Four-Gene Signature Identified Triple-Negative Breast Cancer Subgroups

The use of a four-gene signature identified a series of subgroups of triple-negative breast cancer (TNBC), including one subtype that was responsive to platinum-based chemotherapy in the metastatic setting.

Details of this signature were presented (abstract 1006) by Jelmar Quist, a PhD candidate at King’s College, London, at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.

“This subtype highlights distinctive molecular features such as activation of negative regulators of the MAP kinase signaling pathway and enrichment of CD4 and CD8 immune signatures,” Quist said. “This really highlights opportunities for additional treatment avenues in these patients.”

TNBCs are frequently driven by copy number gains and losses that influence the underlying gene expression levels. Chemotherapy is the main treatment for triple-negative disease, but there is limited response in the adjuvant setting.

According to Quist, there are currently considerable research efforts to discover subgroups of triple-negative disease for which researchers can identify actionable molecular targets. In this study, Quist and colleagues wanted to classify TNBC into subgroups using common biological features based on transcriptomic and genomic data. They used CONEXIC (Modified Copy Number and Expression in Cancer) to derive a decision tree signature for classification.

The researchers then tested the decision tree on seven TNBC cohorts including 1,368 patients. The tree classified disease into six subtypes: five smaller groups and one major group called MC6.

Patients classified as MC6 had disease that was enriched for basal-like 1 TNBC subtype and was non-synonymous with basal-like PAM50 subtype. The MC6 subtype also had a reduction in negative regulation of the MAPK signaling pathway and this reduction “suggests that MEK inhibitors may be an effective treatment in this subset,” Quist said. In addition, the MC6 subtype had increased expression levels of CD4-positive and CD8-positive immune signatures. Lastly, there was in an increase in genomic instability.

Next, the researchers tested the decision tree in a phase III study of patients treated with gemcitabine, carboplatin, and iniparib in metastatic TNBCs. Of 319 patients in the trial, 224 had gene expression and clinical outcome data available; 61 patients were considered to have MC6 disease. The overall response rate in patients with MC6 disease was 46% compared with 30% in other groups (P = .04). This was compared to patients with the basal-like 1 subtype where the overall response rate was 41% compared with 32% in non–basal-like disease.

Given these positive results, Quist and colleagues performed a similar analysis in another trial, PrECOG 0105, which tested neoadjuvant gemcitabine, carboplatin, and iniparib in early-stage TNBC. Of the 64 patients on the trial, 41 had MC6 disease. The overall response rate for MC6 disease was 61% compared with 57% for other subtypes (P = .79). Similarly, the overall response rate in the 17 patients with basal-like subtype was 65% compared with 58% in non–basal-like disease (P = .77).

“Given that early-stage triple-negative breast cancers are more likely to respond to platinum-based chemotherapy, the MC6 subtype is not able to differentiate those that do and don’t respond,” Quist said. “However, in the metastatic setting where patients are less responsive to platinum-based chemotherapy the MC6 subtype seems to be more discriminative.”

To further validate this decision tree, the researchers plan to test it in the TNT trial, a phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple-negative or BRCA1 and BRCA2 breast cancer.