This article is more than 5 years old. Information may no longer be current.
Residual cells from triple-negative disease showed genetic diversity after chemotherapy
SAN ANTONIO — Ninety percent of residual cancer cells in patients with triple-negative disease who underwent neoadjuvant chemotherapy had clinically targetable mutations, according to data presented here.
Justin M. Balko, PharmD, PhD, of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said neoadjuvant chemotherapy can induce a pathologic complete response in 30% of patients. This, in turn, has been linked to a favorable prognosis. Patients with residual disease in the breast have a poorer prognosis.
“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,” Balko said.
There were 114 patients with triple-negative disease included in the trial. The researchers performed protein expression in 112, gene expression in 89 and next-generation sequencing in 81 patients. Eighty-one tumors were available for analysis.
“We found 182 amplifications, mutations or deletions of known or implied functional significance,” Balko said. “The most commonly mutated gene was TP53, which was not surprising. MCL1 and MYC were the other common mutations.”
Ninety percent of tumors had an aberration in one of the following pathways: PI3K/mTOR, DNA repair, Ras/mitogen-activated protein kinase, cell cycle and growth factors receptors.
“These are all clinically targetable pathways in triple-negative breast cancer,” Balko said. “PI3K/mTOR inhibitors, DNA-repair targeting agents, RAF/MEK inhibitors, cell cycle/mitotic spindle inhibitors and targeted RTK inhibitors may be effective in these mutations.”
Balko also noted amplifications in the JAK2 locus in approximately 10% of patients. This pathway had been previously unidentified, according to Balko. He added that Pan-JAK and JAK2 inhibitors are currently in clinical trials.
“These data provide a targetable catalog of the alterations present in the residual disease of triple-negative breast cancer after neoadjuvant chemotherapy, and support genomically driven adjuvant trials in this patient population,” Balko said.
For more information:
Balko JM. #S3-6. Presented at: the 2012 CTRC-AACR San Antonio Breast Cancer Symposium; Dec. 4-8, 2012; San Antonio.
Disclosure: Balko reports no relevant financial disclosures.
Perspective
Back to Top
This is a discovery exercise that to me suggests not necessarily a change in clinical care, but a strong direction for discovery and research. For patients who have residual disease in the breast after neoadjuvant chemotherapy, the standard of care is just to observe them. But many of them are going to recur and die from metastases. The reason we don't treat it may be because we don't know how to treat it. This study suggests that there are actionable molecular lesions in those cancers that we may one day be able to act upon early and potentially change the natural history of that micro-metastatic disease that is waiting there to recur in a few months or a couple of years. Some research may change practice patterns, but others, like this study, point to research directions that we should follow.