Their study included tissue samples from 114 women, which were analyzed by 3 methods. With next-generation sequencing, the researchers were able to ultimately look for 182 oncogenes and tumor suppressor genes in 81 samples.

Dozens of genes were found to be amplified, deleted, or mutated. Ap­proximately 90% of all patients had an aberration in at least 1 of the following 5 common pathways: PI3K/mTOR (involved in signaling and cellular death), DNA repair genes (eg, BRCA1 and BRCA2), RAS/MAP kinase pathway (cellular proliferation, differentiation, and death), cell cycle genes, and growth factor receptors, such as the epidermal growth factor receptor, which is important in lung cancer.

The most common aberration was p53, a well-known oncogene, which was found in 90% of the triple-negative tissue samples, Dr Balko reported.

Some combinations of these genetic variants heralded a worse prognosis than others. In a univariate analysis of 62 patients, the presence of the MEK kinase gene plus amplification of the MYC oncogene had a synergistic effect. Women with these 2 aberrations were more likely to relapse than women with only 1 of the variants.

“In addition, we identified novel JAK2 amplifications in about 10% of the patients, which may be therapeutically targetable,” Dr Balko said. The JAK2 inhibitor ruxolitinib (Jakafi) is approved for the treatment of patients with myelofibrosis, and a number of other JAK2 inhibitors are in clinical trials.

“These data provide a ‘targetable’ catalogue of the alterations present in the residual disease of triple-negative after neoadjuvant chemotherapy, and support genomically driven adjuvant trials in this patient population,” Dr Balko concluded.