Next-generation sequencing of 81 triple-negative breast cancer residual-disease tumors has shown that about 90% had an aberration in at least one gene targeted by PI3K/mTOR inhibitors, DNA-repair targeting agents, RAF/MEK inhibitors, cell-cycle inhibitors, or growth factor receptor tyrosine kinase inhibitors.

Patients with triple-negative breast cancer typically receive neoadjuvant chemotherapy. Treatment typically stops after their surgery—even for the 70% who show treatment-refractory residual disease, although that condition is linked to poor survival rates—because no therapies have been proved effective at that point.

A molecular profiling study has taken a first step toward developing potential therapies by identifying a diverse group of mutations in residual-disease tumors, many of which might be targeted by drugs that are already approved or in clinical testing.

The study began “by hypothesizing that residual disease is likely to mirror the molecular alterations in clinically silent micrometastases that are ultimately destined to occur in such patients,” explained Justin Balko, PharmD, PhD, a postdoctoral research fellow in the lab of Carlos Arteaga, MD, at the Vanderbilt-Ingram Comprehensive Cancer Center (VICC) in Nashville, TN.

These exploratory molecular analyses thus might help to zero in on effective measures against the metastases, said Balko, who presented the research at the San Antonio Breast Cancer Symposium on December 6.

Molecular profiling by Balko and his colleagues at VICC; Foundation Medicine in Cambridge, MA; and the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru, included next-generation sequencing for 182 oncogenes and tumor suppressors in triple-negative residual-disease tumors from 81 patients.

About 90% of these patients had an aberration in at least one gene targeted either by phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, DNA-repair targeting agents, RAF/MAP–ERK kinase (MEK) inhibitors, cell-cycle inhibitors, or growth factor receptor tyrosine kinase inhibitors.

Many of the tumors showed multiple genetic alterations, some appearing to interact with each other. Among the findings, MYC amplifications coexisted with MCL1 amplifications, and MYC amplifications coinciding with high MEK pathway transcriptional output were associated with short survival, Balko said.

The study also found amplifications among 11% of tumors in the JAK2 locus, not previously identified as a possible target for triple-negative breast cancer, according to Balko. The interleukin-6 (IL-6)/JAK/STAT pathway is thought to regulate “cancer–stem-cell-like” behavior in breast cancer. IL-6 was highly expressed among these tumors and associated with very low survival rates, he said. Balko noted that pan-JAK and JAK2 inhibitors are in clinical trials for other types of cancer and proposed that JAK2 could be a biomarker for trials with such inhibitors in triple-negative cancer.

This early molecular profiling work needs to be broadened to include follow-up for disease recurrence, analyses of much larger patient populations, and extensive work in cell and animal studies of inhibitor mechanisms, Balko said. “We believe that this has significant potential therapeutic impact and should be assessed in adjuvant studies,” he added.